The Peter Attia Drive - #302 - Confronting a metabolic epidemic: understanding liver health and how to prevent, diagnose, and manage liver disease | Julia Wattacheril, M.D., M.P.H.

Episode Date: May 20, 2024

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Julia Wattacheril is a physician scientist and director of the Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) program at Columbia University Irving Medical Center. In this episode, Julia delves deep into the complex world of liver health, beginning with a foundational overview of liver physiology. She provides an in-depth look at how alcohol impacts liver function, breaking down the metabolism of ethanol and its detrimental effects. Julia then shifts the focus to understanding liver function tests and optimal enzyme levels, providing a detailed explanation of AST and ALT and elucidating why fluctuations in these levels may or may not be concerning. She provides a primer on the four major stages of liver disease, discussing risk and emphasizing the importance of early diagnosis. Julia highlights the role of liver disease in increasing the risk of cancer and cardiovascular disease and covers in detail the various strategies for diagnosing, treating, and preventing the progression of liver disease. We discuss: Julia’s training, the importance of liver health, and the challenges and innovations of hepatology [3:15]; The complex and crucial functionality of the liver, its four most essential functions, and more [8:45]; Liver injuries: historical and evolving understanding of causal factors, and the progression to liver diseases and cancer [13:15]; How the liver metabolizes nutrients and what happens in the presence of excess calories or alcohol [24:45]; Methods of diagnosing liver disease and how insights guide treatment and management strategies [33:30]; The poisonous nature of ethanol to the liver [40:30]; Varied responses to alcohol, damaging effects of alcohol beyond the liver, and the process of advising patients on their alcohol consumption [47:15]; Understanding liver enzymes AST and ALT—interpreting levels, lifestyle factors that affect them, and diagnostic approaches [58:30]; Interpreting liver function tests for fatty liver disease, and the challenges of diagnosing liver pathologies, particularly in children versus adults [1:13:15]; Comprehensive liver health assessments via imaging and various diagnostic tools to prevent overlooking potential liver pathologies [1:18:45]; Potential impact of recreational drugs, statins, and other medications on liver function test results [1:26:45]; Shifting nomenclature from NAFLD to MASLD to reflect accuracy in the underlying pathophysiology and understanding of liver diseases [1:30:30]; Pathophysiology of MASLD, the need for proactive screening, and the significance of liver fat percentage as an indicator of metabolic health [1:36:30]; The importance of screening for rare conditions alongside common metabolic diseases associated with fatty liver accumulation [1:42:45]; Practical strategies for managing MAFLD [1:45:30]; The impact of fructose consumption on liver health and the challenges of disentangling its effects from other factors like obesity and insulin resistance [1:52:45]; The potential of GLP-1 agonists for the treatment of MASLD [1:57:45]; How the four stages of liver disease have evolved [2:00:30]; Increased cancer and heart disease risk associated with early-stage MAFLD [2:05:15]; Emerging drugs and therapies for addressing fat accumulation and fibrosis related to MAFLD [2:12:15]; Peter’s major takeaways [2:18:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.

If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to PeterAtiyaMD.com forward slash subscribe. My guest this week is Dr. Julia Wadacharrow. Julia specializes in non-alcoholic fatty liver disease, as well as all forms of hepatitis, chronic liver disease, and liver cancer, in addition to being a hepatologist who takes care of patients pre and post liver transplantation.

Her research interests include hepatic steatosis, insulin resistance, gut hormones, and metabolic liver disease in adults. Julia is an associate professor of medicine and the director of the Metabolic Dysfunction Associated Steatotic Liver Disease Program, the Center for the Liver Disease and Transplantation Program at Columbia University Medical Center.

Julia earned her MD and completed her residency at Baylor College of Medicine, followed by a fellowship in gastroenterology at Vanderbilt University, where she also earned a master's in public health. Julia then completed a second fellowship in transplant hepatology at Columbia University before becoming and attending there where she is today. In this episode, we start by speaking about the basic physiology and the four functions of the liver, the history of liver disease and liver transplantation, and the details of acute versus chronic liver injury.

We speak about alcohol-related injury and what it is about the mechanism and metabolism of ethanol that is problematic for the liver. We look at what the optimal levels for liver function tests and liver enzymes might be in the blood test. And Julia explains in fantastic detail what AST and ALT, two very common measurements that we talk about a lot and that you all have undoubtedly seen on your blood test, what do these do in the cell? What do they refer to? And what is it about their elevation that we should or shouldn't be worried about? We then discuss

how to improve metabolic health in relation to the liver and why the liver is truly the mothership of all organs. Lastly, Julia outlines the four major stages of liver disease, discussing the risk, treatment options, and the importance of early diagnosis. So without further delay, please enjoy my conversation with Dr. Julia Botticella. Hey. Hey. Hey. Hey.

Hey, Julia. Thank you so much for joining me today. Very important topic and very relevant topic, both in the narrow scope of what I do clinically, and I think the broader scope of what many clinicians do and frankly what anybody listening needs to be mindful of given the epidemic we're about to discuss. But why don't you tell folks a little bit about your training, what it means to be a hepatologist and what led you there?

Sure. Thanks for having me and thanks for being concerned about the liver. So I am a transplant hepatologist. So my clinical hat is about 50% divided into liver transplant and 50% divided into general liver care. How I got to that path, so I did medical school in Houston at the Baylor College of Medicine residency there as well, a GI fellowship at Vanderbilt in Nashville,

and then my transplant fellowship at Columbia. When it comes to sort of my faculty time division, I tend to focus on Masold or Nafold as it used to be called. And so metabolism and a nexus with endocrinology is also a big focus of mine. So let's take a step back maybe and just give folks a sense of what the liver does. People have probably heard me say this before,

but it's always worth repeating. The liver is this essential organ for which we don't have extracorporeal support. That's just a fancy word that means outside of body support. So if a person's lungs don't work, we saw this a lot during COVID, but obviously we see this all the time. You have extracorporeal support. You have a ventilator that can do the job of the lung for a temporary period of time, hours, weeks, even months. Believe it or not, if the heart doesn't work, we have extra corporeal support in terms of intra-rheoric balloon pumps or even ventricular

assist devices. And obviously if the kidneys don't work, we have extra corporeal support in the form of dialysis. Now, I'm not suggesting any of these things are a substitute for the real thing, but they're remarkable bridges that save many lives. And yet, Julia, we don't have anything that even remotely resembles extracorporeal support for the liver. So we have this essential organ, and yet if it is injured, we don't even have a way to bridge people to transplantation. Anything you want to say about that? I mean, is that just kind of a staggering feature, I think, of this organ? It's not for lack of trying.

There have been some devices like the Mars machine that have been developed. And I think as you're appropriately bringing up what we learned in COVID, a lot of liver disease, the bulk of liver disease has historically been chronic. And so you have time for intervention. It's the acute phases that we really need, either a 3D printed liver or an accessory liver that could function either inside the body or outside of the body. So those efforts are being undertaken, but

it both hearkens to the complexity of what the liver does and how hard it is to mimic when the liver is injured, what it can do. But it also gives you a focus on sort of the panoply of liver diseases, the timeline to development of liver disease and the functional aspect of what it takes to actually get some of these devices to market. Yeah. I'll share one last funny story about this. You might be aware of this, but when I was at Hopkins, one of the attendings who had trained at one of the universities in Virginia

told a story about when he was in his training, they were using baboons as a bridge to transplantation. So I'm not talking about xenotransplantation. They would literally put a baboon in a bed next to the human in acute liver failure. They would run conduits between them and obviously they had somehow a-b-o matched the baboon to the human. They would basically circulate the human's blood through the baboon using the baboon's liver to detoxify and carry out gluconeogenesis or whatever other features were critical in the acute moment. And apparently this somewhat worked.

You could take a person who was completely jaundiced on the verge of death and buy them another week or so until a liver transplant showed up. And according to the story of this one attending, it worked really well until once a patient emerged from basically a state of unconsciousness due to their liver failure and realized what was going on and freaked out and panicked and pulled the cannulas out and it turned into a big bloody mess that of course ended with the baboon dying and the patient nearly dying and that put an end to it. I don't know if you've ever heard any of these stories, but that always stuck with me as

the depths to which one had to go to try to basically save people during this period of acute liver failure while you either hoped for a recovery and or found a transplant. Any of those stories ever come your way? Not so much the animal portion, but if you've read about accessory livers, and so you learn a lot about this from Living Don donation, how much liver is required when people are in acute liver failure. It's not something apart from the pediatric population that a small segment of liver could

actually solve. But for accessory livers, you're implanting human liver to basically function as a temporary means of metabolism and recovery of immune function and all the other functions that we'll get to. But it's much more on the human side than cannulas to a baboon, which is a good mimicker. I think we learned a lot in liver disease from alcohol. And the baboon was one that mimicked human responsiveness more so than other animal models. So I could see that being teleologically making sense. 2.5 Meaning there were baboons that were forced to drink alcohol so that we could sort of

better understand the impact of alcohol on the human liver. And how much is nutrient deprivation from carbohydrate load from alcohol versus direct injury to the liver? Yeah. Interesting. Let's talk a little bit about what the liver does. I mean, why is it that this organ, everything we've just said is true? One, it's clearly complex enough that in the year 2024, we still do not have a way

to approximate it the way we do most other vital organs. And two, there's something about it that's obviously quite susceptible to injury in the modern environment. So maybe just start with anywhere you want, whether it be just the basic physiology of it, or how would you get people to understand and appreciate the absolute beauty of this, what I consider, very underappreciated organ? I'll start with what comes up, and when patients bring up misinformation, it's an opportunity to learn

that we need to do better about informing. So it's about three and a half pounds, sits underneath your right rib cage. Sometimes people get it on the wrong side. In most humans, it's on the right. And it's the largest internal organ. So basic functions, there's over 300 functions. So we exhaust our entire time together if we went through all of them.

But a big one that hepatologists don't necessarily get trained in much is metabolism. We've left a lot of that to the endocrinologists. So we think about parenchymal liver diseases, so common things like mazold or navel alcohol, autoimmune hepatitis, things that affect the whole liver. And then cholestatic liver diseases are viled up to the plumbing system of the liver. Hopefully in your show notes, you can give a basic anatomy or a diagram of what the liver looks like. But a lot of what's read about the liver is focused on one versus another component. So it's just really important for any audience member who's looking at a tiny piece of liver information, whether it's biochemistries or

a picture to understand it in the context of what the liver does. And some of the basic functions of the liver, so we said metabolism, and that's proteins, lipids, and fat, carbohydrate metabolism. It serves an immune function. We learn a lot about what the liver does from what happens when it doesn't work well. So one of the major proteins that it makes are the synthetic proteins that help you clot blood. So bleeding disorders are common in people with liver dysfunction. The other one that comes up a lot is detoxification. And so whether it's

metabolism of pharmacologic agents that people are taking in or any supplement or exogenous compounds or even toxins, environmental toxins, all of those get processed in the liver, handled by the liver, and hopefully detoxified by the liver. So those are just a few of the many functions. I include the nutritional components, so bile acid production, all of those things within the metabolic chamber, the way that I think about the functions of the liver. But that in and of itself could be a whole different category, some of that nutrient load handling. Dr. Kagan- So would you kind of agree with my non-hepatologist framework, which is I think of the big four things that the liver does,

which we've largely touched on, although one we didn't quite touch on, but clearly metabolism, as you've said, and that includes what I think is the most amazing thing that the liver does, which is regulate blood glucose. I think that's something that's almost impossible to describe how perfect the liver is able to do this, including in someone with type 2 diabetes, which we'll talk about, where you end up being about 2X too much blood sugar.

But that's still a relatively narrow band with which blood glucose is regulated compared to the extremes. If it ever falls below about 50 milligrams per deciliter or half a teaspoon total glucose circulating, you're dead. If it really ever gets above 400 or 500 acutely, you're dead. Then it can keep most of us around 100 to 200 is incredible at the minute by minute, second by second deviation. You talked again about synthetic stuff. I'm sure we will talk about that and how again, in extreme cases, if the liver can't make those clotting factors.

And then we talked about detoxification. That's probably the one I know the least about, but obviously we see the results of it. But the other one that I think probably doesn't get enough attention from most people is the amazing role that the liver plays in managing the lipoproteins and the clearance of lipoproteins, in managing the lipoproteins and the clearance of lipoproteins, the generation of lipoproteins, and again, just a herculean feat for one organ to be involved in these four profoundly important things.

So look, I think if by now we haven't made the case for why everybody should care about this organ, we probably never will. Let's talk a little bit about the history of liver disease because I think there's a bit of an evolution here. This thing we're going to spend most of our time talking about is a quasi recent phenomenon in the last, depending on how far back you look, but it's clearly not the dominant issue. Is it safe to say, Julia, that infectious agents were the predominant driver of liver injury, you know, 100 years ago, 200 years ago? Is that what really led to it? Or was

it toxins in the environment? I mean, when people died from liver disease 100 years ago, what was the cause? Your question also hints at common popular conceptions of why does someone have liver disease? So I think toxins, alcohol being the number one thing that we've studied since the 1700s, 1800s. And then the onset of viruses and the study of non-A, non-B, which eventually became hepatitis C. So all of that to say the liver was this recipient of external harm. And so I think that goes to show why we've sort of undervalued some

of the natural resilience and endogenous effects of its inherent metabolic function. Because we've focused on derangements, which as doctors, we tend to focus on the problem and try to treat the problem. But those perturbations in normal liver physiology based on an exogenous agent leads to structural issues, leads to histologic issues. And that sometimes limits us when we talk about the study of metabolic disease. For instance, if we perseverate on an ALT or aminotransferases, that's probably not the best marker of understanding fatty liver disease or metabolic dysfunction and the framing around how we think about liver injury from an exogenous compound or as a result of a metabolic derangement

plays a role in understanding longitudinal progression of the disease. Is it an external insult? And then taking care of humans, no one is in isolation. So behaviors, environments change over time, habits change over time. And all of those serial perturbations and how to monitor and follow those perturbations also inform how we're gonna move forward from our old way of thinking about how to measure liver disease injury,

how to prevent it, and again, how much time we have to intervene. So one of my favorite books I read in residency was the biography of Thomas Starzl who pioneered liver transplantation. So everyone who pioneered an organ transplant is kind of a giant in the field, whether it's the pioneers Murray of kidney transplantation or Shumway in cardiac transplantation. Notice I omitted the guy in South Africa, not just because I forgot his name for the moment, but because I think he sort of ripped off Shumway and cardiac transplantation. Notice I omitted the guy in South Africa, not just because I forgot his name for the moment, but because I think he sort of ripped off Shumway. But I think none of these figures

was bigger to me than Starzl, in part because I think it was the hardest organ to transplant. And this is true, not just technically, but I think perhaps metabolically. At the time when Starzl finally succeeded, and when I say Starzl, really, I really mean is Starzl and all of his colleagues, of course.

If my memory serves me correctly, it was probably in the late 60s when they finally succeeded in doing this. 67-ish. Yeah, that rings a bell. What was the dominant indication for liver transplant? How often was it being done for an acute injury in that first era versus chronic injury that became untenable. So I think whenever you're talking about a new intervention and surgeons are any high

risk taker for a new intervention, the indications are going to have to justify some of the risk. And so acute liver failure, liver injury without failure would not be an indication. So there has to be sort of a life-threatening situation for someone to justify the risk that's associated not with just the explantation and implantation, but also the post-care. So indications at that time from a liver disease perspective would be a little bit different than they are now. Well, now in the pandemic, alcohol has really, really surpassed a lot of other more chronic indications that we thought were going to sort of eclipse alcohol at this point, and that's behavior and coping mechanisms with stress.

But alcohol-related liver injury and then viral hepatitis, I'm talking about chronic, sorts of chronic adult liver diseases would be the top two, same ones we've referenced before. But acute liver failure, paracetamol or acetaminophen injury, most common cause of suicide attempts outside of the United States. King's College criteria, how we've learned a lot about the function and dysfunction of the liver during acute liver failure is all learned from those toxin-related exposures in acute liver failure.

What percentage of patients who overdose on Tylenol and who cause a fatal or what would be fatal injury of the liver are able to receive a transplant in time? I assume it's a very small number. It's small. I think Will Lee's work at UT Southwestern has really encapsulated this. So there's lots of variables. And whenever we talk about studies versus real world, I'll just re-emphasize. In terms of accessing liver transplantation, there's many logistic variables, including

payment and social supports. It's a complex decision. But for indications versus transplantation at our center, it's under 10% are due to acute liver failure. And a sub-fraction of those are acetaminophen injuries. It's on the order of single digit percentages if you look at most large centers. You mentioned something a moment ago that I think was a bit unexpected. When I was in medical school, we were told that hepatitis C was basically going to be the sole indication for liver transplant by now.

Meaning this is more than 25 years ago, looking forward, hey, within whatever, 2025, virtually all liver transplant will be in response to hepatitis C. Maybe a couple things happened that weren't anticipated. The first was an effective treatment for hep C. I assume that hep B is potentially a greater problem than hep C, although we have a vaccine for hep B. I'm curious about the relationship between hep B and hep C. Then secondly, we'll come back to this, but I want to hear a little bit more about alcohol-related injury as well, which seems to be on the rise as opposed to the decline. So maybe we start with the hep B versus hep C distinction. Yeah.

I'll zoom out a little bit because so much of what we're talking about is limited based on what we know. And the numbers of aggregate, large, well-done population studies where you're looking at all comers, that's just not how we've been able to study diseases. We are now, but I think it's important to understand why we look at things the way that we do, because it can be frustrating to patients to not understand, hey, this is a soon-to-be eclipsing

pandemic, why are we still ignoring X, Y, Z? So that aside, non-A, non-B, hepatitis C, we think of it being chronic, we think of it being progressive. And again, I'm speaking to the pre-DAA direct acting antiviral era before 2014, where it was a common indication for transplant, where it took time to actually discover what the virus did, how it functions, how it results in liver injury, and how that liver injury is progressive, chronic and progressive. With hepatitis B, it's a lot less predictable.

One, we have really good antiviral medications. Two, you named it, we have a very effective vaccine, and that's a virtue of a population health sort of intervention. In the East Asian population, which is oftentimes where we see hepatitis B, it's important to emphasize that the variability and the progression of the disease is reassuring in the sense that we think that fewer people are going to progress to advanced fibrosis, cirrhosis, need for liver transplant. But it's the one liver disease that is an outlier in terms of oncologic potential. We see liver cancer develop in people with hepatitis B independent of going through the

progression to advanced fibrosis or cirrhosis. Our radar has to be up to screen for cancer in people that have chronic untreated hepatitis B, and the effectiveness of antiviral treatment on the cancer potential is still an unknown. I didn't know that, Julia. So let me make sure I restated so that A, I know I'm correct and B, others hear it if they missed it as well. We didn't state this earlier, so it's worth restating or we're stating that hepatitis B or C also increases your risk of hepatocellular cancer.

This is a bad actor. This is a very bad cancer. So part of the mortality here results not just from the reduction of synthetic function in the liver, but from actual oncology. But then you just said something that I didn't realize, which was, and I assumed that your probability of developing cancer moved in lockstep with the extent to which your disease progressed. And what I think I heard you say is that's only true with C, it is not true with B.

Right. So we're learning and we're starting to reframe how we think about metabolic dysfunction as well when we think about the milieu within the liver and how injury is handled within the liver. So our big comers, alcohol-related liver disease, chronic hepatitis C, mazoled, most of our thinking is when that person moves towards advanced fibrosis, their cancer risk increases where we start screening for it when someone has cirrhosis. We screen for liver cancer and chronic hepatitis B independent of their degree of scar tissue or injury.

If I may just add to that, since we're just barely touching on the cancer aspect of things, one that is a rare disease, relatively rare disease that also has a high oncologic potential is hereditary hemochromatosis. That's something, again, I get the biased point of view of being referred cases that may not have been diagnosed early on and so I see part of what I'm speaking to is things that could have been intervened on earlier had someone known about relative risk I probably knew this at some point is that true of every one of these like Wilson's disease where you accumulate copper and as you mentioned Hemochromatosis the risk of disease moves with the risk of parenchymal injury to the liver. Sorry, the risk of cancer, to be clear, the risk of cancer increases with the risk of

parenchymal injury. Yeah, parenchymal injury to a liver doctor, sort of the card-carrying metric that we frame very highly is fibrosis, and that's our term for scar tissue. And so most of our cancer outcomes are associated with what we call stage four scar tissue or cirrhosis. I'm cautious with the use of staging because patients oftentimes relate it to cancer in the sense that a terminal diagnosis and stage non-reversible plume and doom. Cirrhosis is stage four scarring of the liver but the natural history of cirrhosis is widely variable. It's not a death sentence, nor is it an indication for transplant.

It's an indication for increased monitoring. Yes. And to be clear, you can have fibrosis long before you have cirrhosis, which means you don't need to be all the way at, quote unquote, a terminal stage of cirrhosis to be at increased risk of cancer. Correct. I know we will come back to this when we get into NAFLD, NAFLD-1, and then we'll go to at quote unquote a terminal stage of cirrhosis to be at increased risk of cancer. Correct. I know we will come back to this when we get into NAFLD, NASH, cirrhosis, this continuum,

but I want to try to stay a little bit further on the side of what's going on at the basic level. So do you think, Julia, it makes sense to talk a little bit more about the way that a healthy liver metabolizes nutrients in a eucalloric nutrient appropriate manner to then explain what's happening when excess calories are present or alcohol is present. I mean, what do you think is the easiest way to explain what is happening in the pathology? The pathology of what? I'd want to talk about non-alcoholic and alcoholic fatty liver disease as two examples that are

quite ubiquitous. At least the way I've sort of talked about it with patients is maybe talking a little bit about how the liver normally functions in metabolism and how VLDL works or triglycerides and what happens when you start to basically create more fat de novo and all of a sudden you have an inability to export it. My guess is you have a much more eloquent way to describe this so I don't necessarily want to impose my framework. I think that probably we approach patients the same way when you get the luxury of time and being able to get somebody's story, it's looking at the liver in context of the development of various aspects of their lives.

And so why someone drinks excessively is as important as the actual toxin, especially one of the beauties of the liver is its resilience. And so shy of more dense fibrosis, even in cirrhosis, of more dense fibrosis even in cirrhosis, largely reversible and decades of potential time to intervene. The way that I think about it, and I think this often gets forgotten, it's a general knee-jerk assumption when someone sees hepatic steatosis, so increased fat in the liver, to assume that it falls within what we used to call non-alcoholic fatty liver disease that we now call metabolic dysfunction associated steatotic liver disease

without sort of doing the detailed work around alcohol. Why does this matter? Because you see dysregulated metabolism even with alcohol related injury. It is seven calories per gram pure carbohydrate. And so when there is an excess nutrient load that the liver sees, the mechanism, there's some evidence that the mechanisms early on may be related, not exactly the same.

But let's speak specifically to what's going on in the liver. You have a liver, about 80% of the liver is hepatocytes. Those are the sort of primary liver cell where your AST and your ALT live. Ordinarily, they live in this sort of cuboidal cell that's working, or hexagonal oftentimes is the way that we describe the whole lobule, that's working hard. And those enzymes are basically immunotransferases that have a host of different activities. But until that cell gets stressed and releases those enzymes in a detectable way in the bloodstream, we think

that the liver has some degree of resilience and function. So when you talk about what is happening in the liver with both of these types of diseases, there's altered redox potential and there's free fatty acid handling differences. So you mentioned and I think that the glucose aspect of things is incredibly important. And so when we think about a normal functioning liver for someone that has, as you described, eukalluria, and then all of a sudden, there's a relative excess caloric imbalance. So what they're taking in outpaces what they're able to expend. And so there's nutrient excess that's happening.

The liver was never designed to store fat. And so, we commonly think of an abnormality, I'll speak specifically to Maslod and its definitions as more than 5% of the hepatocytes containing fat. Usually subcutaneous fat is our component where processing of fat storage but in a dynamic way is handled. But oftentimes, when those compartments are overwhelmed, they start to deliver more substrate to the liver. And so there's two big ways that the liver manufacturers are two big ways in terms of

liver fat metabolism. One is de novo lipogenesis. We think in most people that that's the secondary mechanism and it's the exogenous input through nutrition that supplies the majority of the lipid. So de novo lipogenesis is manifested mostly with the triglyceride component. You mentioned there's cholesterol, there's triglycerides, and there's phospholipids. And then you mentioned lipoproteins, which I in my mind link to trafficking and metabolism of lipid molecules in terms of function. But how the liver and again, the

beautiful nature of the way that we study it is oftentimes through close collaboration with patients where any component is deranged. And so one of the areas that I think we are starting to see now that we hadn't seen before is the presence and largely this is by virtue of technology, we have means of detecting increased hepatic fat independent of insulin resistance or predating insulin resistance. And so the relationship between how the liver accumulates triglyceride and starts to dispose of glucose is one that I think the endocrinologists have started to or continue to dig a little bit deeper because we know that this relationship exists between insulin resistance and liver

storage of fat, but the exact mechanism and timing is still undetermined. It's called bidirectional in a lot of ways. One of the junior scientists that I work with describes different thresholds. So at some point, the insulinization of the liver leads to fat storage and that a second threshold is crossed when you start to see decreased hepatic glucose production. Let's talk a little bit about what hepatic glucose production actually is. I referred to it earlier, obviously, which is that the liver is constantly titrating out. But again, worth stating how important this is because you and I are not eating at the

moment and yet we're alive. Something miraculous is actually happening given the glucose thirst of our brains. And all of the glucose that is being supplied to our brains right now, as we have this discussion for the next hour or so, is coming from our liver. Our liver is the thing that is meeting out that amount of glucose, which is kind of remarkable, as I said, because it knows to not do too little and not do too much. So it can make glucose, it can store glucose, and it can temper this output. First of all, anything that we get in the way of that strikes me as incredibly problematic, especially on the low end.

So we see in diabetes, presumably, we have not just insulin resistance at the level of the cell, so you have a harder time disposing of glucose peripherally, and that leads to an increase in glucose. But we also probably see an increase in hepatic glucose output, which is where a drug like metformin that suppresses hepatic glucose output becomes valuable. What's happening clinically when we see decreased hepatic glucose output? What's true in the liver for that to be the case? Before hepatic glucose production goes up. So at this point, what are the clinical observations?

So if you look at our guidelines, they'll have multiple ways of looking at insulin resistance. One that I'm quite fond of is the HOMA-IR. So what is going on in the body at this time is a hyperinsulinemic state. And whether or not you're seeing increased glucose is sort of this sweet spot that we're starting to see increased triglyceride deposition within the liver, but not yet a compensatory response

with circulating hyperglycemia. And so what is going on at the level of the hepatocyte and my sort of obsession, what's going on with the lipid droplets that are associated with this precursor are unknowns yet to be determined. When you look at somebody clinically and they show up with hepatic steatosis and you want to know where in the spectrum they are and how to counsel them to avoid the downstream consequences that are potentially avoidable for them, you want to look at what is their relative insulin resistance. So you are looking at circulating isolated insulin values and calculating either a home IR or some people do glucose tolerance tests.

But you want to try to catch people in this window of either early insulin resistance or not yet developed insulin resistance. Let's define for folks, how are you defining steatosis? Is it being defined as at least 5% of the hepatocytes contain fat? Yes. So we're looking at the aggregate, 5% greater than or equal to 5%. Okay. And how is that diagnosis made? Is that typically made just through ultrasound or ever doing that with an MRI? How do we go about making that diagnosis accurately?

When we talk about such a prevalent phenomenon like steatosis, we have to maintain practicalities. So the vast majority is going to be an imaging-based modality rather than something like a biopsy. It was originally defined based on histologic evidence. The MRI PDFF is costly and not necessarily that readily available. We have point-of-care techniques that we use in our clinics that are based on ultrasound technology.

A plain old ultrasound that someone gets is generally not detecting steatosis at levels under 30%. So an important take home is, you know, a negative ultrasound does not mean that you don't have hepatic steatosis. Can you say more about that, Julia? So if a regular ultrasound needs a threshold of basically a third of the liver has fat in it, that's a big threshold. Clearly, someone

who's getting a routine ultrasound for some other reason, their kidney and the tech just goes and puts the probe on the liver. What is it about the technique or the imaging software or hardware that allows a dedicated scan to detect with much greater sensitivity at that 5% threshold. For MRIs, it's proton related. The proton density fat fraction has to do with basic physics and how reverberations occur with different fractions, water versus fat. Namely, for something that we use called vibration controlled transient elastography, it's point

of care. It's something that a lot of liver doctors are fond of. We'll talk about it probably later when it comes to sequential testing. It applies a calculator called a controlled attenuation parameter to attenuate some of the echoes, some of the light signals that the ultrasound is emitting in order to get to a more granular level of fat. How much?

And this is the measures of it are in the level of sound waves. So we're talking about decibels. So when it comes to fat accumulation in the liver that results from a nutritional imbalance, i.e. when a person is over nutrition, you basically have some combination of exogenous fat making its way into the liver and even endogenous fat production, i.e. de novo lipogenesis within the liver. But the net result is more fat is entering and staying in the liver than is exiting the liver.

Although amazingly, in most cases, we also see a remarkable fat exodus from the liver as evidenced by a very high VLDL and a very high triglyceride burden. In other words, the liver is trying its darness to get the fat out and we measure this high amount of fat, which might be a clue that there's a high amount being accumulated, correct? That's correct. And I think the other thing to say is before the liver even sees that is you're overwhelming your subcutaneous compartments, too. They are shuttling free fatty acids towards the liver. Because I always think about it in terms of where can we intervene as well? So that liver is seeing increased fat, increased nutrients

and trying to handle it. I think the important point I'd also like to make is because given the complexity of metabolism and the liver's desire to maintain homeostasis, whenever you see anomalies, so outliers, those are very important. When you see people that are not expressing circulating triglycer people that are not expressing circulating triglycerides that are higher, that don't have some of these metabolic features. That's a tip to you as a clinician that maybe this isn't sort of garden variety, metabolic dysfunction, fat deposition in the liver, and you might need to be thinking about something a little bit more rare.

But you're talking about something different than the obvious and well-known race-based differences. So for example, even in situations of fluoride type 2 diabetes, African Americans will rarely exhibit an elevated triglyceride level the way a Caucasian will. And you'll see literally a triglyceride of 400 versus a triglyceride of 90 in two people that are equally insulin resistant. You're saying something different than that? Yes, I'm speaking much more to some of the rarer causes

that get lumped into a phatic steatosis where there's a trafficking, there's an export problem, and you lead to how does this come up clinically? So I put a probe on someone and I see their BMI is 22. They have very little evidence of insulin resistance and their cap score, something that we use to grade fat is very, very high, 400. That's gonna tip me off that potentially there's a genomic familial hyperlipidemia. There is something that's going on that may be making their liver store fat in an anomalous way

that's not reading the room in terms of metabolic risk. And the reason I say that is because of the prevalence of the disease, it becomes important to sort of pick out the folks that may not respond or be best served by some of our current recommendations. Yeah, I had a friend who had, this is a case that you would have obviously solved with your eyes shut. He did have elevated transaminases.

I do want to come back and talk about transaminases by the way, and clearly didn't fit the bill of anything lean, athletic, et cetera. It wasn't until he had an MRI for an unrelated reason that they noticed the amount of iron accumulation in his liver. And of course he had hemochromatosis that had somehow been previously undiagnosed. He had accumulated enough iron in his liver that it was actually beginning to show these signs of injury through the elevation of transaminases. So yes, that's one of the drawbacks I suppose of the ubiquity of all of this liver disease besides the obvious which is it sometimes makes it harder to

identify the zebras when there's so many horses everywhere. If you think about how we pick out the quote unquote extreme phenotypes, I think about this a lot when I look at how we can better understand some of the biological targets that are driving the disease. An easier way to do that is look at some of the extremes. So the folks that don't have all of the metabolic risk factors but do have pretty aggressive disease,

for example, lean, people that are a normal body habitus and then manifest rip roaring metabolic dysfunction, including steatohepatitis plus or minus fibrosis. And back to your point of, you described some racial differences. We talk a lot about ancestry. And when you have ancestry distributions, for example, South Asians, same predominance

that you'll see with sort of lean diabetes, some of the modi phenomenon that you are aware of, you can see very, very aggressive forms of not just altered metabolism within the liver, but aggressive inflammation and scar tissue, which is usually what is needed to sort of get the attention of a lot of the liver folks. Except injury, not just the accumulation of fat,

which is important, but it's much more important from a metabolic and a chronologic perspective. And then we tend to perseverate on the people with a lot of liver injury. Let's talk a little bit now about how ethanol is poisonous to the liver. And I want to be mindful of the word poison,

because it's a controversial word. People get all bent out of shape. So feel free to use whatever word you want. I mean, I sort of think the dose makes the poison. Everything is technically a poison. Tylenol is clearly a poison, whereas a low dose of Tylenol is a wonderful thing if you've got a splitting headache or a poison. Tylenol is clearly a poison, whereas a low dose of Tylenol is a wonderful thing if you've got a splitting headache or a fever. But at some point, you exceed the capacity

of the liver to metabolize it and it goes from being not harmful to deadly. So clearly that applies to everything out there, including oxygen. So let's put the nomenclature aside. What is it about the metabolism of ethanol that is problematic for the liver? So again, let's go back to our friend the hepatocyte and you have ethanol or alcohol that starts to get processed. So how does the normal liver cell process this? Alcohol dehydrogenase, you're going from alcohol to acetaldehyde. Acetaldehyde is then metabolized further and it eventually becomes carbon dioxide water, ordinarily type of moieties, right?

But where you start to see problems is some of the redox potential when the capacity and again these are very variable. If you look at populations, how alcohol is handled in various populations and even just the dimorphic differences in sex between men and women, how livers metabolize alcohol, that normal process can be overwhelmed and then all of a sudden you start to have peroxidation. And that's a feature that we see in the non-alcoholic or the metabolic dysfunction that's not associated with alcohol-related liver disease. That's about 80% of the alcohol metabolism. There's another pathway that's

also invoked. But what we're talking about when there's alterations and injury and toxicity, that's when you have the acetaldehyde behaving badly. And so, it's behaving kind of like you're describing as a toxin. It's attracting free radicals. It is attracting immune cells. It is leading to fat deposition, altered metabolism at the level of the cell. And so that's some of the commonalities. Different enzymes are being used, but that's some of the commonalities when we look histologically at somebody who's not using alcohol versus someone who is.

There are some features that you cannot distinguish histologically because at somebody who's not using alcohol versus someone who is, there are some features that you cannot distinguish histologically because the injury pattern is so similar. I'm not sure if that's answering your question or not. It answers it, but of course poses many more. So let's unpack that a bit. Again, I'll just try to translate it a little bit so that I make sure I'm understanding it. But when we talk about the metabolism of ethanol, we have this enzyme alcohol dehydrogenase.

Of course, we know as some people genetically are lacking in that enzyme or don't have as effective aversion of it, these people tend to be incredibly sensitive to alcohol. They get beet red when they drink it. In some regards, I guess they're largely protected from the toxicity of alcohol because they simply can't tolerate it. But for most people, you go ahead and you metabolize it. And while the downstream stuff is ultimately the same as the normal carbohydrates, basically CO2 and water, you get acetylaldehyde as an intermediary. I guess my question for you is, why is acetylaldehyde toxic as an intermediary? Does it stick around long enough to cause problems?

Why isn't it all just being flushed to CO2 and water quickly? It's sort of like saying when we have as glupose, we stock the pyruvate before we go to acetyl-CoA and CO2 and water. You wouldn't think of pyruvate being problematic unless it's stuck around for a really long time. So yeah, help me understand why it is that is it just any minor exposure to it is problematic even if it's very brief? It'd be hard to say unless you had a system-wide, pretty diverse cohort to be able to say, where is the system overwhelmed? But what we can say that it does attract inflammatory cells. So there's something about it at a certain level to be determined that attracts, I kind

of analogize it to the lipotoxicity model and my favorite disease metabolic dysfunction associated disease. There's something about that moiety that makes it pro-inflammatory and how the body, how an individual and how that liver will handle the inflammation that's a resultant of the acetaldehyde attracting free radicals and overwhelming the redox potential of that cell is one mechanism by which injury is occurring. Know that not every cell is going to behave similarly. And so the relative injury of some cells versus others, the compensatory damage and recruitment of inflammatory handlers, you know, whether it's monocytes, macrophages, or lymphocytes, is also going to play a role. So we're starting to get at some of the complexities

that are extremely hard to tease out unless you're thinking not just molecularly, but as a liver as a whole. You also mentioned that there are, besides the obvious genetic difference I gave people with and without alcohol dehydrogenase polymorphisms, you also mentioned that there are, besides the obvious genetic difference I gave people with and without alcohol dehydrogenase, polymorphisms, you also mentioned that there are sex differences. I wrote about this somewhat recently. Maybe you could say a little bit more

about the differences between men and women in this regard. And then within sexes, I'm also curious to hear about how much heterogeneity there is in both the capacity to metabolize ethanol and of course the susceptibility to its toxicity. You know, the old studies, and this is why alcohol has been studied longer than any of the viral hepatitis, a lot of the sex differences were just attributed to the fact that alcohol

is a polar compound and so it's less soluble in fat. And women, body composition wise, typically have more fat. And so the relative damage that could be done was based on body composition-wise, typically have more fat. And so, the relative damage that could be done was based on body composition. I don't know that that's necessarily true, but it was an easy way to sort of explain some of the early differences at that point. So when it comes to gene expression, again, you're gonna have to look specifically at premenopausal women versus postmenopausal women and not just androgen components and estrogen components but also the upstream signaling of all these. As far as I know,

and I'm not an alcohol expert, none of those have been teased apart in terms of sex differences specific to the premenopausal woman handling of... It's 14 grams, you know, no matter what the alcohol component is, it's approximately 14 grams that we see. So how that liver and subcutaneous fat component and hormonal responses to the compound, acetaldehyde generation or other potential toxic moieties, those are all variables to be studied. I mean, that's sort of what we kind of wrote about, which was that, look, it's historically been chalked up that the differences between men and women are size differences, but I think there are differences in gene expression that play a much greater role than size, which then leads to this next question, which is, okay, so you've got two people who both weigh 85 kilos, so their size is comparable, their body composition is similar

enough. Let's even grant that they're metabolically comparable in health. They can have two very different responses and susceptibilities to alcohol. I'm sure there are a lot of people listening who think, well, I'm one of those people who can drink a lot and it doesn't seem to have an effect on me. Does that mean that alcohol is less toxic to me? I'll give you my biases because a lot of people think that toxicity is only occurring at the level of the liver. And we see in our, especially post-transplant, post-reformed alcohol use, the effects on the brain, the effects on the heart, the effects on the pancreas. There's

a panoply of organs that can be affected by what's considered normal or moderate, less than moderate alcohol intake. And so how someone is considering themselves not affected is also really important. There's, of course, the psychosocial components as well. And then the big one that I think a lot of people are failing to talk about, I don't know, the World Health Organization came out with consensus statements in 2023 is the oncologic potential, the DNA disruption, and how to measure that and how to mitigate some of those risks. So, I think if someone's subjectively saying, I don't feel affected from a central nervous

system perspective, they don't feel like their sensorium is altered. Sensorium for us when we grade hepatic encephalopathy, there are some mood changes that happen. And so, the CNS, either depressant effects or removal of inhibitions. Some of those effects are also, I think, socially acceptable CNS-related effects, but they're effects. And I'm sure you get asked this question all the time at parties, which is, at what point does the dose of ethanol in grams per day or per week start to become problematic? This is a topic we've written about at length, which is that we kind of reject the data that

says that there's a J curve. We have not internally been convinced by the J curve data, which is largely epidemiologic and largely suggests that at very low doses, zero alcohol is actually slightly worse than some alcohol. And then of course, the risk goes up as drinks go up, but there's some sweet spot, which depending on the study can be actually quite high for alcohol consumption to produce the lowest all-cause mortality. Again, there are many ways to explain those data that I think are a better explanation than alcohol is good for you at some dose. I think the Mendelian randomizations point to the opposite,

which is a monotonic change in risk that increases consistently from zero and upward. But of course, this dose is still non-linear. This risk is non-linear with dose, I should say. It begs the question then for people who want to choose to drink responsibly, at what point do you say the risk is probably too great? If we're not going to be complete abstainers, at what point do you tell somebody that's a little too much? Dr. Julie Kinn It's a loaded question because I'm thinking about more than the liver, even though they might be approaching me with a liver-centric point of view.

than the liver, even though they might be approaching me with a liver-centric point of view. So, if there's evidence of injury, an injury...so, the way that we liver doctors think about it are markers of necroinflammation, AST and ALT, are not functional. They're markers of injury. And we think of much more meaningful things in terms of being functional, albumin, synthetic function in terms of coagulation, and then also glucose handling. So if you start to see, and again, with the patients that we see, we have many patients

that have a degree of hepatic steatosis, and their only risk factor is alcohol intake. If they're not having any dysregulated metabolism, they're not distressed by this abnormality, and we're able to monitor them. And the net gain to them from all sorts of inputs, including social inputs, is that their alcohol level is not causing major life events, including effects on their family or things that maybe are harder to talk about. There's sort of a permissivity to that. But it's just like supplement use. At some point, contaminated supplements or unknown supplements may cause evidence of liver injury. So with an openness to can you give this up if it becomes problematic, either physiologically to the liver, to another organ, to relationships, etc. So that's how we counsel

people point in time. We also have all sorts of ways of looking at problematic use disorders. The big driver for all liver diseases, parenchymal liver diseases, is what is sort of the behavior and the motivation behind engaging some of these things. And that's how the relational component with understanding why someone is doing what they're doing can really make a big impact. Because two or five years down the road when you ask them to give it up, because there's a new breast cancer diagnosis, the risk of breast cancer is higher than the risk of liver disease for most women who are consuming alcohol. So if they have a new cancer diagnosis and we're asking them to give it up in that instance or the patient

themselves brings it up. In terms of what disease modifying changes can I make and I implement in order to improve my lifespan, those are things that we need to go back to what was the origin, what's the desire in terms of engaging some of these behaviors. Humans are far more likely to give up something that they don't find beneficial, at least in my 14 years, 13 years of taking care of liver patients. Let's use a specific example. So you have an individual that comes to you and says,

I consume alcohol socially. And if you go and talk to my friends, family, children, they would all tell you it's not a problem in my alcohol consumption, meaning there's no unintended consequence that is negative. It's all pro-social beneficial. And they have a normal liver synthetic function, which again, you would expect. That's a pretty late finding if they don't. Their transaminases are normal.

Again, we're going to come back to this. I want to put a pin in that for everybody. We're going to explain in much more detail what transaminases are and what normal is. You mentioned toxicity to other organs in as much as we can assert that, that normal kidney function, normal cardiac function, all those other things. Do you say, look, the most sensitive indicator I have that you might be drinking too much are your transaminases?

And as long as those stay below a threshold, which you're gonna tell me, and all of these other factors look okay, I'm all right with you drinking two glasses of wine in evening, or are you still saying, look, there are still things I can't measure, and even normal transaminases don't give me a good enough confidence that you are not causing irreversible harm here?

So I wouldn't use immunotransferases as a good marker. I think more often we use a bedside imaging technique, the vibration controlled transient elastography, because the sensitivity of picking up on hepatic steatosis is higher than something. It actually takes quite a bit of derangement and problematic drinking to derange your aminotransferases. And when you start to see fat accumulation in the liver, early warning sign, potential

downstream metabolic consequences, potential inflammatory consequences, doesn't mean that they have to give it up. But I think it really tattoos to the patient in their experience that there are measurable effects of even moderate what's considered social. And what's considered social is very, very variable. That's why it is good for the audience members that are clinicians quantifying the use, especially now during and post-pandemic. There have been just like the ALT has been perturbed based on environmental changes in

our population. So it has the definitions of moderate use. So just going through that with patients can sometimes give you a little bit more information about how they're perceiving their risk, which is obviously if you're counseling someone about the impact to their life and whether or not something would be wise to continue

or not, you have to understand how they're perceiving risk. How do you ask people specifically about that? We ask patients, on average, how many drinks do you have in a given week? And what's the variance of that? I assume there's a much smarter way to ask this question. I'm so glad you're asking. So first of all, we define what alcohol is.

Oftentimes what has happened is one drink might be double the quantity that we're used to seeing. And so concentrations, so I say one and a half ounces of hard liquor, five ounces of wine, 12 ounces of beer is considered a standard drink. So that in and of itself gets some raised eyebrows from people because they don't know about those quantities. So when we, and then I say, you know, ballpark, oftentimes people will say, I don't have a

problem with drinking, I don't have a problem with drinking. I don't drink every day. And daily drinking at a certain threshold, we consider two drinks per day for men, one drink per day for women, and these are standard drinks. What's considered the CDC definition of moderate alcohol intake? A lot of younger people don't drink daily. That's a gross assumption, but it's much more of a binge type picture. And so quantity over what period of time for those standard drinks is also what we ask.

Then I also ask what's going on in these situations that you feel is that you're with family gathered over the weekend, is it at home? In the pandemic, it was a lot of isolated drinking at home. And so that's where we started to see some of the chemical changes, some of the imaging-based changes, and then more importantly, some of the social changes that happened with problematic drinking. Because the slope can vary without an individual

being aware. So I think it is important to quantify it. The other test that we oftentimes do as liver specialists is we measure sort of the longer range metabolites, something called phosphatidyl ethanol or a Peth and that measures, it's a little bit more like an A1C than a rapid identifier like an ethyl glucuronide but it gives us an idea and it fits great in terms of moderate versus severe and sometimes that gives you an aspect,

another angle to interview a patient. And again, there's a lot of shame around alcohol use and what's going on in an individual at times. And so when you see really severe heavy alcohol use, but a self-report of something far less severe, it's again an opportunity to figure out what's going on. How far back does the phosphatidyl ethanol or Peth study go? If the A1C looks back about 90 days, how far back does this look?

It's on the order of weeks. It's not something that lasts 90 days. We usually think of it in one to two week timeframes. Is that a readily available test? Can you order that through LabCorp or is that a super specialty test? I think it's available in all the Quest and LabCorp for sure. Very interesting. Okay.

Let's come back to these transaminases. So everybody listening to this, Julia, has had a blood test. Certainly if they've listened to this podcast, they know to look at that AST and that ALT. You already alluded to them a little bit, but I want to go back and talk about it. People have heard me say this. They get called liver function tests, but they're really not proxies for liver function. So what does AST do in a cell? What does ALT do in a cell under normal working physiologic, everything is hunky dory circumstances and what happens that leads to their elevation in the serum, in the plasma when things go awry.

So AST or Faspartate Amino Transferase, ALT, Alanine Amino Transferases are enzymes and they are usual working enzymes to help process things that go through your liver. So normal liver physiology, two supplies, that go through your liver. So normal liver physiology, two supplies, blood supplies to the liver. One from the portal circulation, that's what drains your guts, all the nutrients that you take in that are processed in your intestines, they get shown to your liver through that portal system and then the hepatic artery. That's another system. It's one of the many forms of resilience of the liver.

It's that it has two blood supplies. The blood percolates in this very porous milieu showing all the hepatocytes, what they have by way of nutrients, toxins, et cetera. And then those things are filtered through hepatocytes and there's lots of enzymes. These are enzymes that we typically measure. And so when we talk...and they also exist in muscle. So whenever we get some rare cases of elevated immunotransferases, we have to make sure that they're coming from where we think they're coming from. That's an aside.

But the definitions of normal have evolved over time. And sometimes different thresholds are set for different diseases. I don't want to get too much in the weeds of how the hepatologists think about things, but oftentimes, you know, the earlier days, we sort of said 19 and 30 were our thresholds in terms of women and men, what we expected their immunotransferases, what we would consider abnormal. The lab, any one of your audience members

who's looking at their own labs, the labs oftentimes flag them now when they're in the upper 40s or 50s. That's a population-based perturbation that I think you've talked about a lot. And so what is the definition of normal? How much does this matter? When it is red, when it is flagged as abnormal,

how much should you get anxious about that? In general, again, we wanna harp on the fact that the liver is extremely resilient. And so when you get an isolated abnormality, what that is telling you is that liver cell, that hepatocyte is now under so much stress that it's a now what we call necroinflammatory marker. Necro being cell death and inflammation mostly, what is going on around that liver that tells us I'm under stress and I'm now bursting. And so when that liver cell bursts, it released these enzymes into the bloodstream and that's what we're checking with blood tests.

The question is, why are those enzymes elevated? And is it an isolated phenomenon? You had mononucleosis, you're over your virus, or is it something that's continuing over a period of...we define it as around six months in terms of chronic liver disease. Where those elevations have persisted is when we start our work up. Why is this inflammation and cell death happening in this liver? Is it due to our top three in adult, alcohol, viral hepatitis, or mazold, mazold being the most common globally and in the country. And is there something more rare that we are missing? Is there a potential that there is

something treatable, that there is something reversible at this earliest stage of laboratory detection? So you've reiterated a point that I've tried to make several times over the past several years, which is that we never want to confuse a laboratory's standard for what is normal for what might be optimal, because the laboratory is simply reporting on a population distribution. And if the population's health is deteriorating over a 50-year period of time, well, that isn't necessarily a reason we should hold ourselves to the standards of unhealthy people today. So as you point out, I just had my labs done last week. So I forget, I think LabCorp has a cutoff of 40 or 44 for the AST and the ALT. But if you went and looked at what was the cutoff, and presumably that's the 80th or 90th percentile of the population, if you went and did that exercise 50 years

ago, you'd see a much lower number, probably 25 to 30. So is it that the liver has changed from an evolutionary perspective in 50 years? Probably not. It seems more likely that we've seen more drift towards liver injury. But if someone just came to you and said, Julia, I don't wanna hear about what the population does. Tell me where you think the right place to have those transaminases be as one more piece of the puzzle. Not the only piece of the puzzle. We're gonna talk about all the pieces.

But just if we're looking at this piece of the puzzle, where do you look and say, boy, I'm really happy? You're not just okay, you're optimized. So I'd say for the vast majority, and I'm going to speak across age and across race, ancestry and biological sex, I would say I'm generally a telepatient that they're doing well when it's under 30. It's a whether or not they are post-transplant or have very, very early stage disease.

That's all comers. When do I start to get alarmed? It's when it's persistently in what we think of fold differences in liver disease world. So when it's consistently in that one and a half to two times the upper limit of normal. So when it's in the 50s and 60s, it again tells us there is something potentially going on in the liver. And whether it's a cause, if it's a result or a cause of other symptoms in their

body, other disease processes is when we start to pursue a workup. So again, it's very difficult for me to just stick on one value, but because you put that in front of me, I would say under 30. Let's talk a little bit about the differences between the A-L-T and the A-S-T. So again, I'll just share with you, I'm trying to get a free hepatology consult during this podcast, by the way. My A-S-T is always significantly higher than my A-L-T. So last week on Friday, when I had my blood drawn, my A-L-T was 21, but my A-S-T was 34.

And that's actually quite typical of my blood draws. My A-L-T typically hovers between about 20 and 25, and my AST typically is above 30, but shy of 40. I'd love to hear your thoughts on that. Feel free to ask me any questions you want if I can elucidate clarifying information. I realize that your audience is also fully capable of reading our guidelines and things like that.

So I do want to say when I use a Gestalt of around under 30, that's a thumbnail expert sort of after I've made a diagnosis and someone's already part of an intervention. I do want to make sure that thresholds for sort of workups, et cetera, we still think about being around 40. So it's also pertinent to you. So the questions I would ask just with that pattern in and of itself is, curiously, did you work out within 24 hours of that

laboratory assay? And if so, what type of resistance work or muscle work did you do? Yes, I went to my doctor in the afternoon. I had already done a two-hour workout in the weight room that morning. That blood draw was probably at noon. I was in the weight room from 8 to 10. And I'd say, Peter, you know, have we ever drawn blood on you on a non-workout day, on a rest day? Yes, I would still see the same pattern if I drew that blood first thing in the morning, but it would still be within 24 hours of a workout because I would have lifted or been on my bike or been rocking the day before.

So if your question is, have I done a blood draw with more than 24 hours of no exercise? Probably not. That's one thing I would be curious about. I would be curious if you had ever had a CK done, a creatine kinase, just to look if there's any evidence of muscle breakdown. Yes. Anytime I get a CK done, let's pretend that the threshold of abnormal is 200. I'm typically right about there. And I'm, again, looking at you, knowing a little bit about you and making some assessments

just based on body composition and potential risks, the line of questioning may be very different with someone else. But I do drink alcohol, just so you know. Yep, I was about to go there next. So can you also tell me about not just that one lab draw from last week, but when your labs are done in relationship to alcohol intake and if you're able to quantify that.

I wish I could say I was more thoughtful about this, but I'm one of these guys that never likes to cram for the test. So I try to never change behavior before my blood tests. Like, it's not like I don't drink for a week or something. So what I think I can safely say is, any blood test I've had is probably a reasonable sampling of my typical pattern

of alcohol, which is I'm mindful of what we described as the doses. So five ounces of wine, 12 ounces of beer, one and a half ounces of liquor based on those metrics. I think I'm probably in the six to eight drinks per week category, virtually never more than two in a day. I don't know. That's a moderate drinker, I suppose. That classifies as moderate alcohol intake.

Assuming that your laboratories are assessed in this non-cramming sort of way. Let's say you had about 30 grams of alcohol before, within 24 hours. Yeah, I would say there's a decent chance that there were 30 grams of ethanol in my system 12 hours prior to that, but it's possible that it would have been 36 or 48 because I wasn't trying to game the system. Sure. I think I would also ask, is there anything that's bothering you

about your blood tests? What is your impression of them? Well, I think the only thing that quote unquote bothers me is I look at many of my patients who have ASTs and ALTs in the teens. And I think, I wish my ASTs and ALTs were in the teens, but I also realize in that case, most of them are women, a very slight build. There may be a component that's just muscle mass related.

By the way, I should also point out my creatinine is always quite high, but my cystatin C is very low. Renal function is great. If you look at my EGFR by creatinine, you would think it's about 70, whereas by cystatin C, it's about 110. And I know that we see that a lot in patients who exercise. So there may be that component. It's the injury component to the muscle,

not just having a big build, a muscular build is not necessarily injurious in terms of detection of immunotransferase elevations, to be clear. The most common one that we talk about are like marathon runners with Rabdo, et cetera. It's not just having the component of muscle, but also just the workout and the injury component

and recovery component. Yeah. The other thing I wonder about, of course, are supplements and medications. I do take one medication that at least in patients we often see an elevation of transaminases, and that's azetimibe. So I guess I could do the test of just stopping azetimibe and seeing, does that have any effect? These days with patients taking lots of medications, I'm trying to think if there's any supplements.

I'm a little lean on supplements these days, and the ones I take tend to be pretty straightforward things like fish oil and magnesium and things like that. Like I'm not kind of taking too many sort of funky supplements that we've seen in patients where they can really sort of have negative impacts on liver function tests. So you're going down, was curious whether or not your team had questions about two,

which is the drug-induced liver injury, and that can include not just pharmacologic agents, but also supplements. That's where we see a lot of elevations in immunotransferases. So whether or not it's you or an individual who's taking recreational substances, that's also something that we use in the differential for that sort of laboratory assessment. The reason I want to know about context is there are some individuals that perseverate if their fat fraction is 7% and they're living an optimized life. And the number itself is problematic to them. They think something is potentially abnormal or wrong. So in your instance, rather than

withdrawing the azetamide, I might say, let's do labs. I'd throw it out to you. Would you consider doing labs after a series of rest days plus no alcohol intake to see... You're doing a controlled experiment. I have patients that do this all the time. They'll withdraw from alcohol for six weeks to see what is the effect on their fat fraction. They're just curious. Most of the time, you can't predict what your reaction will be. You might think, oh, my ALT will be 20 and I don't care that much.

I enjoy alcohol too much. But there's something to be said about a measurable effect and how motivating that is. That's something I've been humbled by a lot with some of our imaging-based studies. So assuming that those are your influences, the things that I would think about is not just the framing of who you are at this point in time, but what has potentially happened in the decades of life before and that's where I would do something like a fibrosis assessment. It could be a quick calculator, something like a fib four, etc. To figure out whether or not even with those numbers being as good

as they are, there's some degree of accumulation of potential stiffness or injury to the liver because all those time points between when you measure them, there's things that are going on in your liver and the rest of your body, of course, but we don't necessarily need a biological measurement by way of a biochemistry in order to determine what those are. How valuable do you think the... So again, we use LabCorp for much of our labs. I think the last time I did a blood test, so not the one I just did last week,

but maybe three months ago, I did one where we did the full LabCorp NASH score thing. Again, this was sort of just me being me, and I don't really think I have fatty liver disease, but I was like, look, we order this test on patients. I'm curious as to what it shows. And so it came back negative. There was no evidence.

The scores were very, very low. I have to be honest with you. I've kind of forgotten how the score is generated. Can you explain how that score is generated? Because I suspect it's going to be used more and more frequently now as clinicians are becoming more and more aware of screening for this. Again, I won't go specifically into it because there's so many. There's a whole serum-based biomarker milieu and imaging-based.

And some of them were derived based on hepatitis C population and then subsequently validated in metabolic dysfunction. So if we're looking at something like a Fibrospect, et cetera, something that's been studied in NASH, you're usually looking at something that's got components of collagen matrix, of metalloproteinases, et cetera. And so it's looking at measurable CK18 fragments, et cetera, that are detectable in the blood that suggest not just fat accumulation in the liver, so that's diabetes risk, as I describe it to patients, but then subsequent inflammation, cell death, and eventual scar tissue, decades to development. And so, are you picking up on any...I think most of the

proprietary serum-based tests will give you like a steatosis score, like a fat score, and then they'll also give you a fibrosis score. I think those of us that take care of a lot of livers rely a lot less. We use our bread and butter hepatic function panels, which are not functions necessarily. But then we also use a lot of imaging-based tests because they're so much more sensitive rather than these biomarkers that leave you with a lot of intermediate risk. It's really hard to counsel patients with that type of information. Okay. So this is very, very good to hear.

So what you're basically saying is, look, and now let's shift from me to an actual example of a patient. We have a patient who's very persistently got transaminases in the 40s. They're not quite there to trigger a full million dollar workup, but there's something not normal. We're going to be politically incorrect and say that's not normal. There's something pathologically going on, even if it's very, very low grade and doesn't pose an immediate threat to them in any way, shape or form.

But hey, we're in the business of medicine 3.0, not medicine 2.0. I don't want to wait until there's a problem. If we get one of those NASH scores and it comes back zero, you're saying, Peter, you're not out of the woods yet. There's a lot of nonsense that can be going on there. We didn't talk about GGT. Should we mention GGT? Does that at all factor into your thinking beyond AST and ALT?

I'm just going to speak very sort of clinically relevant here. GDT, alkaline phosphatase measurements. So one of the things that we notice is that in kids, the development of NASH looks different histologically than in adults. There's a lot to be said about what we know and what we don't know. And so the pattern of liver injury,

if we were to look at your liver tissue under a microscope, we usually have all these zones. And the zones, when we're doing detective work as to why is Peter or his relatives liver tests abnormal, and we're coming at it from a histologic lens, where the activity is in the liver sometimes gives us a mini differential. And for kids, the activity of fatty liver disease typically behaves like other chronic liver diseases. So it's what we call portal-based. So it's around the portal triad, which is a functional unit of the liver. The liver in many ways is beautiful and worthy of respect, but its architecture is really elegant. And so the

portal-based diseases, autoimmune disease is there, hep C localizes there, but we see a lot of the changes in children around that portal area. In adults, we see it much more around the central vein. So this drainage vein around the middle of that hexagon that I described before. You see fat, you see inflammatory cells. There are these things called ballooned hepatocytes that we and pathologists love to perseverate over and it's a precursor to cell death. It's like a hot air balloon. It's shaped as a stressed out cell that's pre-epitotic. And so when we see that type of injury pattern around the central vein, that's more typical of what we call adult, what we used to call NASH, but now call MASH.

So how is this relevant? So around the portal diseases, we see much more of the GGT, alkaline phosphatase, things that affect the bile ducts. And so we oftentimes with pediatric fatty liver disease, we'll see elevations in the GGT, alkaline phosphatase, not necessarily to the point of having an elevated bilirubin or a plumbing problem, but those are some of the laboratory, again, looking at a whole bunch of people over a long period of time, just pattern recognition. We also see higher degrees of elevation and amino transferases, AST and ALT in kids and

adolescents, than would be predicted necessarily from an adult. Again, so many degrees of variation that we can describe clinical observations to you, but it doesn't necessarily get at the mechanism or the driver as to what's causing those differences. That's actually really interesting. I didn't know that. I did know that there was a slight difference in the pattern between children and adults, but I didn't realize that it was anatomically that distinct and that it resulted in a differential pattern of enzyme secretion. So again, yet another reason why it's so easy to be fooled. So let's now go back to the way in which you want to see an ultrasound done.

Cause frankly, even just from the standpoint of our own practice, I want to make sure we are relying on the gold standard and I want to make sure we are absolutely not missing this, whether the injury, the inflammation, the fibrosis is the result of alcohol or nutrient or something else. I worry that if we're just relying on ASTs and ALTs and NASH scores and things, we're running a bit of a risk here. The framing around how to deal with the relative risk and the anxiety provoked or alleviated by negative testing and sort of a modicum of humility that a whole bunch of negative testing doesn't necessarily mean that nothing ever bad will happen.

I do a lot with genomic analyses and depending on how targeted the testing can be, a negative test does not mean nothing is ever nor will be wrong with you. Sometimes folks get anxious and it's more sort of an off-ramp. I don't necessarily think that that's your audience. I don't know. But I always like to, again, understand the psychology behind why people are interested and how they're gonna utilize that information. So all that aside, if I were to see a patient and oftentimes, very, very often for our early stage disease, so non-cerotic, non-portal hypertensive, non-transplant, they're at very early stage, they are referred because of an imaging abnormality, absolutely no blood

test abnormality. The two most common causes, common referrals for hepatologists or abnormal amino transferases are abnormal imaging. And again, these are not the super sick people. And so the abnormal liver imaging may be a reflection of hepatic steatosis. The error we want to prevent anyone who sees something like that is just a knee-jerk reaction that that is naffle and mazzled. And not to forget about asking about the biggest differential, which is alcohol, and then also when to invoke some of the more rare biochemical involvement. That's where just talking to your patient is going to give you a lot of information.

For my people who do not drink alcohol, who present with an abnormal image, or are interested in sort of being proactive about their liver health. It boils down to the conversation. What are their risks? Do they have metabolic risks? Do they have habit risks in terms of either recreational drug use or pharmaceutical agents, methotrexate being one that needs monitoring, liver-based monitoring? But if I were to get a snapshot of the liver and their overall health,

we always start with a basic blood test. That's what you have described already, including aminotransferases, and then whether or not a liver image is warranted. And so when we advise population at the population level for people that are not specialists, we advise those clinical risk factors. So what is their metabolic health?

BMI, metabolic syndrome risk factors, cardiometabolic risk factors, habits, what are their social habits, exercise, and engagement around different forms of nutrition. And then also in addition to theirathetic function panel, calculating something like a FIB-4 where those functions have been elevated over a period of time or that person may be male over 50 plus or minus insulin resistant diabetic. Those are some of the things that tell us that person needs secondary testing. And I hardly ever will refer for an ultrasound because most of the time that has already been done already. Threshold for detection, as we mentioned, was around 30-33% to pick up on hepatic fat. A lot of it will depend on what is available to you around you. And so the tools that are

price performance based, VCTE and then ultrasound elastography, our radiology colleagues have picked up on some of the different ways that you can attenuate the ultrasound in order to calculate fat fractions and so those can either be in a doctor's office or a radiology type facility. For very sophisticated testing, again, MRI, PDFF, pro-tendency fat fraction, that's what we use in research studies and they're increasingly available clinically. MRIs are very good at detecting and quantifying the amount of fat, but also depending on the

protocol amount of iron. And when you add what we call an elastography component, so what does that mean? That means you're not just shining a light or changing the imaging signal intensity to the liver, but you're not just shining a light or changing the imaging signal intensity to the liver, but you're also creating vibrations. A normal liver, soft like a sponge. I'm sure you've operated on many people. When it's filled with blood, it's a little bit more dense. A serotic liver or one that's full of scar tissue is much harder like a brick. And so all of these elastography-based techniques, whether it's MR elastography or vibration-controlled

elastography are literally shaking the liver. They're sending vibrations across the liver and saying, is that vibration as it's coming back being detected more in a sponge-like fashion or more in a brick-like fashion? And those scores, typically, we walk away with two scores, a fat score and a scar score. And that scar score matters a lot to us in liver disease world. The fat score is the one that's easiest to modify. If you give up drinking, if you were to lose an modest amount of weight, again, if depending on how you see lipid-related risks from a cardiovascular health perspective, very often a statin or a lipid-lowering compound results in a tiny elevation in an amino transferase.

And when we're looking at net-net cardiovascular risk, we give blessings in the same way that we give blessings to chemotherapy-induced liver injury because we're prioritizing what the overall risk to that human is. I've gone off on a little bit of a tangent, but that's just sort of how I frame how to view an individual that's coming to me for overall liver health. That is not including family history, first-degree relatives, and cancer potential. I think the big thing that we need to talk about that we don't necessarily talk a lot about is metabolic risk and cancer.

And so oncologic risk in addition to metabolic risk is something that we're seeing more and more of. And again, not in a causal way, but in a disease association, especially in the young way. Okay, a lot of things I want to double click on there, Julia. So let me just ask a few seemingly unrelated questions. When you use the term vibration controlled elastography and ultrasound elastography,

are they being used interchangeably or are those two different tests? Two different tests. There's many, many different types of tests. The proprietary name of the Ecosense machine is called Fibroscan. You'll hear that talked a lot about among liver doctors. That is point of care. You get an image generated at the time you see the patient and it uses both ultrasound based technology for the fat score and then the elastography vibration technology for the stiffness. It's a measure of liver stiffness. There's errors, but it's generally widely studied, well validated across different groups including people with a lot of subcutaneous tissue. I'd say it's not technically feasible

in about 8 to 10% of my patients. Shockwave elastography, ultrasound elastography are typically done by radiologists as are MR elastographies. Every site, every pavilion, every place is a little bit different. Sometimes like for my center, they don't unbundle an MRI from the elastography. So from a price performance availability,

when I talk to general, to either internists or endocrinologists, becoming familiar with one or two tests and using them will help train that sixth sense as to, am I missing something? Is this person best served by this test or is this something that I need to sort of refer for expertise on? The list of tests are huge, and the elastography component can be either MRI-based or ultrasound-based. Unrelated, you mentioned twice now recreational drug use. Can you say a little bit more about which recreational drugs might be the driving feature if you're seeing otherwise unexplained elevations of LFTs?

Yeah, I think this came up a little bit, I think when we talked about the viral hepatitis, if your doctor asks you not just about what you're doing currently, but what you may have done in the 70s or 80s. When we talk about recreational drug use, that's oftentimes a risk factor. Injection drug use, IV drug use for intranasal cocaine that is shared between different individuals. There's a ton of people with undiagnosed hepatitis C that are picked up on screening exams and the only thing we find is drug use

in the late 80s, et cetera. Back in the day before we screened blood products as well, again, it's really in sort of the seventh, eighth decade of life that I still see women that may have had a hysterectomy. So contaminated blood products, I'm just thinking through all our questions that I have to normalize for our patients.

Dental work abroad, contaminated types of things are risk factors for various forms of viral hepatitis. That's where that comes from. Yeah, got it. It's not that current use of, pick your favorite drug, marijuana, is necessarily hepatotoxic. There are cannabinoid receptors, and we come up

against this question infrequently. But no, it's not in terms of what you're asking about. OK. And then again, you mentioned the use of lipid-lowering agents. I would say the most predictable manner in which we see an elevation of transaminases is indeed with the addition of statins, especially

if combined with Zetia. So I know that the general consensus is that unless the elevation exceeds one and a half, maybe two X the upper limit of normal, it's deemed not clinically relevant. I'm not sure that's what I heard you say though. What I think I heard you say is the benefits outweigh the risks. And I think those are two different things. In other words, if a person takes Crestor and Zedia and their transaminases pre-therapy are in the 20s and post-therapy, they're 50. I hope there's a reason they're taking Crestor and Zetia, and I hope that that speaks to a risk reduction that's significant with respect to ASCVD.

But we shouldn't conclude from that that their liver is happy, should we? No, and I think this is where we sort of get into the full differences. If you're looking at a change from 19 to 25, 19 to 30, you're still within the range of normal, I think most people would say, risk-benefit favors continuing on that lipid-lowering agent. If you're persistently elevated, and we've gone so far as to like look with biopsies, et cetera, in very rare circumstances, is there actual liver injury that's happening with some of these drugs? And I can count on one hand how many times we've seen demonstrable liver injury that

we think is associated with one of these lipid lowering agents. The real summary point is that there's so many alternatives that oftentimes that don't induce or cause elevations that are well tolerated and have a either more potent lipid lowering effect or better tolerated by that person. So it depends on degree of elevation within the bounds of what we expect is sort of the upper limit of normal, or is there some evidence of liver injury going on and is there an alternative?

Yeah, I mean, we tend to be very aggressive on this, Julia. We don't really tend to like to tolerate elevations of AST and ALT. And as you said, we obviously today have far more tools in our toolkit to get people off those drugs if that's what's happening. Let's now talk again about kind of this nomenclature change that has occurred over the past year. So I think for people listening to us right now, they're going to be very familiar with the term NAFLD, non-alcoholic fatty liver disease, and NASH, non-alcoholic steatohepatitis. But you've now alluded to it several times that there's a different term you're using, MasLD.

So first, define the term, and secondly, and perhaps more importantly, explain why the people far smarter than me have decided to make this change. There's got to be a good reason for it. I think a big component is we're listening to patients a lot more and trying to incorporate their thoughts about how we label their disease. That's one. So defining the disease, when we talk about Masold D, this gets at some of the problems that we had with NAFLD. It was defined by what it wasn't. So not only was non-alcoholic fatty liver disease non-alcoholic in the alcohol component, but you had to go through a laundry list of things that it wasn't, that weren't well explained by the name.

And so it left patients confused. It's a compendious name. It's hard to say. We didn't really get around that with the new naming. And it didn't hint at the underlying physiology, which is metabolic dysfunction, what we spent a lot of time talking about earlier. What prompted the change, there are several things, but the terminology alcoholic, it was reflected differently in different global populations. Some global populations really

liked the non-alcoholic because it was clearly not alcohol-related and they felt that alcohol was very stigmatizing. But a lot of the US population and Western population felt just having that term in there was quite stigmatizing. A common, common scenario that we have with people who do not drink alcohol at all and are found to have liver disease is that they are labeled alcoholic by their friends, by their families, by doctors. There's just a natural assumption that if you have liver disease, that it must be a result of alcohol. So the patient point of view was a big one. Even with NAFLD and NASH? The terminology alcoholic in and of itself. There's also stigmatizing feelings that were

named with the term fat or fatty. And so that's some of the rationale behind changing it to the steatotic as opposed to there was an interim name of metabolic dysfunction associated fatty liver disease. And again, patients are now involved in a way that we probably should have, not we probably, we needed to in the past. Not all impressions reign similarly in different parts of the world. So one is adherence to what is the actual underlying pathophysiology. And then along with that, so now we have an umbrella term called steatotic, steato just means is a Greek for fat, steatotic liver disease. And Maslod is one group underneath that, metabolic dysfunction associated steatotic liver disease. We now have a category, I think one of the issues with renaming is that we're actually

taking into account what humans do. And they may have metabolic dysfunction, but they also may be drinking moderate amounts of alcohol. So we call that metabolic alcohol liver disease or MET-ALD. We have a category for alcohol-related steatosis. We have a category for monogenic. More and more, we're discovering abnormal, particular autosomal recessive conditions that are associated with increased fat in the liver. And then what we are least favorite term, cryptogenic, in terms of as yet unknown, that

has fat deposition in the liver. You know, one of the things we didn't talk about that we oftentimes have to do with our patients is go through a list of all their medications because some medications are known to be associated with fat deposition in the liver. The mechanisms vary, but that's also something that if you are patients, if you're listeners, and if you're clinicians who are following, that is a widely available in terms of what is known and there's resources that we can supply. So while it sounds incredibly confusing, Julia, it is more granular than what we used to have. What we used to have was aphelde and naphalde. So either you're getting all this fat in your liver

because you drink too much alcohol and that fat accumulation is leading to fibrosis. And if that fibrosis isn't halted, it's going to lead to cirrhosis. Or you're getting too much fat in your liver because of overnutrition. And we went through the endogenous and exogenous differences. That fat itself is inflammatory just as all sources of fat that exists outside of the subcutaneous space are, whether they be visceral or peripancreatic, or all sorts of things, right? Perinephric, all of these things are pretty painful.

And that kicks off the cascade. And what you're saying now is, no, no, no, no, come on. This was a gross oversimplification. And there are lots of pathways that get us here and they're not even mutually exclusive, right? I mean, how many people are consuming alcohol and as a result of that or independent of that, frankly, are also are consuming alcohol. And as a result of that, or independent of that, frankly, are also over consuming calories.

And so they have excess fat accumulation from a nutritional perspective, plus the alcohol toxicity, and all of these things are leading to this. I think the subset I most wanna focus on at the moment is the side that is more related to nutrition. Because in many ways, this is, you've alluded to this already, which I think is that in North America,

we would place the metabolic associated disease even above hepatitis and alcohol associated disease. Did I hear you correctly? In terms of overall prevalence or risk for transplantation, it depends on what your end point you're asking about. Prevalence. Prevalence, yeah. In terms of all comers, prevalence of disease, yes.

Not just the US, but globally. And it's also the one that disproportionately affects children. If you think about the exogenous influences, for sure. It varies, but most children do not get exposed to medications, alcohol, or some of the other hepatotoxins until they're teens. And so I wanna now understand this progression more. So we'll kind of narrow our scope a little bit

to just talk about the metabolic association. So let's talk about the pathophysiology. So we've now got a patient who just triggers diagnostic criteria. And I assume that the diagnostic criteria are some combination of the right clinical picture. So, part of that is a diagnosis of exclusion. We don't believe you're consuming too much alcohol.

We've ruled out hepatitis. We've ruled out pharmacologic toxicity, et cetera. And you fit the clinical picture of a person with metabolic syndrome. But I assume you don't have to have metabolic syndrome. I'd like you to clarify that. So you're insulin resistant, with or without metabolic syndrome, and you hit the 5% threshold on your Fibroscan or whatever test we've used that has a high enough degree of sensitivity. That qualifies you as having Maselde, correct? Yeah, so you're going through the sort of the diagnostic algorithm that we are hoping to do a better job of educating

the population about. So it's not just exclusion of those things, but it's picking up on what our current technology or means for patients to reach out. So either biopsy or imaging that's suggestive of steatosis. Let's just start there. And then you start working through this process. I think I mentioned this earlier, a lot of hepatologists sort of downplay the metabolic components of livers

just because of the history of the nature of liver disease and how we've studied it. But the cardiometabolic risk does not require metabolic syndrome. Metabolic syndrome is important to pay attention to, particularly if we're looking at quick clinical grab bag things that should make you think that that person has a risk factor for NAF. For sure, metabolic syndrome increases the risk for having the inflammatory phenotype, the one that we think progresses, again, unintervened upon unmitigated. From a Maslow D definitions perspective, how we get at staging of disease and progression is

dependent on multiple risk factors. The take-home point to what you're asking in terms of teasing out cardiometabolic risk, we have all the parameters that are listed and they vary a little bit by ethnicity. We're much more sensitive about definitions of obesity and metabolic risk across different ethnic backgrounds that were not well described in our previous definitions. So any sensitive about definitions of obesity and metabolic risk across different ethnic backgrounds that were not well described in our previous definitions. So any one of those cardiometabolic features will start to push you into the category of metabolic dysfunction associated with steatotic liver disease or Maslow.

That's really interesting. I sort of envision a world in which we move so far beyond using something like Met syndrome as the all singing, all dancing diagnostic criteria. And I say that with all great respect and appreciation for the work of someone like Jerry Reeven, who even brought this to the attention of people 30 years ago or 40 years ago through syndrome X. But when you think about how crass it is to say, well, when your blood pressure finally hits this and your waist circumference finally hits that and your glucose level hits that, that's when the trouble begins. Imagine a world in which once your

liver fat hits 2%, we're paying attention. Because even though at 5% you now have this disease, that doesn't mean that 2% of your hepatocytes accumulating fat is necessarily a good thing. In other words, you could really start to take an organ-centric view of metabolic health. And if you could really only look at one organ, I think you've got to start with the liver. Again, I'm a bit of a hepatophile. That's my bias, which obviously you share, but it really is the mothership. It's got to be the canary in the coal mine for when things are going wrong. And so to me, the idea that we should be doing scans on people, again, a fiber scan, it seems like a totally reasonable idea. It's relatively low cost. And if it gives us any

insight even before you trigger that threshold, that strikes me as far more useful than looking at something as anodyne as hemoglobin a1c Which is so prone to error by the way the other point I want to get is a sense of prevalence you said it's the most prevalent but just to put some numbers to it What fraction of the people listening to us today in this podcast? Assuming they are representative of the population United States. That's probably not a fair assumption But what percentage of the people listening to this without their knowledge might have MathLD or AthLD?

25 to 35%. Those are pretty conservative projections. We can get a lot of information. One of my mentors, he's a surgeon who did a lot in terms of metabolism outside of the liver said, I wish we could get all the CT data. Granted, it's not the best imaging data from airports so that we could really get some estimates of prevalence because that's a good way to look at everybody that's coming through a population. We don't recommend screening from a fatty liver disease or steatotic liver disease perspective yet. But even if your

audience is relatively healthy, and one of the reasons that I agreed with your prior riff on how unsophisticated some of our current ways of thinking about things are understandably given some of the costs associated with it, but how much that underserves a lot of very proactive patients who can handle a lot of health information and make and implement meaningful change. It really underestimates the capacity of having a test. You know, oftentimes people will check out doctors or advisors will check out and say, we can't do anything about this, therefore there's no relevance in checking. There is a lot of relevance to the majority of our patients in terms of understanding that they're at risk for something and how to implement changes,

longitudinal changes, not just to themselves. But families eat similarly, families exercise similarly. When we counsel an individual, I have many, many, many patients who do not fit the standard phenotype. That's why I like to see patients in succession because it really does change the way that you frame risk, quantitative and qualitative risk across diverse populations. But to your point, your audience, even if they themselves don't have it, I'd say 100% of them know someone in either their family or their close circle who does. And I can say this because as soon as I give a talk like this, everybody starts to

identify themselves as having it, but not knowing what to do about it. Adam Backer I want to just touch on one thing before we go further down that, which is at what point is it important or how does one go about doing some of the other dotting of I's and crossing of T's? Tom Dayspring, a lipidologist that works with us in our practice, mentioned some of these liposomal acid, lipase loss of function, basically sterile accumulation disorders that can masquerade very similarly,

histologically and biochemically, but of course it's a totally different disease. You've already alluded to several of these conditions. At what point should one be looking at the zebras when they see all the hoof prints on the ground, given the prevalence of up to a third of the population actually just has metabolic disease associated with fatty liver accumulation? So if you're frontline-lined general clinician either, and this could be anyone that's not in a,

when I say specialist, I just mean specialist from my tiny corner. So either a gastroenterologist or a hepatologist. If you are a primary care, an intensivist, endocrinologist, cardiologist, and you're seeing this, this is the point of having colleagues, expert referrals, and people to reach out to when you're starting to think about rare causes.

I think the most common reason people reach out is when do we need a biopsy? It's very, very obvious that people look at metabolic risk, they do their viral hepatitis screens and we don't expect them to do alpha-1 antitrypsin phenotype testing initially. When someone is an outlier, they're lean, they have elevated ALT. They've got a stiffness that puts them in moderate range halfway to cirrhosis by the age of 35. We need to involve a specialist in terms of what's going on because the reason is some of the downstream testing, cascade testing for families, whether it's genome sequencing versus genotypes versus targeted genomics versus some of the molecular

diagnostics that we do with histology, you're gonna want some of the expertise that comes sort of free of cost by referring to a center where they see some of the zebras. Do we see people identify zebras out there? Yes, but most often, again, when you're, this is all you do and it's what you love to do, your sixth sense is being trained on what are the reasons to think about outliers.

We're all humbled. We all are surprised by people that surprise us with diagnostics, but oftentimes we come to it in an indirect sort of way. So all that to say, many of the rare zebras that we pursue genomic testing on, if you're identifying through a lipid profile and liver-based screening that they're already an outlier, that's the reason to refer. That's helpful. Again, just bringing it back to the standard case, which I realized to the hepatologist

is very common and is not typically the person that's walking in your door. You're not typically seeing somebody with Mathel D minus cirrhosis who doesn't have any other diagnosis unless it progresses and becomes problematic. But given that that is just an enormous volume of people, I definitely want to spend some time talking about A, what are the most important things to be doing besides the obvious? And we'll discuss the obvious. Are there any treatments on the horizon, even as it progresses to steatohepatitis and before it gets to cirrhosis? Are there any deficiencies in a person's diet that can play a role in this? Are there any other predisposing factors that people need to be aware of? So we'll start back at the beginning, which is the traditional therapy for this is weight

loss. Weight loss is the most important tool that's going to improve metabolic health, maybe at the population level, that's true, but we should also talk about exercise, sleep, and things like that. But things that improve metabolic health should improve Math-O-D. Would you add to that? Would you put a finer point on that? Yes. Specifically, the building blocks of good health, you've named them, exercise, sleep, and nutrition, but they're the ones that are sort of least studied. So the evidence that

we have to talk about histologic changes, and again, I want to be very clear, we're using histology as a surrogate marker for outcomes that are sometimes five to 50 years down the road. And so a lot of the evidence that I'm citing is based on histology where the natural history studies are yet to be born out. So with a lot of humility towards the cardiovascular endpoints. So for the most part, the average person you're seeing with Masel D is much more at risk for cardiovascular-related outcomes and malignancy-related outcomes from their metabolic health than they are for liver-related risks. About 30% of my patients self-refer.

So they read their own report and they convince their doctor to refer to me. They're not necessarily super high risk at all, exactly the same types of patients that you're talking about, but they are proactive. So I don't want to dismiss patient-centered lifestyle intervention. So micronutrient, macronutrient, those are things that we usually involve in specific certain circumstances. So post-bypass surgery for some individuals, shortcut syndrome, that's when we start to think about choline deficiencies and some of the things that your audience might be reading about either in preclinical testing or clinical testing. When we think about precision exercise,

precision nutrition, sort of formulation for an individual, again, context of disease, context of life. And so if a person already has relatively moderate amounts of low glycemic and intake food, the things that we want to sort of really regulate and why a lot of patients hear fatty liver disease and assume the confession that I get a lot is, I don't eat that much fat. When it comes to metabolism, this is again what we've played into what we've talked about a lot, it's glucose handling. So a lot of it is exogenous carbohydrates and trying to switch into smarter burning, sort of the slow burn carbohydrates, your complex carbohydrates.

So we do spend some time talking about that. A lot of patients want very, very detailed information as they should, but a lot of that comes about in meetings with either someone who is of the nutrition sciences. And part of that is we need to know their day-to-day intake and make it culturally appropriate. If we tell you to take something in that's completely outside the bounds of what you normally intake, it's not really easily implementable for everyone's life. So I always spend my time, doctor time talking about exercise and doing an exercise assessment, physical activity assessment. This may sound gendered, but a lot of my female patients, especially with lean naffold, are low in the muscle component. Muscle is typically quite hard to build after the age of 60. So we spend

a lot of time talking about increasing resistance work, combination activity of a lot of single moms who are working very hard and don't necessarily have that much time to dedicate to exercise. So we talk about combination, aerobic and resistance activity. We talk about increasing...and this is part of healthy aging. We see a lot of people become more insulin resistant with aging as they become more sarcopenic, again, even lean individuals. So, figuring out what someone's baseline level of activity is, for some people, it's a walking prescription. They're doing nothing, they're quite sedentary.

It's a walking prescription, increasing their aerobic activity and building habits. So that's where the behavior motivation aspect of change really is very, very critical. So again, nutrition component, I outsource a bit to a registered dietitian with detailed information. There's a lot to be said about this. The one thing that I will bring to your audience if they're unfamiliar is the impact of coffee. I don't know if you've brought this up yet in terms of liver health and coffee. So again, we haven't isolated... There's some metabolomic studies we can point to when it comes to caffeine, but coffee and we're talking about black coffee or limited added sugar and added milk components has been shown to be beneficial for multiple liver diseases and fatty liver

disease, hepatitis C, fibrosis, even HCC. Again, there's many reasons people do not drink coffee and we are not recommending it as a prescription. But up to three cups of coffee has been shown in multiple studies now, it's part of the European guidelines and made it into the American ones as well in terms of anti-fibroidic effects and good metabolic effects as well in terms of anti-fibrotic effects and good metabolic effects as well. So that's one very specific nutrition fine point that I can add to what you're saying about metabolic liver disease.

Dr. Kahn I've got two follow-up questions on that. With respect to coffee, do we have a sense of what component of the coffee it is? And obviously if it's caffeine, that has one set of implications. If it's polyphenols or things like that, then it also has a huge implication as far as the form of the coffee. A highly filtered drip coffee versus a French press, you're going to have totally different amounts of those polyphenols making their way in. I'm sure everybody, myself included, who loves coffee is asking the question, what do we know about the constitutive components responsible for that benefit? And how should

that impact our coffee drinking choices? The short answer is not enough. As I harkened to earlier, in terms of the granularity of nutrition detail, huge opportunity. In terms of metabolomics, caffeine is a signal, but that when given caffeine in and of itself, it does not mimic some of the effects that we observe. So that's not one thing. Like many things that we talk about with nutrition, extracting a nutrient versus taking it in its natural form are two different components. And so the methodology of coffee extraction and the caffeine component, the instances of tea, a lot of cultures drink much more tea than coffee, including green

tea. These are all areas for further exploration. So I wish I had a more detailed answer for you, but we don't have that yet. The times I've looked into this, I've come to the conclusion that the more of the coffee bean you're ingesting, the better. When in doubt, I opt for a French press because it's the least filtered and I'm getting the most of everything. Again, there's no rationale to that other than my teleologic two cents. The other nutrition related question I have for you is the role of fructose specifically. is the role of fructose specifically. And to be more clear, what I really wanna understand

is at isocaloric levels, do we believe that fructose is more injurious than glucose, i.e. two very similar molecules that happen to have very different paths of metabolism. There has certainly been a lot of discussion and I myself have largely subscribed to this that in the case of what we historically called NAFLD, we really want to eliminate liquid sources of fructose. If we're trying to get patients to change their diet, yeah, by all means, keep eating

your berries and your fruit, but get rid of the smoothies, get rid of any sugar sweetened beverages, not just because of their caloric content, but because of that huge bolus of fructose that is hitting the gut and then as you described, heading through the portal circulation to the liver. So what do we know about that today?

The evidence around fructose that's been studied in kids and adults, specifically high fructose corn syrup and some of the more processed forms. And again, taking something in isolation, much easier to do in animal models than in humans. But the first thing I would say is any study that you're looking at, most of the mechanism for any type of liver disruption comes through an insulin resistance pathway. So you would have to tease apart the presence or absence of overweight and obesity and the presence or absence of insulin resistance as the mediating, the big driver of whatever you're observing in the liver.

When studies have been done looking at that, and I think there's only one or two, there's no net difference. There's a couple of studies that have been done that look at liver exposure from fructose, not parsing out those. And again, these are population level data type interventions. Then you do see evidence of liver injury, more significant activity. And by that, I mean inflammation, plus or minus scar tissue. Yeah. My reading of this literature is that it has been very difficult to disentangle the relationship between the macronutrient and, for example, weight loss. In other words, if you look at studies that have removed all fructose from the diet and have actually demonstrated a remarkable amelioration of what

was called NAFLD, the patients still, I say unfortunately, I say unfortunately from the scientific standpoint, they lost weight. Even though these were meant to be studies that were eukaloric, just taking fructose out of a person's diet presumably led to less spontaneous consumption. I think there are lots of great mechanisms for why a high fructose diet leads to overeating. While that's maybe a great outcome, A, we don't know if that's really sustainable in the long run, B, it doesn't answer the mechanistic question, which we so badly want to answer. What I'm hearing you say is you do not specifically counsel people to eliminate fructose from their diet other than that being part of an overall general dietary pattern. In other words, if you're

advising people to eat less and move to lower glycemic foods, that often comes with a pattern that is consistent with what I just described that's going to be lower in all forms of fructose that come from refined sources. So when we get into specific recommendations, it's gotta be dialed in for the individual and what they have capacity for at that time. The range of patients that I see, some people can hire a personal chef and a personal trainer,

the vast majority of my patients cannot. So if the effort to eliminate a specific component causes so much distress to the average person, that's a lot of mental work. And to isolate one particular component, it's much easier and implementable to say, avoid processed foods. So if you're buying from a podega versus buying from a grocery store in New York City, where is your source?

The best way to study this would be in areas where the government or some regulatory body has excluded some of the high fructose corn syrup and processed foods. There are communities that do that. So if you want to dial down on population level effects, that's probably the best way to study it because humans doing what they do be very, very difficult to longitudinally exclude a single component over the long haul, just given the nature of how humans interact with their environment. Completely doable from a mouse model perspective, but what we know about fatty liver disease, Maslow, Naphold,

any way that you study it, the translation from preclinical to clinical, let alone phase one to phase three, does not always borne out with the biology, given the beauty of the liver and homeostasis. I want to talk a little bit about GLP-1 agonists, at least the two most popular ones that are out there today, so semiglutide and terzepotide. Obviously, they have a profound impact on weight loss. They generally tend to have a very favorable impact on insulin sensitivity as well. So it would seem to me that one could have make the case today that the most effective drug we have for treating NAFLD, formerly NAFLD and NASH, are indeed these drugs. What is your view of that and what have you seen clinically?

Let's start with my view. So in terms of when to bring in these drugs and what you're actually treating with it, I tend to go based on published evidence and what we have data for and what we have approvals for and anything that's not being used in that context that we're specific about why. So if you have someone who is a known diabetic, it is low-hanging fruit to reach for one of these agents. Again, when there is weight to be lost, a certain percentage of patients can't afford to lose weight, especially some of the muscle loss effects that are also associated with these drugs. So when I have the average person who's BMI 28 to 40, they have stage two estimations

from non-invasive tests. They've maximized their lifestyle modifications for their current demands in life. What are we working with endocrinologists? Most of them have already had the discussion if they have diabetes about bringing in a GLP-1 receptor agonist. If they're not, we strongly move forward that conversation, but we don't do it outside of the context of,

at some point, you will likely have to come off of this medicine. We need to talk about how many people regain the weight afterwards and what's the longitudinal benefit for a longitudinal disease if two years down the road, you regain the weight and the injury pattern resumes. So we do take a long lens on it. I do have very overt conversations when patients are in the stage three range for cirrhosis, early cirrhosis, about bariatric surgery, metabolic and weight loss surgery,

and the involvement of some of these weight loss drugs with a clear open discussion about what happens when you come off of the drugs and what's the longitudinal weight regain post-bariatric surgery from some of the surgical interventions. So when to bring it in? Comorbid obesity, comorbid overweight status, comorbid diabetes. And do we use it specifically? It has clearly in the evidence, it's been tested in multiple phase two studies and recently released data in terms of the effects on

the liver. The effects on the liver are difficult to tease out in terms of how much of it is due to overall weight loss versus a direct liver related effect. When we used to talk about NAFLD and NASH, related effect. When we used to talk about NAFLD and NASH, I assume that those were largely biopsy differentiated terms and NAFLD focused on fat accumulation, NASH focused on the inflammation that was present, and then of course cirrhosis was the end stage of fibrosis. Today you're talking about it in terms of staging. Does that allow us to move past biopsies and rely on some of the elastography and ways to look at both fat and fibrosis scores?

And if so, how do you delineate the staging today? Most of us are using non-invasive tests. So those are things that are apart from biopsy, any of the ones that we named before for the vast majority of our clinical patient follow-up. The time that we bring in biopsies, usually for anything, oftentimes we'll get, especially women with a positive ANA, smooth muscle antibodies, some indication that there may be an autoimmune component. So treatments are very different between the two. So to exclude a biomarker of interest in a population, about 18 to 20% of people, patients

with Masel D will have one of those positive biomarkers. So we use it to exclude other types of diseases. We also use it for clinical trials purposes. And then we use it oftentimes in diagnostic testing prior to procedure, prior to an elective surgery, prior to an intervention that may or may not result in liver where you need to know about cirrhosis before an abdominal surgery or a cardiothoracic surgery might be done. Those are the three instances that we see most often.

Because of the explosion of non-invasive tests, being a recipient of all the confounders, we also help use it to delineate when there needs to be a tiebreaker. You get one non-invasive test that suggests very advanced fibrosis. You get an MRI that suggests, with elastography, that suggests something very different, where there's such discordance that you need something to adjudicate the in-between area. So I'd say there's four instances. And so what are the stages? When you talk about stage one, two, three, and four, what makes up those stages today?

Fibrosis scores. So the way that we look at the liver and there's different scoring systems that are based on different types of diseases, but the way that we think about a normal liver, assuming no genetic influences, most humans are born with a normal liver. Let me define some of these disease processes. So we defined what steatosis development looked like in Masel D and that's more than 5% fat.

When you start to move into fat plus inflammation, so inflammatory cells infiltrating the liver, plus what we call hepatocyte ballooning that stressed out hepatocyte, that's the definition of NASH. NASH does not necessarily mean that they're scar tissue. Oftentimes, you will see some scar tissue but the fibrosis component is different. Stage one scarring is early stage scarring. It's usually, like I said, in adults around the vein. We call it chicken wire because that's what it looks

like under the microscope. And then depending on the distribution and presence of scar tissue, we stage it stage one, stage two, stage three, stage four. The way that the liver architecture looks under the microscope around stage three, we start to see connections between that portal-based area and some of the central vein areas. So you'll hear people say expansion, bridges, and then stage four scarring is what we consider cirrhosis. And that's where you have a lot of architectural disruption, nodules forming in the liver. It looks lumpy, bumpy, sometimes on an ultrasound, sometimes on an MRI. Our thinking around cirrhosis and reversibility has also changed in the field. And a lot of

this was learned after the potent hepatitis C cures. We used to teach that any form of cirrhosis we thought was very...the scar tissue was very fixed and irreversible. Now, we've subdivided cirrhosis into different stages and early cirrhosis or stage four scarring of the liver. We've started to see evidence that even that is reversible. Time course between each of these stages for something like Masold is five to seven years. That's largely based on European ancestry information and that's why it is such a hopeful disease because there's tons of time to intervene before there's progression to the next stage.

So, I mean, those are two very uplifting pieces of information, right? The first is that you've got five to seven years between each of those stages. And then the second is that you've got five to seven years between each of those stages. Then the second is that even at least a subset of cirrhosis might be reversible. That again, stands in the face of the traditional teaching that we had, which was stages one, two, three, reversible, stage four, not. Talk a little bit about the oncology risk. You've alluded to it a couple of times now, and you've also, if I want to make sure I'm hearing you correctly, said that, look, if you're in the early stages of Mathel D, you might say, well, why should I care? And you're saying you should care more based on the risk to

your heart and the risk to cancer than you should have your immediate risk to liver disease. Because if you're in the first stages of this disease, you're 15 to 20 years away from liver failure, but you could be much closer to cancer or heart disease. I want to make sure that I'm representing what you said correctly. And two, I want to particularly focus on how you would quantify the increased risk of cancer there. Let me tackle the first portion.

I think that the general community and a lot of patients self-report this. They pick up their impressions based on how clinicians deliver the news. And I think there's been a jadedness in terms of tackling diabetes, obesity, any type of metabolic diseases as if the general population will not take that information and act on it. And some of that, I guess, is justified in the diabetes world. That said, I think we have a lot to do in terms of how we counsel patients and whether or not they feel empowered by the information we're giving them and if we're taking it seriously. A lot of hepatologists want to see, and we should from a stewardship

perspective, see the more advanced perspective. But that means that we garner understanding and support from our endocrinology, cardiology, general folks in terms of understanding metabolic risk and how to modify that risk long-term. So for the average person, including patients that are included in our stage one, stage two, stage three clinical trials, a main outcome is cardiac, major adverse cardiac events. And so that's a longitudinal risk that we need to think about. When I see a patient, I am trying to figure out what is the leading risk for their, not just mortality, but quality of life implication. Is it something that is liver-based or is it something outside of the liver? And this is not necessarily including willington's e-risk, but sometimes does.

And this is not necessarily including willignancy risk, but sometimes does. For very early stage disease, so not even stage one fibrosis, we talk a lot about eventual development of diabetes. A common thing that I'll say is somebody with an elevated cap score on a fibroscan, here's your fat score, here's your scar score. Your scar score is normal. Your fat score is exceedingly high. It's very modifiable. Six weeks to six months,

it can be in the normal range. Unchanged, you will most likely develop diabetes in X number of years, depending on what their insulin risk profile will be. That's not usually received in a scary way. That's received in a, oh, I can actually change my diabetes-related risk in a meaningful way and see an outcome in a year or two on a scan. So empowering patients with information and then also working in partnership with endocrinology and cardiology in terms of what their cardiovascular risk might look like and how to modify it and how to make it sustainable. I think that's the biggest thing that we deal with when it comes to liver disease and scar.

If it is five to seven years on average to develop stages to progress, that's a lot of sustainability. And a lot of the behavior changes that we see are related to circumstances. So how to build resilience, not just in terms of their metabolism and their metabolic flexibility, but what their coping skills are, what they reach for in different instances. That's early stage disease. From an oncologic risk perspective, and I'll speak first about the liver-related oncologic risk. So our primary liver disease, our liver-related cancer is hepatocellular carcinoma. It's origin is in the liver. I'm not speaking about metastatic disease that lands in the liver. We generally

think that that occurs with cirrhosis. And for most liver diseases, around 3% to 5% per year is what we quantify risk. Highest risk, hereditary hemochromatosis. Next, combination hepatitis C and alcohol. This was mostly quantified before hepatitis C cure has existed. Then hepatitis C, alcohol, Masl D. Once and again, when you take care of the ones that escape your escape hatch phenomenon alerts always come on hepatitis B. And then whether or not this is a subject of a large multidisciplinary group that we're part of is looking at whether or not we were getting case reports basically of people with stage three scar tissue from fatty liver disease

developing cancers, really bad cancers. When liver cancers are slow growing, they're quiet, they're silent, you have to look ahead of time. So that is a population, people with cirrhosis are a population that we recommend looking for cancers before anyone is symptomatic. So every six months, we recommend screening. Whether or not that needs to be done at an earlier stage in fatty liver disease world, that Masel D world is to be determined. There's some early evidence that around the metabolic reprogramming that's going on in the liver, the insulin sensitization, the insulinization of the liver, the oncologic potential is changing. Whether or not that person needs to be screened at an earlier stage of disease is a current area of interest in the

field and within my group. Yeah. I mean, that's the million dollar question, Julia, is if you quoted that three to 5% per year increase in the risk of paticellular carcinoma, that's once you have stage four. Was that what you said? Correct. And obviously, once you're at stage four, you got a lot of problems. Your risk of HCC is one of them, but at this point, everything is a four alarm fire. But given, again, the prevalence of a Maffledy, Naffledy, Nash, whatever we want to call it along that progression, yeah, it would be really helpful to know, is your risk of hepatocellular carcinoma 2x the normal, 3x the normal, 5x the normal? Admittedly, it's a low baseline, even if you're at stage one or stage two.

Could be a while to answer those questions, obviously, because of the sample size is needed. To that point, that's an obvious opportunity to have a discussion with a patient about whether or not to involve pharmacologic agents or surgical agents to massively decrease their risk of not just fat, but scar tissue in their liver in a meaningfully reversible and hopefully sustainable way to decrease potential cancer risk is a big one. And I would say a lot of patients come to us, and again, I have a biased point of view because of my specialty, cirrhosis is not a death sentence. A lot of times we have new diagnoses of cirrhosis in people in their 30s, 40s,

because this disease starts so young. You can live, you can have relatively good metabolic health for quite some time before your liver falls off the curve from a dysfunction standpoint. So even with cirrhosis, you need to undergo some appropriate screening, but the timeline for that is not you're gonna need a transplant in two years.

Once you involve portal hypertension, it's a different story. Some of your listeners, a good percentage of your listeners might have stage three scar and not know it. And at the age of 40, might be told that they have pretty early onset stage four disease. But again, it's not like stage four cancer. It is something that there are opportunities to do a lot of good in that population. I want to spend a minute just talking about drugs, either currently used drugs, which are obviously drugs that are used to treat other things.

So we clearly are going to rely heavily on drugs whose primary purpose is treating diabetes, which improve, at least in the case of metformin, very likely improve insulin sensitivity as well. Or GLP-1 agonists that weformin, very likely improve insulin sensitivity as well. Or GLP-1 agonist that we've already discussed that both target insulin sensitivity and appetite regulation, which then feeds back. But are there any other drugs out there today or in what I would call kind of late stage three

that are specifically targeting fat accumulation in the liver due to metabolic consequence or even due to alcohol. So your group might be familiar with the resumeteron output New England Journal probably 10 days ago, phase three. So what we have learned about the liver, whenever you have so many biological processes that are being regulated and a lot of exogenous inputs. There's a lot of potential for therapeutics, but that also means a lot of potential for error because of the biology of the disease. So that's a thyroid hormone receptor agonist

that has been studied and now shows very good promise in terms of late stage efficacy, late stage by way of phase three, efficacy and safety in a population. There are a couple of limitations in terms of the population. I think it's 90% European ancestry or self-described white with a disease prevalence in the United States and around the world being very, very heavily diverse. So how that will play out in a different population is one thing to be watched. But thyroid hormone signal, again, some of the omics-based studies that we do sometimes get at the disease agnostically, which old reductionist ways of doing science sort of were refractory too.

But it's a common way to think about what does have biological plausibility that might have an actionable effect within the liver. So when it comes to advanced scar tissue, and this one looked at that particular study, looked at agents that are stage one, stage two, stage three. There's different forms, tons of clinical trials have been done at various stages, including what we call decompensated. That's when somebody with cirrhosis falls off the curve, all of a sudden their liver stops working. So those types of agents have been studied as well.

When you think about promising agents independent of weight loss, where as metarome is one, there are some that act on multiple types of pathways like FGFs, FXR, agonists. Different when you look at the pleiotropy of expression of where the injury can occur and keeping front of mind that the liver talks to subcutaneous tissue, subcutaneous adipose and muscle. That's where some of the PPAR agonists come from. That's where some of the vitamin E, the PIVIN trial. So there are different agents that have been studied depending on the stage of disease. But what's messy about this work is that oftentimes things that show biological activity from

a histology perspective don't necessarily result in some of our endpoints that we have as a community developed with the FDA. And that's reversal of NASH and no progression of fibrosis. And so whether or not those histologic endpoints are representative of the disease at large within the liver, and then also the cardiovascular, and very importantly, lysemic effects are what makes doing these trials so hard.

And you're looking at multiple variables, not just liver related, but also endocrine and cardiac. So Julie, if patients come to you and say, should I be taking choline supplements, vitamin E supplements based on the histologic changes that didn't quite meet clinical endpoints, do you see a downside in doing that? For choline deficiencies specifically,

those are sometimes measurable. Those are things that we can do assays. We see them a lot in people post bypass surgery, the malnutrition form of steatotic liver disease. So I'm not terribly aware of any downsides. I'm cautious when I say this because every day I see a patient with some sort of new formulation that has a hyperpotent level of what we think they're getting. And so when it comes to supplementation, quantifying exactly what's in it, from a vitamin E perspective, you know, there are some downsides,

all comers, the annals, cardiovascular, longitudinal risk, and then prostate cancer, just things to think about in terms of whether or not I would choose to use it or at least have a discussion with a patient. The vitamin E is very sort of low-hanging fruit from a steatotic perspective, but we do think we have additional discussions in people that have diabetes. It's generally okay now. There's studies have been done on people with cirrhosis

because again, there've been some studies that indicate increased in all-cause mortality depending on the dose of vitamin E and what it's being used for. What's in the pipeline as far as any of the mitochondrial uncoupling agents? This was sort of talked about a lot a few years ago. I haven't been paying attention, so maybe it's still being talked about, but is that something that is still looking promising?

So I think a lot of the work that's been done in that area, if you look at early development, again, if we go back to the de novo lipogenesis pathways, where there's beta oxidation, where there's failures in beta oxidation, where there's overwhelm, there's a putative mechanism there. I see most potential interventions just like siRNA-based agents in combination-based therapies. And that's because for approval, you're going to have to get a component of fibrosis. And the most potent aspect to deal with both steatosis and fibrosis right now are some of the blockbuster weight loss drugs.

In order to have liver-specific directed therapy for something like mitochondrial-based pediology, and we typically think of microsteatosis and development in that way, rather than the macrosteatosis, the large flat droplets that we see with metabolic-associated steatotic liver disease. So I see them used potentially, I'm not conflicted in terms of speaking about this, in forms of combination therapy. There are so many different agents being talked about that are not yet public from a preclinical perspective. So I could see that.

I could envision that as a potential putative agent from a steatotic-based application, but in combination. Well, Julia, this has been really interesting. We've covered a lot of ground today. I've taken a lot of notes. You probably can't tell, but that speaks to how much I've been learning and how much I think this is going to sharpen my pencil when it comes to patient management and our diagnostic acumen within the practice. Again, I think the takeaway here is many things for me, but probably the most important takeaways

are that we need to be very thoughtful in how we make the diagnosis here, and we need to be very thorough in evaluating the clinical history and that the overlap could be much more significant than previously realized between metabolic dysfunction and alcohol use, and that it doesn't take a whole lot of alcohol consumption to impact these steatohepatitis pathways. Indeed, many patients are probably walking around with some combination of what was formerly aphelde and nathelde. So the other thing I've really taken away from this is that really the near-term cardiometabolic risk and the near-term oncology risk might even outweigh the near-term hepatology risk in the early stages of that disease. There's still a great unknown there, it sounds like in terms of quantifying some of those risks, but nevertheless,

I was actually very taken aback by the statement you made, which was in the stage one, two and three clinical trials, you're using MACE, major adverse cardiac event as the clinical outcome. I think that speaks to the proximity of cardiovascular disease as a bad thing as the thing that you ought to care about. If clinical trials are looking at MACE as an outcome, that tells you how tightly linked these conditions are with cardiovascular disease. It's not the primary endpoint. We're still looking at liver-based endpoints. But when

we look at longitudinal clinical outcomes data, where post-approval surveillance will be and clinically significant outcomes for the FDA for certain cardiovascular outcomes are a huge one. Got it. Okay. Thanks for clarifying that. Yeah, that was an amazing statement if I was correct that it was a primary outcome, but good to hear that maybe more logical to hear that it's not.

Anyway, thank you very much for sharing all this insight. There are literally hundreds of thousands of people listening to us right now who are afflicted by this, some of whom know it, but I suspect many of whom don't. The hope is that they can get the proper diagnosis and that that diagnosis perhaps by itself serves as the motivation to go after this and address it because, again, the other takeaway here is imminently treatable, imminently reversible, and therefore there's no reason to not know that this is something going on inside your body. Couldn't agree more.

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