The Peter Attia Drive - #302 - Confronting a metabolic epidemic： understanding liver health and how to prevent, diagnose, and manage liver disease

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Julia

00:01:06.300 Wattachero. Julia specializes in non-alcoholic fatty liver disease, as well as all forms of hepatitis,

00:01:13.740 chronic liver disease, and liver cancer, in addition to being a hepatologist who takes care of patients

00:01:19.600 pre- and post-liver transplantation. Her research interests include hepatic steatosis, insulin

00:01:25.640 resistance, gut hormones, and metabolic liver disease in adults. Julia is an associate professor

00:01:32.260 of medicine and the director of the Metabolic Dysfunction Associated Steatotic Liver Disease

00:01:37.480 Program, the Center for the Liver Disease and Transplantation Program at Columbia University

00:01:42.220 Medical Center. Julia earned her MD and completed her residency at Baylor College of Medicine,

00:01:47.380 followed by a fellowship in gastroenterology at Vanderbilt University, where she also earned a

00:01:53.020 master's in public health. Julia then completed a second fellowship in transplant hepatology

00:01:58.140 at Columbia University, before becoming an attending there, where she is today. In this episode,

00:02:04.180 we start by speaking about the basic physiology and the four functions of the liver, the history of

00:02:10.220 liver disease and liver transplantation, and the details of acute versus chronic liver injury.

00:02:15.880 We speak about alcohol-related injury and what it is about the mechanism and metabolism of ethanol

00:02:22.240 that is problematic for the liver. We look at what the optimal levels for liver function tests

00:02:28.600 and liver enzymes might be in the blood test, and Julia explains in fantastic detail what AST and ALT,

00:02:36.440 two very common measurements that we talk about a lot and that you all have undoubtedly seen on your

00:02:40.460 blood test. What do these do in the cell? What do they refer to? And what is it about their elevation

00:02:46.020 that we should or shouldn't be worried about? We then discuss how to improve metabolic health in

00:02:51.400 relation to the liver and why the liver is truly the mothership of all organs. Lastly, Julia outlines the

00:02:57.580 four major stages of liver disease, discussing the risk, treatment options, and the importance of early

00:03:02.500 diagnosis. So without further delay, please enjoy my conversation with Dr. Julia Guattachero.

00:03:13.600 Hey, Julia, thank you so much for joining me today. Very important topic and very relevant topic,

00:03:19.440 both in the narrow scope of what I do clinically and I think the broader scope of what many clinicians

00:03:24.700 do and frankly, what anybody listening needs to be mindful of given the epidemic we're about to

00:03:29.860 discuss. But why don't you tell folks a little bit about your training, what it means to be a

00:03:34.120 hepatologist, and what led you there? Sure. Thanks for having me and thanks for being concerned about

00:03:38.960 the liver. So I am a transplant hepatologist, so my clinical hat is about 50% divided into liver

00:03:46.120 transplant and 50% divided into general liver care. How I got to that path, so I did medical school in

00:03:53.220 Houston at the Baylor College of Medicine, residency there as well, a GI fellowship at Vanderbilt in

00:03:58.840 Nashville, and then my transplant fellowship at Columbia. When it comes to sort of my faculty

00:04:05.580 time division, I tend to focus on MASLD or NAFLD as it used to be called, and so metabolism and a

00:04:13.240 nexus with endocrinology is also a big focus of mine. So let's take a step back maybe and just give

00:04:18.020 folks a sense of what the liver does. People have probably heard me say this before, but it's always

00:04:23.600 worth repeating. The liver is this essential organ for which we don't have extracorporeal support.

00:04:30.340 That's just a fancy word that means outside of body support. So if a person's lungs don't work,

00:04:35.420 we saw this a lot during COVID, but obviously we see this all the time, you have extracorporeal

00:04:40.480 support. You have a ventilator that can do the job of the lung for a temporary period of time,

00:04:45.020 hours, weeks, even months. Believe it or not, if the heart doesn't work, we have extracorporeal

00:04:50.420 support in terms of intra-aortic balloon pumps or even ventricular assist devices. And obviously

00:04:55.620 if the kidneys don't work, we have extracorporeal support in the form of dialysis. Now, I'm not

00:05:00.480 suggesting any of these things are a substitute for the real thing, but they're remarkable bridges

00:05:05.460 that save many lives. And yet, Julia, we don't have anything that even remotely resembles extracorporeal

00:05:12.500 support for the liver. So we have this essential organ, and yet if it is injured, we don't even have a

00:05:20.100 way to bridge people to transplantation. Anything you want to say about that? I mean, is that just

00:05:24.480 kind of a staggering feature, I think, of this organ? It's not for lack of trying. There have been

00:05:29.600 some devices like the Mars machine that have been developed. And I think as you're appropriately

00:05:34.840 bringing up what we learned in COVID, a lot of liver disease, the bulk of liver disease has

00:05:39.880 historically been chronic. And so you have time for intervention. It's the acute phases that we really

00:05:45.540 need either a 3D printed liver or an accessory liver that could function either inside the body

00:05:52.100 or outside of the body. So those efforts are being undertaken, but it both harkens to the complexity

00:05:58.840 of what the liver does and how hard it is to mimic when the liver is injured, what it can do.

00:06:04.920 But it also gives you a focus on sort of the panoply of liver diseases, the timeline to development

00:06:11.700 of liver disease and the functional aspect of what it takes to actually get some of these devices

00:06:17.140 to market. Yeah. I'll share one last funny story about this. You might be aware of this,

00:06:21.640 but when I was at Hopkins, one of the attendings who had trained at one of the universities in

00:06:26.960 Virginia told a story about when he was in his training, they were using baboons as a bridge to

00:06:35.040 transplantation. So I'm not talking about xeno transplantation. They would literally put a

00:06:38.940 baboon in a bed next to the human in acute liver failure. They would run conduits between them.

00:06:46.100 And obviously they had somehow ABO matched the baboon to the human. And they would basically

00:06:52.360 circulate the human's blood through the baboon using the baboon's liver to detoxify, you know,

00:06:59.440 and carry out gluconeogenesis or whatever other features were critical in the acute moment.

00:07:04.060 And apparently this somewhat worked. You could take a person who was completely jaundiced on the verge

00:07:11.100 of death and buy them another week or so until a liver transplant showed up. And according to the

00:07:17.160 story of this one attending, it worked really well until once a patient emerged from basically a state

00:07:24.540 of unconsciousness due to their liver failure and realized what was going on and freaked out and

00:07:29.280 panicked and pulled the cannulas out. And it turned into a big bloody mess that of course ended with

00:07:34.260 the baboon dying and the patient nearly dying. And that put an end to it. I don't know if you've ever

00:07:38.660 heard any of these stories, but that always stuck with me as the depths to which one had to go to try

00:07:45.220 to basically save people during this period of acute liver failure while you either hoped for a recovery

00:07:51.580 and or found a transplant. Any of those stories ever come your way?

00:07:55.020 Not so much the animal portion, but if you've read about accessory livers, and so you learn a lot about

00:08:02.140 this from living donation, how much liver is required when people are in acute liver failure.

00:08:07.300 It's not something apart from the pediatric population that a small segment of liver could

00:08:11.640 actually solve. But for accessory livers, you're implanting human liver to basically function

00:08:17.340 as a temporary means of metabolism and recovery of immune function and all the other functions that

00:08:24.200 we'll get to. But it's much more on the human side than cannulas to a baboon, which is a good

00:08:29.940 mimicker. I think we learned a lot in liver disease from alcohol and the baboon was one that mimicked

00:08:36.040 human responsiveness more so than other animal models. So I could see that being teleologically

00:08:40.740 making sense. Meaning there were baboons that were forced to drink alcohol so that we could sort of

00:08:45.140 better understand the impact of alcohol on the human liver. And how much is nutrient deprivation

00:08:50.100 from carbohydrate load from alcohol versus direct injury to the liver. Yeah. Interesting. Let's talk

00:08:56.480 a little bit about what the liver does. I mean, why is it that this organ, everything we've just said

00:09:00.240 is true. One, it's clearly complex enough that in the year 2024, we still do not have a way to

00:09:08.620 approximate it the way we do most other vital organs. And two, there's something about it that's

00:09:14.660 obviously quite susceptible to injury in the modern environment. So maybe just start with

00:09:19.080 anywhere you want, whether it be just the basic physiology of it, or how would you get people to

00:09:23.820 understand and appreciate the absolute beauty of this, what I consider very underappreciated organ?

00:09:29.620 I'll start with what comes up. And when patients bring up misinformation, it's an opportunity to

00:09:36.020 learn that we need to do better about informing. So it's about three and a half pounds, sits underneath

00:09:40.700 your right ribcage. Sometimes people get it on the wrong side. In most humans, it's on the right.

00:09:45.380 And it's the largest internal organ. So basic functions, there's over 300 functions. So we

00:09:50.740 exhaust our entire time together if we went through all of them. But a big one that hepatologists don't

00:09:56.020 necessarily get trained in much is metabolism. We've left a lot of that to the endocrinologists.

00:10:01.180 So we think about parenchymal liver diseases, so common things like mazeled or NAFLD, alcohol,

00:10:09.120 autoimmune hepatitis, things that affect the whole liver. And then cholestatic liver diseases are

00:10:14.840 viled up to the plumbing system of the liver. Hopefully in your show notes, you can give a

00:10:19.200 basic anatomy or a diagram of what the liver looks like. But a lot of what's read about the liver is

00:10:24.940 focused on one versus another component. So it's just really important for any audience member who's

00:10:30.580 looking at a tiny piece of liver information, whether it's biochemistry or a picture,

00:10:35.760 to understand it in the context of what the liver does. And some of the basic functions of the liver,

00:10:40.360 so we said metabolism, and that's proteins, lipids, and fat carbohydrate metabolism. It serves an immune

00:10:47.260 function. We learn a lot about what the liver does from what happens when it doesn't work well. So one of

00:10:52.680 the major proteins that it makes are the synthetic proteins that help you clot blood. So bleeding

00:10:58.580 disorders are common in people with liver dysfunction. The other one that comes up a lot is detoxification.

00:11:04.260 And so whether it's metabolism of pharmacologic agents that people are taking in, or any supplement

00:11:10.760 or exogenous compounds, or even toxins, environmental toxins, all of those get processed in the liver,

00:11:18.680 handled by the liver, and hopefully detoxified by the liver. So those are just a few of the many

00:11:24.260 functions. I include the nutritional components, so bile acid production, all of those things within

00:11:29.640 the metabolic chamber, the way that I think about the functions of the liver. But that in and of itself

00:11:34.920 could be a whole different category, some of the nutrient load handling.

00:11:40.160 So would you kind of agree with my non-hepatologist framework, which is, I think of the big four things

00:11:45.540 that the liver does, which we've largely touched on, although one we didn't quite touch on,

00:11:49.600 but clearly metabolism, as you've said. And that includes what I think is the most amazing thing

00:11:56.020 that the liver does, which is regulate blood glucose. I think that's something that's almost

00:12:01.120 impossible to describe, how perfect the liver is able to do this, including in someone with type 2

00:12:07.780 diabetes, which we'll talk about, where you end up being about 2x too much blood sugar. But that's still

00:12:14.380 a relatively narrow band with which blood glucose is regulated compared to the extremes, right? If it

00:12:22.660 ever falls below about 50 milligrams per deciliter or half a teaspoon total glucose circulating, you're

00:12:28.480 dead. If it really ever gets above 4 or 500 acutely, like you're dead, and that it can keep most of us

00:12:34.920 around 100 to 200 is incredible at the minute by minute, second by second deviation. You talk again

00:12:43.160 about synthetic stuff. I'm sure we will talk about that and how, again, in extreme cases,

00:12:47.780 if the liver can't make those clotting factors. And then we talked about detoxification. That's

00:12:52.960 probably the one I know the least about, but obviously we see the results of it. But the other

00:12:57.480 one that I think probably doesn't get enough attention from most people is the amazing role

00:13:01.420 that the liver plays in managing the lipoproteins and the clearance of lipoproteins, the generation of

00:13:08.500 lipoproteins. And again, just a Herculean feat for one organ to be involved in these four profoundly

00:13:16.980 important things. So look, I think if by now we haven't made the case for why everybody should

00:13:22.300 care about this organ, we probably never will. Let's talk a little bit about the history of liver

00:13:28.200 disease because I think there's a bit of an evolution here. This thing we're going to spend most

00:13:32.340 of our time talking about is a quasi-recent phenomenon in the last, depending on how far

00:13:37.760 back you look, but it's clearly not the dominant issue. So is it safe to say, Julia, that infectious

00:13:43.080 agents were the predominant driver of liver injury, you know, 100 years ago, 200 years ago? Is that

00:13:49.320 what really led to it or was it toxins in the environment? I mean, when people died from liver

00:13:54.240 disease 100 years ago, what was the cause?

00:13:56.760 Your question also hints at common popular conceptions of why does someone have liver

00:14:03.360 disease? So I think toxins, alcohol being the number one thing that we've studied since the

00:14:08.340 1700s, 1800s, and then the onset of viruses and the study of non-A, non-B, which eventually became

00:14:15.940 hepatitis C. So all of that to say the liver was this recipient of external harm. And so I think that

00:14:22.680 goes to show why we've sort of undervalued some of the natural resilience and endogenous effects of

00:14:29.960 its inherent metabolic function, because we've focused on derangements, which as doctors, we tend

00:14:35.700 to focus on the problem and try to treat the problem. But those perturbations in normal liver physiology

00:14:41.800 based on an exogenous agent leads to structural issues, leads to histologic issues. And that sometimes

00:14:49.040 limits us when we talk about the study of metabolic disease. For instance, if we perseverate on an ALT

00:14:54.440 or immunotransferases, that's probably not the best marker of understanding fatty liver disease or

00:15:01.880 metabolic dysfunction. And the framing around how we think about liver injury from an exogenous compound

00:15:08.260 or as a result of a metabolic derangement plays a role in understanding longitudinal progression of the

00:15:15.720 disease. Is it an external insult? And then taking care of humans, no one is in isolation. So

00:15:23.400 behaviors, environments change over time, habits change over time, and all of those serial perturbations

00:15:30.100 and how to monitor and follow those perturbations also inform how we're going to move forward from

00:15:35.960 our old way of thinking about how to measure liver disease injury, how to prevent it, and again,

00:15:42.240 how much time we have to intervene. So one of my favorite books I read in residency was the biography of

00:15:48.580 Thomas Starzl, who pioneered liver transplantation. So everyone who pioneered an organ transplant is kind of a

00:15:54.660 giant in the field, whether it's the pioneers Murray of kidney transplantation, or Shumway and cardiac

00:16:01.200 transplantation. Notice I omitted the guy in South Africa, not just because I forgot his name for the moment, but because I

00:16:06.880 think he sort of ripped off Shumway. But I think none of these figures was bigger to me than Starzl, in part because

00:16:12.280 I think it was the hardest organ to transplant. And this is true, not just technically, but I think perhaps

00:16:18.280 metabolically. At the time when Starzl finally succeeded, and when I say Starzl, really, I really mean is Starzl and

00:16:24.300 all of his colleagues, of course. If my memory serves me correctly, it was probably in the late 60s when they finally

00:16:29.140 succeeded in doing this. 67-ish. Yeah, that rings a bell. What was the dominant indication for liver

00:16:36.700 transplant? How often was it being done for an acute injury in that first era versus chronic injury that

00:16:44.760 became untenable? So I think whenever you're talking about a new intervention and surgeons are any high

00:16:51.180 risk taker for a new intervention, the indications are going to have to justify some of the risk. And so

00:16:59.020 acute liver failure, liver injury without failure would not be an indication. So there has to be

00:17:05.340 sort of a life-threatening situation for someone to justify the risk that's associated not with just

00:17:11.460 the explantation and implantation, but also the post-care. So indications at that time from a liver

00:17:18.600 disease perspective would be a little bit different than they are now. Well, now in the pandemic, alcohol has

00:17:24.900 really, really surpassed a lot of other more chronic indications that we thought were going to sort of

00:17:31.220 eclipse alcohol at this point, and that's behavior and coping mechanisms with stress. But alcohol-related

00:17:36.640 liver injury and then viral hepatitis, I'm talking about chronic sorts of chronic adult liver diseases

00:17:42.760 would be the top two. Same ones we've referenced before. But acute liver failure, paracetamol or acetaminophen

00:17:49.740 injury, most common cause of suicide attempts outside of the United States, King's College

00:17:55.360 criteria, how we've learned a lot about the function and dysfunction of the liver during acute

00:17:59.700 liver failure is all learned from those toxin-related exposures and acute liver failure.

00:18:05.920 What percentage of patients who overdose on Tylenol and who cause a fatal or what would be fatal injury

00:18:14.860 of the liver are able to receive a transplant in time? I assume it's a very small number.

00:18:20.480 It's small. I think Will Lee's work at UT Southwestern has really encapsulated this. So there's lots of

00:18:27.960 variables. And whenever we talk about studies versus real world, I'll just re-emphasize. In terms of

00:18:34.320 accessing liver transplantation, there's many logistic variables, including payment and social

00:18:41.360 supports. It's a complex decision. But for indications versus transplantation, at our center,

00:18:48.280 it's under 10% are due to acute liver failure. And a sub-fraction of those are acetaminophen injuries.

00:18:55.760 It's on the order of single-digit percentages if you look at most large centers.

00:19:00.500 You mentioned something a moment ago that I think was a bit unexpected. When I was in medical school,

00:19:06.800 we were told that hepatitis C was basically going to be the sole indication for liver transplant

00:19:14.180 by now. Meaning, you know, this is more than 25 years ago. Looking forward, hey, within whatever,

00:19:20.040 2025, virtually all liver transplant will be in response to hepatitis C. Maybe a couple things

00:19:26.260 happened that weren't anticipated. The first was an effective treatment for hep C. So I assume that hep B

00:19:31.880 is potentially a greater problem than hep C, although we have a vaccine for hep B. So I'm kind of curious

00:19:36.600 about the relationship between hep B and hep C. And then secondly, we'll come back to this, but I want

00:19:41.800 to hear a little bit more about alcohol-related injury as well, which seems to be on the rise as

00:19:47.400 opposed to the decline. So maybe we start with the hep B versus hep C distinction.

00:19:51.580 Yeah. I'll zoom out a little bit because so much of what we're talking about is limited based on what we

00:19:56.340 know. And the numbers of aggregate, large, well-done population studies where you're looking at all

00:20:02.620 comers, that's just not how we've been able to study diseases. We are now, but I think it's important

00:20:08.680 to understand why we look at things the way that we do, because it can be frustrating to patients to

00:20:13.520 not understand, hey, this is a soon-to-be eclipsing pandemic. Why are we still ignoring X, Y, Z?

00:20:20.760 So that aside, non-A, non-B, hepatitis C, we think of it being chronic. We think of it being

00:20:27.960 progressive. And again, I'm speaking to the pre-DAA direct acting antiviral era before 2014,

00:20:34.240 where it was a common indication for transplant, where it took time to actually discover what the

00:20:39.280 virus did, how it functions, how it results in liver injury, and how that liver injury is

00:20:45.160 progressive, chronic and progressive. With hepatitis B, it's a lot less predictable. One,

00:20:50.500 we have really good antiviral medications. Two, you named it, we have a very effective vaccine,

00:20:58.120 and that's a virtue of a population health sort of intervention. In the East Asian population,

00:21:03.740 which is oftentimes where we see hepatitis B, it's important to emphasize that the variability and the

00:21:10.460 progression of the disease is reassuring in the sense that we think that fewer people are going to

00:21:16.420 progress to advanced fibrosis, cirrhosis, need for liver transplant. But it's the one liver disease

00:21:23.560 that is an outlier in terms of oncologic potential. We see liver cancer develop in people with hepatitis B

00:21:31.240 independent of going through the progression to advanced fibrosis or cirrhosis. Our radar has to be

00:21:37.100 up to screen for cancer in people that have chronic, untreated hepatitis B. And the effectiveness

00:21:43.760 of antiviral treatment on the cancer potential is still an unknown.

00:21:48.080 I didn't know that, Julius. So let me make sure I restate it so that A, I know I'm correct,

00:21:52.660 and B, others hear it if they missed it as well. We didn't state this earlier, so it's worth

00:21:57.000 restating or we're stating that hepatitis B or C also increases your risk of hepatocellular cancer.

00:22:03.540 This is a bad actor. This is a very bad cancer. So part of the mortality here results not just from

00:22:08.940 the reduction of synthetic function in the liver, but from actual oncology. But then you just said

00:22:14.100 something that I didn't realize, which was, and I assumed that your probability of developing cancer

00:22:20.040 moved in lockstep with the extent to which your disease progressed. And what I think I heard you

00:22:26.980 say is that's only true with C. It is not true with B.

00:22:30.900 Right. So we're learning and we're starting to reframe how we think about metabolic dysfunction

00:22:35.260 as well when we think about the milieu within the liver and how injury is handled within the liver.

00:22:41.840 So our big comers, alcohol-related liver disease, chronic hepatitis C, mazeled, most of our thinking

00:22:49.380 is when that person moves towards advanced fibrosis, their cancer risk increases, where we start screening

00:22:56.900 for it when someone has cirrhosis. We screen for liver cancer and chronic hepatitis B independent of

00:23:04.220 their degree of scar tissue or injury. If I may just add to that, since we're just barely touching

00:23:10.220 on the cancer aspect of things, one that is a rare disease, relatively rare disease, that also has a

00:23:16.460 high oncologic potential is hereditary hemochromatosis. That's something, again, I get the biased point of

00:23:22.740 view of being referred cases that may not have been diagnosed early on. And so I see part of what I'm

00:23:30.180 speaking to is things that could have been intervened on earlier had someone known about

00:23:35.200 relative risk.

00:23:36.580 I probably knew this at some point. Is that true of every one of these, like Wilson's disease,

00:23:40.340 where you accumulate copper and, as you mentioned, hemochromatosis? The risk of disease moves with

00:23:46.020 the risk of parenchymal injury to the liver. Sorry, the risk of cancer, to be clear, the risk of cancer

00:23:52.200 increases with the risk of parenchymal injury.

00:23:54.240 Yeah. Parenchymal injury to a liver doctor, sort of the card-carrying metric that we

00:23:59.240 frame very highly is fibrosis. And that's our term for scar tissue. And so most of our cancer

00:24:05.400 outcomes are associated with what we call stage four scar tissue or cirrhosis. I'm cautious with

00:24:10.900 the use of staging because patients oftentimes relate it to cancer in the sense that a terminal

00:24:17.400 diagnosis and stage non-reversible lumen doom. Cirrhosis is stage four scarring of the liver,

00:24:24.620 but the natural history of cirrhosis is widely variable. It's not a death sentence,

00:24:27.740 nor is it an indication for transplant. It's an indication for increased monitoring.

00:24:32.180 Yes. And to be clear, you can have fibrosis long before you have cirrhosis, which means you don't need

00:24:38.980 to be all the way at, quote unquote, a terminal stage of cirrhosis to be at increased risk of cancer.

00:24:44.640 Correct. I know we will come back to this when we get into

00:24:48.540 NAFLD, NASH, cirrhosis, this continuum, but I want to try to stay a little bit further on the side of

00:24:55.840 what's going on at the basic level. So do you think, Julia, it makes sense to talk a little bit more

00:25:01.500 about the way that a healthy liver metabolizes nutrients in a eucaloric nutrient-appropriate

00:25:11.440 manner to then explain what's happening when excess calories are present or alcohol is present? I mean,

00:25:19.860 what do you think is the easiest way to explain what is happening in the pathology?

00:25:25.540 The pathology of what?

00:25:27.720 I'd want to talk about non-alcoholic and alcoholic fatty liver disease as two examples that are quite

00:25:33.180 ubiquitous. At least the way I've sort of talked about it with patients is maybe talking a little

00:25:38.820 bit about how the liver normally functions in metabolism and how VLDL works or triglycerides

00:25:45.180 and what happens when you start to basically create more fat de novo and all of a sudden you have an

00:25:52.060 inability to export it. My guess is you have a much more eloquent way to describe this, so I

00:25:56.180 don't necessarily want to impose my framework.

00:25:58.680 I think that probably we approach patients the same way. When you get the luxury of time and being

00:26:02.720 able to get somebody's story, it's looking at the liver in context of the development of various aspects of

00:26:08.680 their lives. And so why someone drinks excessively is as important as the actual toxin, especially one of the

00:26:17.440 beauties of the liver is its resilience. And so shy of more dense fibrosis, even in cirrhosis, largely

00:26:25.080 reversible and decades of potential time to intervene. The way that I think about it, and I think this often gets

00:26:31.840 forgotten, it's a general knee-jerk assumption when someone sees hepatic steatosis, so increased fat in

00:26:37.840 the liver, to assume that it falls within what we used to call non-alcoholic fatty liver disease that

00:26:43.600 we now call metabolic dysfunction-associated steatotic liver disease without sort of doing the detailed work

00:26:49.580 around alcohol. Why does this matter? Because you see dysregulated metabolism even with alcohol-related

00:26:55.500 injury. It is seven calories per gram, pure carbohydrate. And so when there is an excess

00:27:01.780 nutrient load that the liver sees, the mechanism, there's some evidence that the mechanisms early

00:27:08.100 on may be related, not exactly the same. But let's speak specifically to what's going on in the liver.

00:27:14.980 You have a liver, about 80% of the liver is hepatocytes. Those are the sort of primary liver cell

00:27:21.460 where your AST and your ALT live. Ordinarily they live in this sort of cuboidal cell that's working,

00:27:27.700 or hexagonal oftentimes is the way that we describe the whole lobule, that's working hard. And those

00:27:33.620 enzymes are basically immunotransferases that have a host of different activities. But until that cell

00:27:40.100 gets stressed and releases those enzymes in a detectable way in the bloodstream, we think that

00:27:45.860 the liver has some degree of resilience and function. So when you talk about what is happening in the liver

00:27:52.420 with both of these types of diseases, there's altered redox potential and there's free fatty acid

00:27:57.860 handling differences. So you mentioned, and I think that the glucose aspect of things is incredibly

00:28:04.580 important. And so when we think about a normal functioning liver for someone that has, as you

00:28:11.060 described, eucaloria, and then all of a sudden there's a relative excess caloric imbalance. So what they're

00:28:17.220 taking in outpaces what they're able to expend. And so there's nutrient excess that's happening.

00:28:22.980 The liver was never designed to store fat. And so we commonly think of an abnormality,

00:28:29.060 I'll speak specifically to Masold and its definitions, as more than 5% of the hepatocytes containing fat.

00:28:35.940 Usually subcutaneous fat is our component where processing of fat storage, but in a dynamic way,

00:28:45.140 is handled. But oftentimes when those compartments are overwhelmed, they start to deliver more

00:28:52.180 substrate to the liver. And so there's two big ways that the liver manufactures, or two big ways

00:28:58.900 in terms of liver fat metabolism. One is de novo lipogenesis. We think in most people that that's

00:29:03.940 the secondary mechanism. And it's the exogenous input through nutrition that supplies the majority of

00:29:10.260 the lipid. So de novo lipogenesis is manifested mostly with the triglyceride component. You

00:29:17.460 mentioned there's cholesterol, there's triglycerides, and there's phospholipids. And then you mentioned

00:29:22.180 lipoproteins, which I, in my mind, link to trafficking and metabolism of lipid molecules in terms of function.

00:29:30.020 But how the liver, and again, the beautiful nature of the way that we study it is oftentimes through

00:29:36.740 close collaboration with patients where any component is deranged. And so one of the areas

00:29:42.180 that I think we are starting to see now that we hadn't seen before is the presence, and largely this

00:29:48.820 is by virtue of technology, we have means of detecting increased hepatic fat independent of insulin

00:29:55.940 resistance or predating insulin resistance. And so the relationship between how the liver accumulates

00:30:02.980 triglyceride and starts to dispose of glucose is one that I think the endocrinologists have started

00:30:11.540 to or continue to dig a little bit deeper because we know that this relationship exists between insulin

00:30:18.260 resistance and liver storage of fat. But the exact mechanism and timing is still undetermined. It's

00:30:24.660 called bi-directional in a lot of ways. One of the junior scientists that I work with describes different

00:30:30.340 thresholds. So at some point, the insulinization of the liver leads to fat storage and that a second

00:30:38.100 threshold is crossed when you start to see decreased hepatic glucose production.

00:30:43.060 Let's talk a little bit about what hepatic glucose production actually is. I referred to it earlier,

00:30:48.260 obviously, which is that the liver is constantly titrating out. But again, worth stating how important

00:30:53.380 this is because you and I are not eating at the moment, and yet we're alive. Something miraculous

00:31:00.020 is actually happening given the glucose thirst of our brains. And all of the glucose that is being

00:31:07.540 supplied to our brains right now, as we have this discussion for the next hour or so, is coming from

00:31:12.740 our liver. Our liver is the thing that is meeting out that amount of glucose, which is kind of remarkable,

00:31:19.060 as I said, because it knows to not do too little and not do too much. So it can make glucose, it can

00:31:24.580 store glucose, and it can temper this output. First of all, anything that would get in the way of that

00:31:30.900 strikes me as incredibly problematic, especially on the low end. So we see in diabetes, presumably,

00:31:37.860 we have not just insulin resistance at the level of the cell, so you have a harder time disposing of

00:31:42.260 glucose peripherally, and that leads to an increase in glucose. But we also probably see an increase in

00:31:47.700 hepatic glucose output, which is where a drug like metformin that suppresses hepatic glucose output

00:31:53.060 becomes valuable. What's happening clinically when we see decreased hepatic glucose output? What's

00:31:58.980 true in the liver for that to be the case? Before hepatic glucose production goes up.

00:32:03.940 So at this point, what are the clinical observations? So if you look at our guidelines,

00:32:08.420 they'll have multiple ways of looking at insulin resistance. One that I'm quite fond of

00:32:13.060 is the HOMA-IR. So what is going on in the body at this time is a hyperinsulinemic state.

00:32:18.980 And whether or not you're seeing increased glucose is sort of this sweet spot that we're starting to

00:32:24.740 see increased triglyceride deposition within the liver, but not yet a compensatory response with

00:32:32.260 circulating hyperglycemia. And so what is going on at the level of the hepatocyte? And my sort of

00:32:39.940 obsession, what's going on with the lipid droplets that are associated with this precursor are unknowns

00:32:46.020 yet to be determined. When you look at somebody clinically and they show up with hepatic steatosis,

00:32:51.140 and you want to know where in the spectrum they are and how to counsel them to avoid the downstream

00:32:56.100 consequences that are potentially avoidable for them, you want to look at what is their relative

00:33:01.380 insulin resistance. So you are looking at circulating isolated insulin values and calculating either a HOMA-IR,

00:33:08.340 or some people do glucose tolerance tests, but you want to try to catch people in this window of

00:33:13.220 either early insulin resistance or not yet developed insulin resistance.

00:33:18.660 Dr. Justin Marchegiani Let's define for folks,

00:33:20.500 how are you defining steatosis? Is it being defined as at least 5% of the hepatocytes contain fat?

00:33:26.500 Dr. Amy Moore Yes. So we're looking at the aggregate,

00:33:29.620 5%, greater than or equal to 5%. Dr. Justin Marchegiani Okay. And how is that diagnosis

00:33:34.340 made? Is that typically made just through ultrasound or ever doing that with an MRI?

00:33:38.980 How do we go about making that diagnosis accurately? Dr. Amy Moore When we talk about such a prevalent

00:33:43.380 phenomenon like steatosis, we have to maintain practicality. So the vast majority is going to be

00:33:49.140 an imaging-based modality rather than something like a biopsy. It was originally defined based on

00:33:54.500 histologic evidence. But MRI, PDFF is costly and not necessarily that readily available. We have point of

00:34:01.940 care techniques that we use in our clinics that are based on ultrasound technology. A plain old

00:34:07.460 ultrasound that someone gets is generally not detecting steatosis at levels under 30%.

00:34:14.580 So an important take home is, you know, a negative ultrasound does not mean that you don't have

00:34:19.140 hepatic steatosis. Dr. Justin Marchegiani Can you say more about that,

00:34:21.700 Julia? So if a regular ultrasound needs a threshold of basically a third of the liver

00:34:27.700 has fat in it, that's a big threshold. Clearly, someone who's getting a routine ultrasound for

00:34:33.300 some other reason, their kidney and the tech just goes and puts the probe on the liver. What is it

00:34:38.900 about the technique or the imaging software or hardware that allows a dedicated scan to detect

00:34:46.260 with much greater sensitivity at that 5% threshold? Dr. Amy Moore For MRIs, it's proton related.

00:34:51.380 The proton density fat fraction has to do with basic physics and how reverberations occur with

00:34:57.060 different fractions. Water versus fat. Namely, for something that we use called vibration-controlled

00:35:03.540 transient elastography, it's point of care. It's something that a lot of liver doctors are fond of.

00:35:08.740 We'll talk about it probably later when it comes to sequential testing. It applies a calculator called

00:35:14.420 a controlled attenuation parameter to attenuate some of the echoes, some of the light signals that

00:35:20.100 the ultrasound is emitting in order to get to a more granular level of fat. How much? And this is

00:35:29.860 the measures of it are in the level of sound waves. So we're talking about decibels.

00:35:34.660 So when it comes to fat accumulation in the liver that results from a nutritional imbalance,

00:35:42.500 i.e., when a person is over-nutritioned, you basically have some combination of exogenous fat

00:35:53.140 making its way into the liver and even endogenous fat production, i.e. de novo lipogenesis within the

00:36:00.260 liver. But the net result is more fat is entering and staying in the liver than is exiting the liver.

00:36:07.300 Although, amazingly, in most cases, we also see a remarkable fat exodus from the liver

00:36:14.260 as evidenced by a very high VLDL and a very high triglyceride burden. In other words,

00:36:19.380 the liver is trying its darndest to get the fat out. And we measure this high amount of fat,

00:36:23.940 which might be a clue that there's a high amount being accumulated, correct?

00:36:28.100 That's correct. And I think the other thing to say is before the liver even sees that is you're

00:36:33.060 overwhelming your subcutaneous compartments too. They are shuttling free fatty acids towards the

00:36:38.420 liver because I always think about it in terms of where can we intervene as well. So that liver is

00:36:43.220 seeing increased fat, increased nutrients, and trying to handle it. I think the important point I'd also

00:36:50.420 like to make is because given the complexity of metabolism and the liver's desire to maintain

00:36:56.500 homeostasis, whenever you see anomalies, so outliers, those are very important. When you see people that

00:37:02.900 are not expressing circulating triglycerides that are higher, that don't have some of these

00:37:08.180 metabolic features, that's a tip to you as a clinician that maybe this isn't sort of garden

00:37:13.060 variety, metabolic dysfunction, fat deposition in the liver, and you might need to be thinking

00:37:17.460 about something a little bit more rare. But you're talking about something different than the obvious

00:37:22.420 and well-known race-based differences. So for example, even in situations of florid type 2 diabetes,

00:37:29.060 African Americans will rarely exhibit an elevated triglyceride level the way a Caucasian will and

00:37:35.140 you'll see literally a triglyceride of 400 versus a triglyceride of 90 in two people that are equally

00:37:42.100 insulin resistant. You're saying something different than that? Yes, I'm speaking much more to some of the

00:37:48.180 rarer causes that get lumped into a phatic steatosis where there's a trafficking, there's an export

00:37:55.460 problem and you lead to how does this come up clinically. So I put a probe on someone and I see

00:38:01.540 their BMI is 22. They have very little evidence of insulin resistance and their CAP score, something

00:38:08.420 that we use to grade fat is very, very high, 400. That's going to tip me off that potentially there's

00:38:14.420 a genomic familial hyperlipidemia. There is something that's going on that may be making their liver store

00:38:21.380 fat in an anomalous way. That's not reading the room in terms of metabolic risk. And the reason I

00:38:27.460 say that is because of the prevalence of the disease, it becomes important to sort of pick out

00:38:32.100 the folks that may not respond or be best served by some of our current recommendations.

00:38:38.340 Yeah. I had a friend who had, this is a case that you would have obviously solved with your eyes shut.

00:38:43.620 He did have elevated transaminases. I do want to come back and talk about transaminases by the way,

00:38:48.020 and clearly didn't fit the bill of anything lean, athletic, etc. It wasn't until he had

00:38:55.460 an MRI for an unrelated reason that they noticed the amount of iron accumulation in his liver. And

00:39:01.700 of course he had hemochromatosis that had somehow been previously undiagnosed. He had accumulated enough

00:39:06.980 iron in his liver that it was actually beginning to show these signs of injury through the elevation

00:39:11.220 of transaminases. So yes, that's one of the drawbacks, I suppose, of the ubiquity of all of this

00:39:17.540 liver disease besides the obvious, which is it sometimes makes it harder to identify the

00:39:23.540 zebras when there's so many horses everywhere. If you think about how we pick out the quote

00:39:29.540 unquote extreme phenotypes, I think about this a lot when I look at how we can better understand

00:39:35.700 some of the biological targets that are driving the disease. An easier way to do that is look at some

00:39:40.980 of the extremes. So the folks that don't have all of the metabolic risk factors, but do have

00:39:46.740 pretty aggressive disease. For example, lean people that are a normal body habitus and then manifest

00:39:54.020 rip roaring metabolic dysfunction, including steatohepatitis plus or minus fibrosis.

00:39:59.060 And back to your point of you described some racial differences. We talk a lot about ancestry.

00:40:04.980 And when you have ancestry distributions, for example, South Asians, same predominance that

00:40:11.620 you'll see with sort of lean diabetes, some of the Modi phenomenon that you are aware of,

00:40:16.420 you can see very, very aggressive forms of not just altered metabolism within the liver,

00:40:23.140 but aggressive inflammation and scar tissue, which is usually what is needed to sort of get

00:40:27.700 the attention of a lot of the liver folks. So injury, not just the accumulation of fat,

00:40:32.900 which is important, but it's much more important from a metabolic endocrinologic

00:40:37.220 perspective. And then we tend to perseverate on the people with a lot of liver injury.

00:40:41.300 Let's talk a little bit now about how ethanol is poisonous to the liver. And I want to be mindful

00:40:48.820 of the word poison because it's a controversial word. People get all bent out of shape. So feel free

00:40:54.980 to use whatever word you want. I mean, I sort of think the dose makes the poison. Everything is

00:40:59.540 technically a poison. Tylenol is clearly a poison. Whereas a low dose of Tylenol is a wonderful thing

00:41:05.380 if you've got a splitting headache or a fever, but at some point you exceed the capacity of the liver

00:41:11.860 to metabolize it. And it goes from being not harmful to deadly. So clearly that applies to everything

00:41:18.980 out there, including oxygen. So let's put the nomenclature aside. What is it about the

00:41:24.580 metabolism of ethanol that is problematic for the liver?

00:41:29.620 So again, let's go back to our friend, the hepatocyte and you have ethanol or alcohol

00:41:34.580 that starts to get processed. So how does the normal liver cell process this alcohol dehydrogenase?

00:41:41.140 You're going from alcohol to acetaldehyde. Acetaldehyde is then metabolized further and it eventually becomes

00:41:48.980 carbon dioxide water, ordinary type of moities, right? But where you start to see problems is

00:41:56.260 some of the redox potential when the capacity, and again, these are very variable. If you look at

00:42:01.060 populations, how alcohol is handled in various populations, and even just the dimorphic differences

00:42:06.580 in sex between men and women, how livers metabolize alcohol, that normal process can be

00:42:14.180 overwhelmed. And then all of a sudden you start to have peroxidation. And that's a feature that

00:42:18.900 we see in the non-alcoholic or the metabolic dysfunction that's not associated with alcohol

00:42:24.660 related liver disease. That's about 80 percent of the alcohol metabolism. There's another pathway

00:42:29.620 that's also invoked. But what we're talking about when there's alterations and injury and toxicity,

00:42:36.020 that's when you have the acetaldehyde behaving badly. And so it's behaving kind of like you're

00:42:41.380 describing as a toxin. It's attracting free radicals. It is attracting immune cells. It is

00:42:47.700 leading to fat deposition altered metabolism at the level of the cell. And so that's some of the

00:42:54.340 commonalities. Different enzymes are being used, but that's some of the commonalities when we look

00:42:59.460 histologically at somebody who's not using alcohol versus someone who is. There are some features that

00:43:05.780 you cannot distinguish histologically because the injury pattern is so similar. I'm not sure if

00:43:10.980 that's answering your question or not. It answers it, but of course poses many more. So let's unpack

00:43:15.540 that a bit. Again, I'll just try to translate it a little bit so that I make sure I'm understanding it.

00:43:20.260 But when we talk about the metabolism of ethanol, we have this enzyme alcohol dehydrogenase. Of course,

00:43:25.380 we know as some people genetically are lacking in that enzyme or don't have as effective a version of

00:43:31.220 it. These people tend to be incredibly sensitive to alcohol. They get beet red when they drink it.

00:43:36.180 In some regards, I guess they're largely protected from the toxicity of alcohol because they simply

00:43:39.940 can't tolerate it. But for most people, you go ahead and you metabolize it. And while the downstream

00:43:45.060 stuff is ultimately the same as the normal carbohydrates, basically CO2 and water, you get

00:43:50.500 acetyl aldehyde as an intermediary. I guess my question for you is, why is acetyl aldehyde toxic

00:43:57.780 is an intermediary? Does it stick around long enough to cause problems? Like why isn't it all

00:44:02.580 just being flushed to CO2 and water quickly? It's sort of like saying, when we metabolize

00:44:07.380 glucose, we stock that pyruvate before we go to acetyl-CoA and CO2 and water. You wouldn't think

00:44:13.140 of pyruvate being problematic unless it's stuck around for a really long time. So yeah, help me

00:44:18.340 understand why it is that, is it just any minor exposure to it is problematic, even if it's very brief?

00:44:24.180 It'd be hard to say, unless you had a system-wide, pretty diverse cohort to be able to say,

00:44:30.260 where is the system overwhelmed? But what we can say that it does attract inflammatory cells. So

00:44:36.420 there's something about it at a certain level to be determined that attracts, I kind of analogize it

00:44:43.620 to the lipotoxicity model in my favorite disease, metabolic dysfunction associated disease. There's

00:44:48.660 something about that moiety that makes it pro-inflammatory. And how the body, how an

00:44:55.700 individual and how that liver will handle the inflammation that's a resultant of the acetaldehyde

00:45:01.380 attracting free radicals and overwhelming the redox potential of that cell is one mechanism by which

00:45:11.140 injury is occurring. Know that not every cell is going to behave similarly. And so the relative injury of

00:45:18.100 some cells versus others, the compensatory damage and recruitment of inflammatory handlers, you know,

00:45:25.780 whether it's monocytes, macrophages or lymphocytes is also going to play a role. So we're starting to

00:45:31.220 get at some of the complexities that are extremely hard to tease out, unless you're thinking not just

00:45:36.180 molecularly, but as a liver as a whole. You also mentioned that there are, besides the obvious genetic

00:45:43.060 difference I gave people with and without alcohol dehydrogenase, polymorphisms. You also mentioned

00:45:48.900 that there are sex differences. I wrote about this somewhat recently. Maybe you could say a little

00:45:53.380 bit more about the differences between men and women in this regard. And then within sexes, I'm also

00:45:58.260 curious to hear about how much heterogeneity there is in the, both the capacity to metabolize ethanol,

00:46:04.180 and of course the susceptibility to its toxicity.

00:46:06.100 You know, the old studies, and this is why alcohol has been studied longer than any of the viral

00:46:10.820 hepatitis, a lot of the sex differences were just attributed to the fact that alcohol is a polar

00:46:16.340 compound, and so it's less soluble in fat. And women, body composition-wise, typically have more fat. And so

00:46:23.380 the relative damage that could be done was based on body composition. I don't know that that's

00:46:29.300 necessarily true, but it was an easy way to sort of explain some of the early differences at that

00:46:34.100 point. So when it comes to gene expression, again, you're going to have to look specifically at

00:46:40.500 premenopausal women versus postmenopausal women, and not just androgen components and estrogen

00:46:46.260 components, but also the upstream signaling of all of these. As far as I know, and I'm not an alcohol

00:46:50.740 expert, none of those have been teased apart in terms of sex differences specific to the premenopausal

00:46:56.340 woman handling of, it's 14 grams, you know, no matter what the alcohol component is, it's approximately

00:47:02.660 14 grams that we see. So how that liver and subcutaneous fat component and hormonal responses

00:47:10.340 to the compound acetaldehyde generation or other potential toxic moieties, those are all variables

00:47:17.700 to be studied. I mean, that's sort of what we kind of wrote about, which was that look,

00:47:21.460 it's historically been chalked up that the differences between men and women are size

00:47:25.140 differences. But I think there are differences in gene expression that play a much greater role

00:47:30.180 than size, which then leads to this next question, which is, okay, so you've got two people who both

00:47:34.980 weigh 85 kilos. So their size is comparable, their body composition is similar enough. Let's even grant

00:47:42.660 that they are metabolically comparable in health. They can have two very different responses and

00:47:48.100 susceptibilities to alcohol. I'm sure there are a lot of people listening who think, well, I'm one of

00:47:53.220 those people who can drink a lot and it doesn't seem to have an effect on me. Does that mean that alcohol

00:47:58.740 is less toxic to me? I'll give you my biases because a lot of people think that toxicity is only

00:48:05.060 occurring at the level of the liver. And we see in our, especially post-transplant, post-reformed

00:48:10.260 alcohol use, the effects on the brain, the effects on the heart, the effects on the pancreas, there's

00:48:15.540 a panoply of organs that can be affected by what's considered normal or moderate, less than moderate

00:48:22.260 alcohol intake. And so how someone is considering themselves not affected is also really important.

00:48:29.380 There's, of course, the psychosocial components as well. And then the big one that I think a lot

00:48:33.460 of people are failing to talk about, I know the World Health Organization came out with consensus

00:48:37.780 statements in 2023, is the oncologic potential to get a disruption and how to measure that and how

00:48:43.700 to mitigate some of those risks. So I think if someone's subjectively saying, I don't feel affected

00:48:49.060 from a central nervous system perspective, they don't feel like their sensorium is altered.

00:48:53.940 Sensorium, for us, when we grade hepatic encephalopathy, there are some mood changes

00:48:58.340 that happen. And so the CNS, either depressant effects or removal of inhibitions, some of those

00:49:05.300 effects are also, I think, socially acceptable CNS-related effects, but they're effects.

00:49:11.060 And I'm sure you get asked this question all the time at parties, which is, you know,

00:49:15.060 at what point does the dose of ethanol in grams per day or per week start to become problematic?

00:49:23.940 This is a topic we've written about at length, which is that we kind of reject the data that

00:49:28.900 says that there's a J-curve. We have not internally been convinced by the J-curve data, which is largely

00:49:34.740 epidemiologic and largely suggests that at very low doses, zero alcohol is actually slightly worse

00:49:42.740 than some alcohol. And then, of course, the risk goes up as drinks go up. But there's some sweet spot,

00:49:48.980 which, depending on the study, can be actually quite high for alcohol consumption to produce

00:49:53.940 the lowest all-cause mortality. Again, there are many ways to explain those data that I think are

00:49:59.700 a better explanation than alcohol is good for you at some dose. I think the Mendelian randomizations

00:50:06.660 point to point to the opposite, which is a monotonic change in risk that increases consistently from

00:50:13.860 zero and upward. But of course, this dose is still non-linear. This risk is non-linear with dose,

00:50:20.020 I should say. It begs the question then for people who want to choose to drink responsibly,

00:50:25.780 at what point do you say the risk is probably too great? If we're not going to be complete abstainers,

00:50:34.180 at what point do you tell somebody that's a little too much?

00:50:37.860 It's a loaded question because I'm thinking about more than the liver,

00:50:41.060 even though they might be approaching me with a liver-centric point of view.

00:50:45.140 So if there's evidence of injury, an injury, so the way that we liver doctors think about it,

00:50:52.340 our markers of necroinflammation, AST and ALT are not functional. They're markers of injury. And we think

00:50:59.060 of much more meaningful things in terms of being functional, albumin, synthetic function in terms

00:51:05.060 of coagulation, and then also glucose handling. So if you start to see, and again, with the patients

00:51:12.500 that we see, we have many patients that have a degree of hepatic steatosis and their only risk factor

00:51:18.420 is alcohol intake. If they're not having any dysregulated metabolism, they're not distressed

00:51:24.260 by this abnormality. And we're able to monitor them. And the net gain to them from all sorts of

00:51:32.340 inputs, including social inputs, is that their alcohol level is not causing major life events,

00:51:39.860 including effects on their family or things that maybe are harder to talk about. There's sort of a

00:51:45.060 permissivity to that. But it's just like supplement use. At some point, contaminated supplements or unknown

00:51:51.140 supplements may cause evidence of liver injury. So with an openness to, can you give this up if it

00:51:57.540 becomes problematic, either physiologically to the liver, to another organ, to relationships,

00:52:04.740 et cetera. So that's how we counsel people point in time. We also have all sorts of ways of looking

00:52:10.260 at problematic use disorders. The big driver for all liver diseases, parenchymal liver diseases,

00:52:16.820 is what is sort of the behavior and the motivation behind engaging some of these things. And that's

00:52:21.780 how the relational component with understanding why someone is doing what they're doing can really make

00:52:26.980 a big impact. Because two or five years down the road, when you ask them to give it up, because there's

00:52:32.020 a new breast cancer diagnosis, the risk of breast cancer is higher than the risk of liver disease for

00:52:36.660 most women who are consuming alcohol. So if they have a new cancer diagnosis and we're asking them to give

00:52:42.500 it up in that instance, or the patient themselves brings it up in terms of what disease modifying

00:52:49.540 changes can I make, can I implement in order to improve my lifespan? Those are things that we need

00:52:55.780 to go back to. What was the origin? What's the desire in terms of engaging some of these behaviors?

00:53:01.780 Humans are far more likely to give up something that they don't find beneficial, at least in my 14 years,

00:53:09.220 13 years of taking care of liver patients. Let's use a specific example. So you have an

00:53:13.460 individual that comes to you and says, you know, I consume alcohol socially. And if you go and talk

00:53:18.420 to my friends, family, children, they would all tell you it's not a problem in my alcohol consumption,

00:53:23.540 meaning there's no unintended consequence that is negative. It's all pro-social beneficial. And they

00:53:30.100 have a normal liver synthetic function, which again, you would expect that's a pretty late finding if they

00:53:34.820 don't their transaminases are normal. Again, we're going to come back to this. I want to put a pin

00:53:39.220 in that for everybody. We're going to explain in much more detail what transaminases are and what

00:53:43.140 normal is. You mentioned toxicity to other organs in as much as we can assert that normal kidney

00:53:50.020 function, normal cardiac function, all those other things. Do you say, look, the most sensitive

00:53:54.420 indicator I have that you might be drinking too much are your transaminases. And as long as those stay

00:54:02.340 below a threshold, which you're going to tell me, and all of these other factors look okay,

00:54:07.220 I'm all right with you drinking two glasses of wine an evening. Or are you still saying,

00:54:12.580 look, there are still things I can't measure. And even normal transaminases don't give me a good

00:54:18.180 enough confidence that you are not causing irreversible harm here. So I wouldn't use

00:54:24.100 aminotransferases as a good marker. I think more often we use a bedside imaging technique,

00:54:30.980 the vibration controlled transient elastography, because the sensitivity of picking up on

00:54:35.540 hepatic steatosis is higher than something. It actually takes quite a bit of derangement and

00:54:40.980 problematic drinking to derange your aminotransferases. And when you start to see

00:54:45.860 fat accumulation in the liver, early warning sign, potential downstream metabolic consequences,

00:54:51.620 potential inflammatory consequences, doesn't mean that they have to give it up. But I think it really

00:54:56.260 tattoos to the patient in their experience that there are measurable effects of even moderate,

00:55:02.980 what's considered social. And what's considered social is very, very variable. That's why it is

00:55:07.620 good for the audience members that are clinicians quantifying the use, especially now during and

00:55:13.780 post-pandemic. There have been just like the ALT has been perturbed based on environmental changes in

00:55:19.940 our population. So has the definitions of moderate use. So just going through that with patients can

00:55:26.740 sometimes give you a little bit more information about how they're perceiving their risk, which is

00:55:31.860 obviously if you're counseling someone about the impact to their life and whether or not something

00:55:37.220 would be wise to continue or not, you have to understand how they're perceiving risk.

00:55:41.940 How do you ask people specifically about that? We ask patients on average, how many drinks do you

00:55:49.300 have in a given week? And what's the variance of that? I assume there's a much smarter way to ask

00:55:54.900 this question. I'm so glad you're asking. So first of all, we define what alcohol is. Oftentimes what has

00:56:00.660 happened is one drink might be double the quantity that we're used to seeing. And so concentrations,

00:56:07.620 so I say one and a half ounces of hard liquor, five ounces of wine, 12 ounces of beer is considered

00:56:12.580 a standard drink. So that in and of itself gets some raised eyebrows from people because they don't

00:56:17.300 know about those quantities. So when we, and then I say, you know, ballpark, oftentimes people will say,

00:56:23.460 I don't have a problem with drinking. I don't drink every day. And daily drinking at a certain

00:56:28.100 threshold, we consider two drinks per day for men, one drink per day for women, and these are standard

00:56:33.540 drinks. What's considered the CDC definition of moderate alcohol intake. A lot of younger people

00:56:40.740 don't drink daily. That's a gross assumption, but it's much more of a binge type picture. And so

00:56:46.980 quantity over what period of time for those standard drinks is also what we ask. And then I also ask

00:56:52.900 what's going on in these situations that you feel is that you're with family gathered over the weekend?

00:56:59.220 Is it at home? In the pandemic, it was a lot of isolated drinking at home. And so that's where

00:57:05.860 we started to see some of the chemical changes, some of the imaging based changes, and then more

00:57:11.700 importantly, some of the social changes that happened with problematic drinking because the

00:57:16.100 slope can vary without an individual being aware. So I think it is important to quantify it.

00:57:21.860 The other tests that we oftentimes do as liver specialists is we measure sort of the longer

00:57:26.580 range metabolites, something called phosphatidylethanol or a PETH. And that measures,

00:57:32.740 it's a little bit more like an A1C than a rapid identifier, like an ethyl glucuronide,

00:57:38.100 but it gives us an idea and it's great in terms of moderate versus severe. And sometimes that gives you

00:57:44.820 an aspect, another angle to interview a patient. And again, there's a lot of shame around alcohol use and

00:57:51.220 what's going on in an individual at times. And so when you see really severe, heavy alcohol use,

00:57:57.380 but a self report of something far less severe, it's again, an opportunity to figure out what's

00:58:02.100 going on. How far back does the phosphatidylethanol or PETH study go? If the A1C looks back about 90 days,

00:58:09.780 how far back does this look? It's on the order of weeks. It's not something that lasts 90 days. We

00:58:14.980 usually think of it in one to two week timeframes. Is that a readily available test? Can you order

00:58:19.380 that through LabCorp or is that a super specialty test? I think it's available in all the Quest and

00:58:25.140 LabCorp for sure. Very interesting. Okay. Let's come back to these transaminases. So everybody

00:58:33.220 listening to this, Julia has had a blood test. Certainly if they've listened to this podcast,

00:58:37.380 they know to look at that AST and that ALT. You already alluded to them a little bit, but I want to go

00:58:43.400 back and talk about it. People have heard me say this. They get called liver function tests,

00:58:48.600 but they're really not proxies for liver function. So what does AST do in a cell? What does ALT do in

00:58:57.240 a cell under normal working physiologic, everything is hunky dory circumstances? And what happens that

00:59:05.080 leads to their elevation in the serum, in the plasma, when things go awry?

00:59:10.680 So AST or fispartate aminotransferase, ALT, alanine aminotransferases are enzymes and they are

00:59:19.560 usual working enzymes to help process things that go through your liver. So normal liver physiology,

00:59:26.380 two supplies, blood supplies to the liver, one from the portal circulation. That's what drains your guts,

00:59:31.880 all the nutrients that you take in that are processed in your intestines. They get shown to

00:59:37.960 your liver through that portal system and then the hepatic artery. That's another system. It's one of

00:59:42.500 the many forms of resilience of the liver. It's that it has two blood supplies. The blood percolates in

00:59:48.400 this very porous milieu, showing all the hepatocytes, what they have by way of nutrients, toxins, etc.

00:59:56.220 And then those things are filtered through hepatocytes and there's lots of enzymes. These are enzymes that we

01:00:01.640 typically measure. And so when we talk in there also exist in muscle. So whenever we get some rare cases

01:00:07.860 of elevated aminotransferases, we have to make sure that they're coming from where we think they're

01:00:12.300 coming from. That's an aside. But the definitions of normal have evolved over time. And sometimes

01:00:19.280 different thresholds are set for different diseases. I don't want to get too much in the weeds of how the

01:00:23.660 hepatologists think about things. But oftentimes, you know, earlier days, we sort of said 19 and 30 were our

01:00:30.140 thresholds in terms of women and men, what we expected their aminotransferases, what we would

01:00:36.340 consider abnormal. The lab, any one of your audience members who's looking at their own labs,

01:00:41.920 the labs oftentimes flag them now when they're in the upper 40s or 50s. That's a population-based

01:00:47.780 perturbation that I think you've talked about a lot. And so what is the definition of normal? How much

01:00:54.140 does this matter? When it is red, when it is flagged as abnormal, how much should you get anxious about

01:01:00.780 that? In general, again, we want to harp on the fact that the liver is extremely resilient. And so when you

01:01:07.460 get an isolated abnormality, what that is telling you is that liver cell, that hepatocyte, is now under so

01:01:14.980 much stress that it's a now what we call necroinflammatory marker. Necro being cell death and

01:01:20.340 inflammation mostly, what is going on around that liver that tells us I'm under stress and I'm now

01:01:25.660 bursting. And so when that liver cell bursts, it releases these enzymes into the bloodstream, and

01:01:30.540 that's what we're checking with blood tests. The question is, why are those enzymes elevated? And is

01:01:36.340 it an isolated phenomenon? You had mononucleosis, you're over your virus, or is it something that's

01:01:42.380 continuing over a period of, we define it as around six months in terms of chronic liver disease,

01:01:48.360 where those elevations have persisted is when we start our workup. Why is this inflammation and cell death

01:01:55.140 happening in this liver? Is it due to our top three in adult, alcohol, viral hepatitis, or mazold, mazold

01:02:02.800 being the most common globally and in the country? And is there something more rare that we are missing? Is there

01:02:09.480 a potential that there is something treatable, that there is something reversible at this earliest stage of

01:02:16.280 laboratory detection? So you've reiterated a point that I've tried to make several times over the past

01:02:24.060 several years, which is that we never want to confuse a laboratory's standard for what is normal for what

01:02:31.540 might be optimal, because the laboratory is simply reporting on a population distribution. And if the

01:02:39.220 population's health is deteriorating over a 50-year period of time, well, that isn't necessarily a

01:02:46.860 reason we should hold ourselves to the standards of unhealthy people today. So as you point out,

01:02:52.620 I just had my labs done last week, so I forget. I think LabCorp has a cutoff of 40 or 44 for the AST

01:02:59.600 and the ALT. But if you went and looked at what was the cutoff, and presumably that's the 80th or 90th

01:03:05.880 percentile of the population. If you went and did that exercise 50 years ago, you'd see a much lower

01:03:09.840 number, probably 25 to 30. So is it that the liver has changed from an evolutionary perspective in 50

01:03:16.060 years? Probably not. It seems more likely that we've seen more drift towards liver injury. But if

01:03:23.340 someone just came to you and said, Julia, I don't want to hear about what the population does. Tell me where

01:03:28.660 you think the right place to have those transaminases be as one more piece of the puzzle, not the only piece

01:03:36.660 of the puzzle. We're going to talk about all the pieces. But just if we're looking at this piece of the

01:03:40.920 puzzle, where do you look and say, boy, I'm really happy? You're not just okay, you're optimized.

01:03:47.800 So I'd say for the vast majority, and I'm going to speak across age and across race, ancestry,

01:03:53.340 and biological sex, I would say I'm generally a telepatient that they're doing well when it's

01:04:01.720 under 30. Whether or not they are post-transplant or have very, very early stage disease, that's all

01:04:10.020 comers. When do I start to get alarmed? It's when it's persistently in what we think of fold

01:04:17.220 differences in liver disease world. So when it's consistently in that one and a half to two times

01:04:22.600 the upper limit of normal, so when it's in the 50s and 60s, it again tells us there is something

01:04:28.440 potentially going on in the liver. And whether it's a cause, if it's a result or a cause of other

01:04:35.340 symptoms in their body, other disease processes, is when we start to pursue a workup. So again,

01:04:42.360 it's very difficult for me to just stick on one value, but because you put that in front of me,

01:04:47.820 I would say under 30. Let's talk a little bit about the differences between the ALT and the AST.

01:04:54.660 So again, I'll just share with you, I'm trying to get a free hepatology consult during this podcast,

01:04:58.340 by the way. My AST is always significantly higher than my ALT. So last week on Friday,

01:05:06.240 when I had my blood drawn, my ALT was 21, but my AST was 34. And that's actually quite typical of

01:05:18.920 my blood draws. My ALT typically hovers between about 20 and 25, and my AST typically is above 30,

01:05:29.320 but shy of 40. I'd love to hear your thoughts on that. Feel free to ask me any questions you want,

01:05:34.700 if I can elucidate clarifying information. I realize that your audience is also fully capable

01:05:40.640 of reading our guidelines and things like that. So I do want to say when I use a gestalt of around

01:05:45.680 under 30, that's a thumbnail expert sort of after I've made a diagnosis and someone's already part of

01:05:53.240 an intervention. I do want to make sure that thresholds for sort of workups, et cetera, we still

01:05:58.040 think about being around 40. So it's also pertinent to you. So the questions I would ask just with that

01:06:03.960 pattern in and of itself is, curiously, did you work out within 24 hours of that laboratory assay?

01:06:11.360 And if so, what type of resistance work or muscle work did you do?

01:06:15.420 Yes. I went to my doctor in the afternoon. I had already done a two-hour workout in the weight room

01:06:22.000 that morning. That blood draw was probably at noon. I was in the weight room from eight to 10.

01:06:28.620 And I'd say, Peter, you know, have we ever drawn blood on you on a non-workout day on a rest day?

01:06:34.960 Yes. I would still see the same pattern if I drew that blood first thing in the morning,

01:06:39.020 but it would still be within 24 hours of a workout because I would have lifted

01:06:42.820 or been on my bike or been rucking the day before. So if your question is, have I done a blood draw

01:06:49.860 with more than 24 hours of no exercise? Probably not. That's one thing I would be curious about.

01:06:57.280 I would be curious if you had ever had a CK done, a creatine kinase, just to look if there's any

01:07:02.700 evidence of muscle breakdown. Yes. Anytime I get a CK done, let's pretend that the threshold of

01:07:10.720 abnormal is 200. I'm typically right about there. And I'm, again, looking at you,

01:07:17.500 knowing a little bit about you and making some assessments just based on body composition and

01:07:22.780 potential risks, the line of questioning may be very different with someone else.

01:07:27.020 But I do drink alcohol, just so you know. Yep. I was about to go there next. So can you also tell

01:07:32.680 me about not just that one lab draw from last week, but when your labs are done in relationship

01:07:38.900 to alcohol intake and if you're able to quantify that? I wish I could say I was more thoughtful

01:07:44.040 about this, but I'm one of these guys that never likes to cram for the test. So I try to never

01:07:50.640 change behavior before my blood tests. Like it's not like I don't drink for a week or something.

01:07:56.540 So what I think I can safely say is any blood test I've had is probably a reasonable sampling

01:08:03.200 of my typical pattern of alcohol, which is, I'm mindful of what we described as the doses.

01:08:11.440 So five ounces of wine, 12 ounces of beer, one and a half ounces of liquor. Based on those metrics,

01:08:20.880 I think I'm probably in the six to eight drinks per week category, virtually never more than two in a

01:08:34.160 day. I don't know. That's a moderate drinker, I suppose. That's classifies as moderate alcohol intake.

01:08:40.920 Assuming that your laboratories are assessed in this non-cramming sort of way. Let's say you had

01:08:47.660 about 30 grams of alcohol before within 24 hours. Yeah, I would say there's a decent chance that

01:08:54.560 there were 30 grams of ethanol in my system 12 hours prior to that, but it's possible that it would

01:09:00.940 have been 36 or 48 because I wasn't trying to game the system. Sure. I think I would also ask,

01:09:07.800 is there anything that's bothering you about your blood tests? What is your impression of them?

01:09:14.340 Well, I think the only thing that quote unquote bothers me is I look at many of my patients who have

01:09:19.720 ASTs and ALTs in the teens. And I think, I wish my ASTs and ALTs were in the teens,

01:09:26.800 but I also realize in that case, most of them are women, a very slight build. And so there may be a

01:09:33.760 component that's just muscle mass related. By the way, I should also point out my creatinine is

01:09:39.440 always quite high, but my cystatin C is very low. Renal function is great. If you look at my EGFR by

01:09:47.940 creatinine, you would think it's about 70. Whereas by cystatin C, it's about 110. And I know that we see

01:09:55.200 that a lot in patients who exercise. So there may be that component.

01:09:59.200 It's the injury component to the muscle, not just having a big build. A muscular build is not

01:10:04.240 necessarily injurious in terms of detection of immunotransferase elevations, to be clear.

01:10:10.020 The most common one that we talk about are like marathon runners with rhabdo, et cetera.

01:10:13.940 It's not just having the component of muscle, but also just the workout and the injury component,

01:10:20.520 and recovery component. Yeah. The other thing I wonder about, of course, are supplements and

01:10:27.460 medications. I do take one medication that at least in patients, we often see an elevation of

01:10:34.860 transaminases and that's ezetimibe. So I guess I could do the test of just stopping ezetimibe and

01:10:42.240 seeing, does that have any effect? These days with patients taking lots of medications, I'm trying to

01:10:48.560 think if there's any supplements. I'm a little lean on supplements these days. And the ones I take

01:10:53.860 tend to be pretty straightforward things like fish oil and magnesium and things like that. Like I'm

01:10:58.060 not kind of taking too many sort of funky supplements that we've seen in patients where

01:11:02.840 they can really sort of have negative impacts on liver function tests. So you're going down,

01:11:08.400 was curious whether or not your team had questions about too, which is the drug-induced liver injury.

01:11:12.620 And that can include not just pharmacologic agents, but also supplements. That's where we see a lot

01:11:17.980 of elevations in immunotransferases. So whether or not it's you or an individual who's taking

01:11:24.880 recreational substances, that's also something that we use in the differential for that sort of

01:11:30.660 laboratory assessment. The reason I want to know about context is there are some individuals that

01:11:37.760 perseverate if their fat fraction is 7% and they're living an optimized life. And the number itself

01:11:44.500 is problematic to them, they think something is potentially abnormal or wrong. So in your instance,

01:11:50.660 rather than withdrawing the ezetimibe, I might say, let's do labs. I'd throw it out to you.

01:11:57.220 Would you consider doing labs after a series of rest days plus no alcohol intake to see you're doing

01:12:04.660 a controlled experiment? So I have patients that do this all the time. They'll withdraw from alcohol

01:12:08.760 for six weeks to see what is the effect on their fat fraction. They're just curious. Most of the time

01:12:13.980 you can't predict what your reaction will be. You might think, oh, my ALT will be 20 and I don't care

01:12:18.860 that much. I enjoy alcohol too much. But there's something to be said about a measurable effect and

01:12:24.660 how motivating that is. That's something I've been humbled by a lot with some of our imaging-based

01:12:28.240 studies. So assuming that those are your influences, the things that I would think about

01:12:35.380 is not just the framing of who you are at this point in time, but what has potentially happened

01:12:42.960 in the decades of life before. And that's where I would do something like a fibrosis assessment.

01:12:49.540 It could be a quick calculator, something like a fib four, et cetera, to figure out whether or not,

01:12:55.320 even with those numbers being as good as they are, there's some degree of accumulation of potential

01:13:01.920 stiffness or injury to the liver. Because all those time points between when you measure them,

01:13:07.660 there's things that are going on in your liver and the rest of your body, of course. But we don't

01:13:11.540 necessarily need a biological measurement by way of a biochemistry in order to determine what those

01:13:17.180 are. How valuable do you think the... So again, we use LabCorp for much of our labs. I think the last

01:13:24.300 time I did a blood test, so not the one I just did last week, but maybe three months ago,

01:13:28.100 I did one where we did the full LabCorp NASH score thing. Again, this was sort of just me being me,

01:13:35.140 and I don't really think I have fatty liver disease, but I was like, look, we order this

01:13:39.420 test on patients. I'm curious as to what it shows to me. And so it came back negative. There was no

01:13:43.840 evidence. The scores were very, very low. I have to be honest with you. I've kind of forgotten how

01:13:48.020 the score is generated. Can you explain how that score is generated? Because I suspect it's going to

01:13:52.380 be used more and more frequently now as clinicians are becoming more and more aware of screening for this.

01:13:57.480 And again, I won't go specifically into... Because there's so many. There's a whole serum-based

01:14:02.260 biomarker milieu and imaging-based. And some of them were derived based on hepatitis C population

01:14:10.040 and then subsequently validated in metabolic dysfunction. So if we're looking at something

01:14:15.160 like a fibrospect, et cetera, something that's been studied in NASH, you're usually looking at

01:14:20.540 something that's got components of collagen matrix, of metalloproteinases, et cetera.

01:14:27.200 And so it's looking at measurable CK18 fragments, et cetera, that are detectable in the blood that

01:14:34.680 suggest not just fat accumulation in the liver. So that's diabetes risk, as I describe it to patients,

01:14:41.240 but then subsequent inflammation, cell death, and eventual scar tissue, decades to development.

01:14:47.620 And so are you picking up on any... I think most of the proprietary serum-based tests will give you

01:14:53.440 like a steatosis score, like a fat score, and then they'll also give you a fibrosis score.

01:14:58.160 I think those of us that take care of a lot of livers rely a lot less. We use our bread and

01:15:03.540 butter hepatic function panels, which are not functions necessarily. But then we also use a

01:15:08.780 lot of imaging-based tests because they're so much more sensitive rather than these biomarkers that

01:15:13.620 leave you with a lot of intermediate risk. It's really hard to counsel patients with that type of

01:15:18.360 information.

01:15:18.880 Okay. So this is very, very good to hear. So what you're basically saying is, look,

01:15:22.780 and now let's shift from me to an actual example of a patient. So we have a patient who's very

01:15:27.760 persistently got transaminases in the 40s. So they're not quite there to trigger a full million

01:15:33.640 dollar workup, but there's something not normal. We're going to be politically incorrect and say

01:15:37.540 that's not normal. And there's something pathologically going on, even if it's very,

01:15:42.120 very low grade and doesn't pose an immediate threat to them in any way, shape, or form. But hey,

01:15:45.660 we're in the business of medicine 3.0, not medicine 2.0. I don't want to wait until there's

01:15:49.680 a problem. If we get one of those NASH scores and it comes back zero, you're saying, Peter,

01:15:54.240 you're not out of the woods yet. There's a lot of nonsense that can be going on there.

01:15:58.720 We didn't talk about GGT. Should we mention GGT? Does that at all factor into your thinking

01:16:02.560 beyond AST and ALT?

01:16:03.940 I'm just going to speak very sort of clinically relevant here. GGT, alkaline phosphatase measurements.

01:16:09.580 So one of the things that we notice is that in kids, the development of NASH looks

01:16:14.260 different histologically than in adults. There's a lot to be said about what we know and what

01:16:18.260 we don't know. And so the pattern of liver injury, if we were to look at pure liver tissue

01:16:24.040 under a microscope, we usually have all these zones. And the zones, when we're doing detective

01:16:29.080 work as to why is Peter or his relative's liver test abnormal, and we're coming at it from a

01:16:35.800 histologic lens, where the activity is in the liver sometimes gives us a mini differential.

01:16:41.060 And for kids, the activity of fatty liver disease typically behaves like other chronic liver

01:16:48.140 diseases. So it's what we call portal-based. So it's around the portal triad, which is a

01:16:53.600 functional unit of the liver. The liver in many ways is beautiful and worthy of respect,

01:16:58.840 but its architecture is really elegant. And so the portal-based diseases, autoimmune diseases

01:17:04.160 there, hep C localizes there, but we see a lot of the changes in children around that portal

01:17:10.040 area. In adults, we see it much more around the central vein. So this drainage vein around the

01:17:16.020 middle of that hexagon that I described before. You see fat, you see inflammatory cells. There are

01:17:22.460 these things called ballooned hepatocytes that we and pathologists love to perseverate over. And it's a

01:17:28.160 precursor to cell death. It's like a hot air balloon. It's shaped as a stressed out cell that's

01:17:33.780 pre-epototic. And so when we see that type of injury pattern around the central vein,

01:17:38.480 that's more typical of what we call adult, what we used to call NASH, but now call MASH.

01:17:43.440 So how is this relevant? So around the portal diseases, we see much more of the GGT, alkaline

01:17:49.600 phosphatase, things that affect the bile ducts. And so we oftentimes with pediatric fatty liver disease,

01:17:56.480 we'll see elevations in the GGT, alkaline phosphatase, not necessarily to the point of having an elevated

01:18:02.520 bilirubin or a plumbing problem, but those are some of the laboratory, again, looking at a whole bunch

01:18:08.400 people over a long period of time, just pattern recognition. We also see higher degrees of

01:18:14.180 elevation in aminotransferases, AST and ALT in kids and adolescents than would be predicted

01:18:20.660 necessarily from an adult. Again, so many degrees of variation that we can describe clinical

01:18:26.340 observations to you, but it doesn't necessarily get at the mechanism or the driver as to what's

01:18:30.100 causing those differences.

01:18:31.520 That's actually really interesting. I didn't know that. I did know that there was a slight

01:18:35.420 difference in the pattern between children and adults, but I didn't realize that it was

01:18:39.960 anatomically that distinct and that it resulted in a differential pattern of enzyme secretion.

01:18:46.940 So again, yet another reason why it's so easy to be fooled. So let's now go back to the way in

01:18:54.160 which you want to see an ultrasound done. Because frankly, even just from the standpoint of our own

01:18:58.640 practice, I want to make sure we are relying on the gold standard. And I want to make sure we are

01:19:04.480 absolutely not missing this, whether the injury, the inflammation, the fibrosis is the result of

01:19:12.520 alcohol or nutrient or something else. I worry that if we're just relying on ASTs and ALTs and

01:19:20.060 NASH scores and things, we're running a bit of a risk here.

01:19:23.820 The framing around how to deal with the relative risk and the anxiety provoked or alleviated by negative

01:19:30.360 testing and sort of a modicum of humility that a whole bunch of negative testing doesn't necessarily

01:19:35.080 mean that nothing ever bad will happen. I do a lot with genomic analyses. And depending on how

01:19:40.120 targeted the testing can be, a negative test does not mean nothing is ever nor will be wrong with you.

01:19:46.600 Sometimes folks get anxious and it's more sort of an off-ramp. I don't necessarily think that that's

01:19:51.980 your audience. I don't know. But I always like to, again, understand the psychology behind

01:19:56.340 why people are interested and how they're going to utilize that information. So all that aside,

01:20:02.500 if I were to see a patient and oftentimes, very, very often for our early stage disease,

01:20:10.980 so non-serotic, non-portal hypertensive, non-transplant, they're very early stage.

01:20:16.160 They are referred because of an imaging abnormality. Absolutely no blood test abnormality.

01:20:21.600 The two most common referrals for a hepatologist are abnormal immunotransferases or abnormal imaging.

01:20:28.080 And again, these are not the super sick people. And so the abnormal liver imaging may be a reflection

01:20:33.300 of hepatic steatosis. The error we want to prevent anyone who sees something like that is just a

01:20:40.440 knee-jerk reaction that that is naffled and mazled. And not to forget about asking about the biggest

01:20:46.240 differential, which is alcohol, and then also when to invoke some more rare biochemical involvement.

01:20:52.320 That's where just talking to your patient is going to give you a lot of information.

01:20:56.000 For my people who do not drink alcohol, who present with an abnormal image, or are interested in sort

01:21:04.140 of being proactive about their liver health, it boils down to the conversation. What are their risks?

01:21:10.180 Do they have metabolic risks? Do they have habit risks in terms of either recreational drug use or

01:21:17.120 pharmaceutical agents? Methotrexate being one that needs monitoring, liver-based monitoring.

01:21:23.220 But if I were to get a snapshot of the liver and their overall health, we always start with a basic

01:21:28.340 blood test. That's what you have described already, including aminotransferases. And then whether or not

01:21:34.900 a liver image is warranted. And so when we advise population at the population level for people that

01:21:42.840 are not specialists, we advise those clinical risk factors. So what is their metabolic health,

01:21:49.540 BMI, metabolic syndrome risk factors, cardiometabolic risk factors, habits, what are their social habits,

01:21:56.240 exercise, and engagement around different forms of nutrition. And then also, in addition to their

01:22:02.220 hepatic function panel, calculating something like a Fib4, where those functions have been elevated over

01:22:08.020 a period of time, or that person may be male over 50, plus or minus insulin-resistant diabetic.

01:22:14.900 Those are some of the things that tell us that person needs secondary testing. And I hardly ever will

01:22:20.940 refer for an ultrasound, because most of the time that has already been done already. Threshold for

01:22:27.540 detection, as we mentioned, was around 30-33% to pick up on hepatic fat. A lot of it will depend on

01:22:33.480 what is available to you around you. And so the tools that are price-performance-based,

01:22:39.540 VCTE, and then ultrasound elastography, our radiology colleagues have picked up on some of the

01:22:45.780 different ways that you can attenuate the ultrasound in order to calculate fat fractions.

01:22:50.380 And so those can either be in a doctor's office or a radiology-type facility. For very sophisticated

01:22:57.960 testing, again, MRI, PDFF, per-tendensity fat fraction, that's what we use in research studies,

01:23:03.600 and they're increasingly available clinically. MRIs are very good at detecting and quantifying

01:23:09.800 the amount of fat, but also, depending on the protocol, amount of iron. And when you add what

01:23:16.720 we call an elastography component, so what does that mean? That means you're not just

01:23:20.880 shining a light or changing the imaging signal intensity to the liver, but you're also creating

01:23:26.660 vibrations. A normal liver, soft like a sponge. I'm sure you've operated on many people. When it's

01:23:32.200 filled with blood, it's a little bit more dense. A cirrhotic liver or one that's full of scar tissue

01:23:36.540 is much harder, like a brick. And so all of these elastography-based techniques, whether it's

01:23:43.000 MR elastography or vibration-controlled elastography, are literally shaking the liver.

01:23:48.740 They're sending vibrations across the liver and saying, is that vibration, as it's coming back,

01:23:53.580 being detected more in a sponge-like fashion or more in a brick-like fashion? And those scores,

01:24:00.000 typically we walk away with two scores, a fat score and a scar score. And that scar score matters a lot

01:24:05.680 to us in liver disease world. The fat score is the one that's easiest to modify. If you give up

01:24:11.620 drinking, if you were to lose a modest amount of weight, again, if depending on how you see lipid

01:24:18.840 related risks from a cardiovascular health perspective, very often a statin or a lipid

01:24:25.820 lowering compound results in a tiny elevation in an aminotransferase. And when we're looking at

01:24:31.760 net-net cardiovascular risk, we give blessings in the same way that we give blessings to chemotherapy

01:24:36.840 induced liver injury because we're prioritizing what the overall risk to that human is. I've gone

01:24:43.660 off on a little bit of a tangent, but that's just sort of how I frame how to view an individual

01:24:48.520 that's coming to me for overall liver health. That is not including family history, first degree

01:24:53.580 relatives, and cancer potential. I think the big thing that we need to talk about that we don't

01:24:58.440 necessarily talk a lot about is metabolic risk and cancer. And so oncologic risk in addition to

01:25:05.280 metabolic risk is something that we're seeing more and more of. And again, not in a causal way,

01:25:09.680 but in a disease association, especially in the young way.

01:25:13.440 Okay. A lot of things I want to double click on there, Julia. So let me just ask a few seemingly

01:25:17.920 unrelated questions. When you use the term vibration controlled elastography and ultrasound

01:25:22.460 elastography, are they being used interchangeably or are those two different tests?

01:25:25.600 Two different tests. There's many, many different types of tests. The proprietary name of the

01:25:31.140 Echosense machine is called FibroScan. You'll hear that talked a lot about among liver doctors.

01:25:36.920 That is point of care. You get an image generated at the time you see the patient and it uses both

01:25:42.480 ultrasound-based technology for the fat score and then the elastography vibration technology

01:25:47.340 for the stiffness. It's a measure of liver stiffness. There's errors, but it's generally

01:25:52.040 widely studied, well-validated across different groups, including people with a lot of subcutaneous

01:25:57.540 tissue. I'd say it's not technically feasible in about 8% to 10% of my patients. Shockwave

01:26:03.360 elastography, ultrasound elastography are typically done by radiologists, as are MR elastographies.

01:26:10.540 Every site, every pavilion, every place is a little bit different. Sometimes like for my center,

01:26:15.680 they don't unbundle an MRI from the elastography. So from a price performance, availability,

01:26:22.380 when I talk to general, to either internists or endocrinologists, becoming familiar with

01:26:27.500 one or two tests and using them will help train that sixth sense as to, am I missing something?

01:26:35.240 Is this person best served by this test? Or is this something that I need to sort of refer for

01:26:40.420 expertise on? The list of tests are huge and the elastography component can be either MRI-based

01:26:46.660 or ultrasound-based.

01:26:49.520 Unrelated, you mentioned twice now recreational drug use. Can you say a little bit more about which

01:26:54.280 recreational drugs might be the driving feature if you're seeing otherwise unexplained elevations of

01:27:01.880 LFTs?

01:27:03.120 Yeah, I think this came up a little bit, I think, when we talked about the viral hepatitis.

01:27:07.020 If your doctor asks you not just about what you're doing currently, but what you may have done in the

01:27:11.520 70s or 80s, when we talk about recreational drug use, that's oftentimes a risk factor. Injection drug use,

01:27:17.600 IV drug use for intranasal cocaine that is shared between different individuals. There's a ton of

01:27:23.240 people with undiagnosed hepatitis C that are picked up on screening exams. And the only thing we find

01:27:28.440 is drug use in the late 80s, etc. Back in the day before we screened blood products as well, again,

01:27:35.580 it's really in sort of the seventh, eighth decade of life that I still see women that may have had a

01:27:40.540 hysterectomy. So contaminated blood products. I'm just thinking through all our questions that I have

01:27:45.160 to normalize for our patients. Dental work abroad, contaminated types of things are risk factors

01:27:52.300 for various forms of viral hepatitis. That's where that comes from.

01:27:56.540 Yeah, got it. It's not that current use of pick your favorite drug, marijuana, is necessarily

01:28:02.620 hepatotoxic.

01:28:04.100 There are cannabinoid receptors and we come up against this question infrequently, but no,

01:28:09.760 it's not in terms of what you're asking about.

01:28:11.600 Okay. And then again, you mentioned the use of lipid lowering agents. I would say the most

01:28:18.560 predictable manner in which we see an elevation of transaminases is indeed with the addition

01:28:24.980 of statins, especially if combined with Zetia. So I know that the general consensus is that unless

01:28:36.680 the elevation exceeds one and a half, maybe two X, the upper limit of normal, it's deemed not

01:28:44.380 clinically relevant. I'm not sure that's what I heard you say though. What I think I heard you say

01:28:49.620 is the benefits outweigh the risks. And I think those are two different things. In other words,

01:28:55.880 if a person takes Crestor and Zetia and their transaminases pre-therapy are in the 20s and

01:29:04.600 post-therapy they're 50, I hope there's a reason they're taking Crestor and Zetia. And I hope that

01:29:09.800 that speaks to a risk reduction that's significant with respect to ASCVD. But we shouldn't conclude

01:29:15.600 from that that their liver is happy, should we?

01:29:17.460 No. And I think this is where we sort of get into the full differences. If you're looking at a

01:29:22.100 change from 19 to 25, 19 to 30, you're still within the range of normal. I think most people

01:29:28.520 would say risk benefit favors continuing on that lipid lowering agent. If you're persistently

01:29:36.160 elevated, and we've gone so far as to like look with biopsies, et cetera, and in very rare circumstances,

01:29:41.600 is there actual liver injury that's happening with some of these drugs? And I can count on one hand

01:29:47.260 how many times we've seen demonstrable liver injury that we think is associated with one of these

01:29:53.780 lipid lowering agents. The real summary point is that there's so many alternatives that oftentimes

01:29:59.420 that don't induce or cause elevations that are well tolerated and have a either more potent lipid

01:30:07.780 lowering effect or better tolerated by that person. So it depends on degree of elevation within the

01:30:13.340 bounds of what we expect is sort of the upper limit of normal, or is there some evidence of liver

01:30:18.340 injury going on? And is there an alternative? Yeah. I mean, we tend to be very aggressive on

01:30:23.060 this, Julia. We don't really tend to like to tolerate elevations of AST and ALT. And as you said,

01:30:29.080 we obviously today have far more tools in our toolkit to get people off those drugs if that's what's

01:30:34.040 happening. Let's now talk again about kind of this nomenclature change that has occurred over the past

01:30:39.000 year. So I think for people listening to us right now, they're going to be very familiar with the

01:30:44.160 term NAFLD, non-alcoholic fatty liver disease and NASH, non-alcoholic steatohepatitis. But you've now

01:30:52.100 alluded to it several times that there's a different term you're using, MAZLD. So first define the term

01:30:58.980 and secondly, and perhaps more importantly, explain why the people far smarter than me have decided to

01:31:04.560 make this change. There's got to be a good reason for it. I think a big component is we're listening

01:31:09.000 to patients a lot more and trying to incorporate their thoughts about how we label their disease.

01:31:14.480 So that's one. So defining the disease, when we talk about MAZLD, this gets at some of the problems

01:31:21.580 that we had with NAFLD. It was defined by what it wasn't. So not only was non-alcoholic fatty liver

01:31:28.520 disease non-alcoholic in the alcohol component, but you had to go through a laundry list of things that it

01:31:33.920 wasn't. It weren't well explained by the name. And so it left patients confused. It's a compendious

01:31:39.800 name. It's hard to say. We didn't really get around that with the new naming. And it didn't

01:31:44.360 hint at the underlying physiology, which is metabolic dysfunction, what we spent a lot of

01:31:48.260 time talking about earlier. What prompted the change, there are several things, but the terminology

01:31:53.600 alcoholic, it was reflected differently in different global populations. Some global populations

01:31:59.320 really liked the non-alcoholic because it was clearly not alcohol related. And they felt that

01:32:05.240 alcohol was very stigmatizing. But a lot of the US population and Western population felt just having

01:32:10.820 that term in there was quite stigmatizing. A common, common scenario that we have with people who do not

01:32:16.980 drink alcohol at all and are found to have liver disease is that they are labeled alcoholic by their

01:32:22.500 friends, by their families, by doctors. There's just a natural assumption that if you have liver

01:32:26.560 disease, that it must be a result of alcohol. So the patient point of view was a big one.

01:32:32.620 Even with NAFLD and NASH?

01:32:34.640 The terminology alcoholic in and of itself. There's also stigmatizing feelings that were named with the

01:32:40.560 term fat or fatty. And so that's some of the rationale behind changing it to the steatotic as opposed to

01:32:47.900 there was an interim name of metabolic dysfunction associated fatty liver disease. And again,

01:32:54.980 patients are now involved in a way that we probably should have, not we probably, we needed to in the

01:33:01.000 past. Not all impressions reign similarly in different parts of the world. So one is adherence

01:33:08.320 to what is the actual underlying pathophysiology. And then along with that, so now we have an umbrella

01:33:14.060 term called steatotic. Steato just means as a Greek for fat, steatotic liver disease. And MASLD is one

01:33:19.720 group underneath that, metabolic dysfunction associated steatotic liver disease. We now have a

01:33:24.980 category. I think one of the issues with renaming is that we're actually taking into account what

01:33:29.320 humans do. And they may have metabolic dysfunction, but they also may be drinking moderate amounts of

01:33:34.100 alcohol. So we call that metabolic alcohol liver disease or MET-ALD. We have a category for alcohol

01:33:40.360 related steatosis. We have a category for monogenic. More and more we're discovering abnormal,

01:33:46.840 particular autosomal recessive conditions that are associated with increased fat in the liver.

01:33:53.340 And then what we, our least favorite term, cryptogenic, in terms of as yet unknown, but has

01:33:59.540 fat deposition in the liver. You know, one of the things we didn't talk about that we oftentimes have

01:34:04.440 to do with our patients is go through a list of all their medications, because some medications are

01:34:08.420 known to be associated with fat deposition in the liver. The mechanisms vary, but that's also something

01:34:13.620 that if you are patients, if you're listeners, and if you're clinicians who are following, that is a widely

01:34:19.300 available in terms of what is known, and there's resources that we can supply.

01:34:24.020 So while it sounds incredibly confusing, Julia, it is more granular than what we used to have. What we used

01:34:31.380 to have was AFLD and NAFLD. So either you're getting all this fat in your liver because you drink too much

01:34:37.920 alcohol, and that fat accumulation is leading to fibrosis. And if that fibrosis isn't halted,

01:34:44.600 it's going to lead to cirrhosis. Or you're getting too much fat in your liver because of overnutrition.

01:34:52.360 And we went through the endogenous and exogenous differences. That fat itself is inflammatory,

01:34:57.980 just as all sources of fat that exist outside of the subcutaneous space are, whether they be visceral or

01:35:03.800 peripancreatic or all sorts of things, right? Perinephric, all of these things are pretty

01:35:08.800 painful. And that kicks off the cascade. And what you're saying now is, no, no, no, no, come on.

01:35:12.780 This was a gross oversimplification. And there are lots of pathways that get us here. And they're not

01:35:18.180 even mutually exclusive, right? I mean, how many people are consuming alcohol? And as a result of

01:35:24.560 that, or independent of that, frankly, are also over-consuming calories. And so they have

01:35:30.640 excess fat accumulation from a nutritional perspective, plus the alcohol toxicity and

01:35:35.540 all of these things are leading to this. I think the subset I most want to focus on at the moment

01:35:40.560 is the side that is more related to nutrition. Because in many ways, this is, you've alluded to

01:35:50.320 this already, which I think is that in North America, we would place the metabolic-associated

01:35:58.080 disease, even above hepatitis and alcohol-associated disease. Did I hear you correctly?

01:36:04.080 In terms of overall prevalence or risk for transplantation, it depends on what your

01:36:08.160 endpoint you're asking about. Prevalence.

01:36:09.740 Prevalence, yeah. In terms of all comers, prevalence of disease, yes. Not just the U.S.,

01:36:14.340 but globally. And it's also the one that disproportionately affects children.

01:36:19.260 If you think about the exogenous influences, for sure. It varies, but most children do not get

01:36:24.360 exposed to medications, alcohol, or some of the other hepatotoxins until they're teens.

01:36:30.560 And so I want to now understand this progression more. So we'll kind of narrow our scope a little

01:36:35.500 bit to just talk about the metabolic association. So let's talk about the pathophysiology. So we've now

01:36:41.380 got a patient who just triggers diagnostic criteria. And I assume that the diagnostic criteria

01:36:46.400 are some combination of the right clinical picture. So part of that is a diagnosis of exclusion.

01:36:52.900 We don't believe you're consuming too much alcohol. We've ruled out hepatitis. We've ruled

01:36:57.120 out pharmacologic toxicity, et cetera. And you fit the clinical picture of a person with metabolic

01:37:03.420 syndrome. But I assume you don't have to have metabolic syndrome. I'd like you to clarify that.

01:37:07.940 So you're insulin resistant with or without metabolic syndrome, and you hit the 5% threshold

01:37:13.660 on your FibroScan or whatever test we've used that has a high enough degree of sensitivity.

01:37:18.880 That qualifies you as having Masl-D, correct? Yeah. So you're going through sort of the

01:37:24.360 diagnostic algorithm that we are hoping to do a better job of educating the population about. So

01:37:29.680 it's not just exclusion of those things, but it's picking up on what our current technology,

01:37:34.960 our means for patients to reach out to either a biopsy or imaging that's ingestive of steatosis.

01:37:40.100 Let's just start there. And then you start working through this process. I think I mentioned this

01:37:44.840 earlier, a lot of hepatologists sort of downplay the metabolic components of livers just because of

01:37:50.560 the history of the nature of liver disease and how we've studied it. But the cardiometabolic risk

01:37:55.200 does not require metabolic syndrome. Metabolic syndrome is important to pay attention to,

01:37:59.840 particularly if we're looking at quick clinical grab bag things that should make you think that

01:38:05.360 that person has a risk factor for NAF. For sure, metabolic syndrome increases the risk for having

01:38:11.280 the inflammatory phenotype, the one that we think progresses, again, unintervened upon, unmitigated.

01:38:17.500 From a Masl-D definitions perspective, how we get at staging of disease and progression

01:38:26.100 is dependent on multiple risk factors. The take-home point to what you're asking in terms of teasing

01:38:33.200 out cardiometabolic risk, we have all the parameters that are listed and they vary a little bit by

01:38:38.360 ethnicity. We're much more sensitive about definitions of obesity and metabolic risk across

01:38:43.360 different ethnic backgrounds that were not well described in our previous definitions. So any one

01:38:50.600 of those cardiometabolic features will start to push you into the category of metabolic dysfunction

01:38:56.220 associated steatotic liver disease or Masl.

01:38:58.580 It's really interesting. I sort of envision a world in which we move so far beyond using something

01:39:04.580 like MET syndrome as the all singing, all dancing diagnostic criteria. And I say that with all

01:39:10.580 great respect and appreciation for the work of someone like Jerry Riven, who even brought this to

01:39:16.480 the attention of people 30 years ago or 40 years ago through syndrome X. But when you think about how

01:39:22.840 crass it is to say, well, you know, when your blood pressure finally hits this and your waist circumference

01:39:29.040 finally hits that and your glucose level hits that, that's when the trouble begins. I mean, imagine a

01:39:33.360 world in which once your liver fat hits 2%, we're paying attention. Because even though at 5%, you now

01:39:39.500 have this disease, that doesn't mean that 2% of your hepatocytes accumulating fat is necessarily a good

01:39:45.300 thing. In other words, you could really start to take an organ-centric view of metabolic health.

01:39:50.860 And if you could really only look at one organ, I think you've got to start with the liver.

01:39:54.520 Again, I'm a bit of a hepatophile. That's my bias, which obviously you share, but it really is the

01:40:01.160 mothership. It's got to be the canary in the coal mine for when things are going wrong. And so to me,

01:40:07.120 the idea that we should be doing scans on people, again, a fiber scan, it seems like a totally

01:40:13.240 reasonable idea. It's relatively low cost. And if it gives us any insight, even before you trigger that

01:40:19.420 threshold, that strikes me as far more useful than looking at something as anodyne as hemoglobin A1c,

01:40:25.580 which is so prone to error. By the way, the other point I want to get is a sense of prevalence. You

01:40:30.080 said it's the most prevalent, but just to put some numbers to it, what fraction of the people listening

01:40:34.780 to us today in this podcast, assuming they are representative of the population of the United

01:40:40.400 States, that's probably not a fair assumption, but what percentage of the people listening to this

01:40:44.680 without their knowledge might have mathldy or athldy? 25 to 35%, those are pretty conservative

01:40:51.740 projections. We can get a lot of information. And one of my mentors, he's a surgeon who did a lot in

01:40:57.660 terms of metabolism outside of the liver, said, I wish we could get all the CT data. Granted, it's not

01:41:03.440 the best imaging data from airports so that we could really get some estimates of prevalence, because

01:41:08.840 that's a good way to look at everybody that's coming through a population. We don't recommend

01:41:13.160 screening from a fatty liver disease or steatonic liver disease perspective yet, but even if your

01:41:19.160 audience is relatively healthy, and one of the reasons that I agreed with your prior riff on how

01:41:26.040 unsophisticated some of our current ways of thinking about things are, understandably, given some of the

01:41:31.420 costs associated with it, but how much that underserves a lot of very proactive patients who can handle a lot

01:41:37.880 of health information and make and implement meaningful change. It really underestimates the

01:41:43.060 capacity of having a test. You know, oftentimes people will check it out. Doctors or advisors will

01:41:48.680 check out and say, we can't do anything about this. Therefore, there's no relevance in checking.

01:41:54.840 There is a lot of relevance to the majority of our patients in terms of understanding that they're at risk

01:42:00.740 for something and how to implement longitudinal changes, not just to themselves, but families eat

01:42:08.100 similarly. Families exercise similarly. When we counsel an individual, I have many, many, many patients

01:42:16.420 who do not fit the standard phenotype. That's why I like to see patients in succession, because it really

01:42:22.500 does change the way that you frame risk, quantitative and qualitative risk across diverse populations.

01:42:28.880 But to your point, your audience, even if they themselves don't have it, I'd say 100% of them

01:42:36.680 know someone in either their family or their close circle who does. And I can say this because as soon

01:42:42.560 as I give a talk like this, everybody starts to identify themselves as having it, but not knowing

01:42:48.660 what to do about it. I want to just touch on one thing before we go further down that, which is

01:42:53.040 at what point is it important or how does one go about doing some of the other dotting of I's and

01:43:01.480 crossing of T's? Tom Dayspring, a lipidologist that works with us in our practice, mentioned some of

01:43:07.320 these liposomal acid, lipase loss of function, basically sterile accumulation disorders that can

01:43:13.720 masquerade very similarly histologically and biochemically. But of course, it's a totally

01:43:18.840 different disease. You've already alluded to several of these conditions. At what point should

01:43:25.560 one be looking at the zebras when they see all the hoof prints on the ground, given the prevalence

01:43:33.660 of up to a third of the population actually just has metabolic disease associated with fatty liver

01:43:40.840 accumulation? So if you're frontline general clinician, either, and this could be anyone

01:43:47.420 that's not in a, when I say specialist, I just mean specialist from my tiny corner. So either a

01:43:52.220 gastroenterologist or a hepatologist, if you are a primary care, an intensivist, endocrinologist,

01:43:57.700 cardiologist, and you're seeing this, this is the point of having colleagues, expert referrals and

01:44:02.780 people to reach out to when you're starting to think about rare causes. I think the most common

01:44:08.580 reason people reach out is when do we need a biopsy. It's very, very obvious that people look at

01:44:15.080 metabolic risk, they do their viral hepatitis screens, and we don't expect them to do alpha-1

01:44:20.240 antitrypsin phenotype testing initially. When someone is an outlier, they're lean, they have elevated

01:44:27.920 ALT, they've got a stiffness that puts them in moderate range, halfway to cirrhosis by the age of 35,

01:44:33.540 we need to involve a specialist in terms of what's going on. Because the reason is some of

01:44:40.120 the downstream testing, cascade testing for families, whether it's genome sequencing versus

01:44:45.420 genotypes versus targeted genomics versus some of the molecular diagnostics that we do with

01:44:51.660 histology, you're going to want some of the expertise that comes sort of free of cost by referring to a

01:44:57.080 center where they see some of the zebras. Do we see people identify zebras out there? Yes.

01:45:01.860 But most often, again, when this is all you do and it's what you love to do, your sixth sense is

01:45:07.340 being trained on what are the reasons to think about outliers. We're all humbled. We all are

01:45:12.640 surprised by people that surprise us with diagnostics, but oftentimes we come to it in an indirect sort of

01:45:18.860 way. So all that to say, many of the rare zebras that we pursue genomic testing on, if you're

01:45:25.460 identifying through a lipid profile and liver-based screening that they're already an outlier, that's

01:45:30.480 the reason to refer. That's helpful. And again, just bringing it back to kind of the standard case,

01:45:35.840 which I realize to the hepatologist is very common and is not typically the person that's walking in

01:45:42.140 your door, right? You're not typically seeing somebody with MAFLD minus cirrhosis who doesn't

01:45:48.780 have any other diagnosis unless it progresses and becomes problematic. But given that that is just an

01:45:55.760 enormous volume of people, I definitely want to spend some time talking about, A, what are the

01:46:01.640 most important things to be doing besides the obvious? And we'll discuss the obvious. Are there

01:46:05.060 any treatments on the horizon even as it progresses to steatohepatitis and before it gets to cirrhosis?

01:46:12.060 Are there any deficiencies in a person's diet that can play a role in this? Are there any other

01:46:18.060 predisposing factors that people need to be aware of? So we'll start back at the beginning, which is

01:46:21.700 the traditional therapy for this is weight loss. Weight loss is the most important tool that's

01:46:29.100 going to improve metabolic health. Maybe at the population level, that's true, but we should also

01:46:34.620 talk about exercise, sleep, and things like that. But things that improve metabolic health should

01:46:40.040 improve MAFLD. Would you add to that? Would you put a finer point on that?

01:46:44.400 Yes. Specifically, the building blocks of good health, you've named them, exercise, sleep,

01:46:48.800 and nutrition, but they're the ones that are sort of least studied. So the evidence that we have to

01:46:54.380 talk about histologic changes, and again, I want to be very clear, we're using histology as a surrogate

01:46:59.460 marker for outcomes that are sometimes 5 to 50 years down the road. And so a lot of the evidence that

01:47:06.840 I'm citing is based on histology, where the natural history studies are yet to be borne out. So with a lot

01:47:11.840 of humility towards the cardiovascular endpoints. So for the most part, the average person you're seeing

01:47:17.780 with MAZL-D is much more at risk for cardiovascular-related outcomes and malignancy-related

01:47:23.640 outcomes from their metabolic health than they are for liver-related risks. About 30% of my patients

01:47:28.840 self-refer. So they read their own report, and they convince their doctor to refer to me. They're not

01:47:33.020 necessarily super high risk at all. Exactly the same types of patients that you were talking about,

01:47:37.820 but they are proactive. So I don't want to dismiss patient-centered lifestyle intervention.

01:47:43.540 So micronutrient, macronutrients, those are things that we usually involve in specific certain

01:47:49.960 circumstances. So post-bypass surgery for some individuals, short gut syndrome, that's when we

01:47:55.900 start to think about choline deficiencies and some of the things that your audience might be reading

01:47:59.800 about either in preclinical testing or clinical testing. When we think about precision exercise,

01:48:05.880 precision nutrition sort of formulation for an individual, again, context of disease, context of life.

01:48:12.900 And so if a person already has relatively moderate amounts of low glycemic intake food, the things

01:48:20.920 that we want to sort of really regulate and why a lot of patients hear fatty liver disease and assume

01:48:26.780 the confession that I get a lot is, I don't eat that much fat. When it comes to metabolism, this is,

01:48:32.680 again, what we've played into, what we've talked about a lot, it's glucose handling. So a lot of it is

01:48:37.760 exogenous carbohydrates and trying to switch into smarter burning, sort of the slow burn carbohydrates

01:48:43.980 or complex carbohydrates. So we do spend some time talking about that. A lot of patients want very,

01:48:50.840 very detailed information as they should. But a lot of that comes about in meetings with either

01:48:56.340 someone who is of the nutrition sciences. And part of that is we need to know their day-to-day intake

01:49:02.260 and make it culturally appropriate. If we tell you to take something in that's completely outside the

01:49:07.380 bounds of what you normally intake, that's not really easily implementable for everyone's life.

01:49:13.140 So I always spend my time, doctor time talking about exercise and doing an exercise assessment,

01:49:17.980 physical activity assessment. This may sound gendered, but a lot of my female patients,

01:49:22.040 especially with lean NAFLD, are low in the muscle component. Muscle's typically quite hard to build

01:49:27.980 after the age of 60. So we spend a lot of time talking about increasing resistance work,

01:49:33.000 combination activity of a lot of single moms who are working very hard and don't necessarily have

01:49:38.000 that much time to dedicate to exercise. So we talk about combination aerobic and resistance activity.

01:49:43.540 We talk about increasing, and this is part of healthy aging. We see a lot of people become more

01:49:49.360 insulin resistant with aging as they become more sarcopenic, again, even lean individuals.

01:49:54.200 So figuring out what someone's baseline level of activity is, for some people,

01:49:58.920 it's a walking prescription. They're doing nothing. They're quite sedentary. It's a walking

01:50:02.380 prescription, increasing their aerobic activity and building habits. So that's where the behavior

01:50:06.660 motivation aspect of change really is very, very critical. So again, nutrition component,

01:50:13.000 I outsource a bit to a registered dietician with detailed information. There's a lot to be said

01:50:18.440 about this. The one thing that I will bring to your audience if they're unfamiliar is the impact of

01:50:23.460 coffee. I don't know if you've brought this up yet, in terms of liver health and coffee. So

01:50:28.200 again, we haven't isolated. There's some metabolomic studies we can point to when it

01:50:32.760 comes to caffeine, but coffee, and we're talking about black coffee or limited added sugar and added

01:50:39.660 milk components, has been shown to be beneficial for multiple liver diseases and fatty liver disease,

01:50:45.640 hepatitis C, fibrosis, even HCC. Again, there's many reasons people do not drink coffee,

01:50:51.220 and we are not recommending it as a prescription, but up to three cups of coffee has been shown in

01:50:56.700 multiple studies now. It's part of the European guidelines and made it into the American ones as

01:51:00.900 well in terms of anti-fibrotic effects and good metabolic effects as well. So that's one very

01:51:07.360 specific nutrition fine point that I can add to what you're saying about metabolic liver disease.

01:51:14.660 Julie, I've got two follow-up questions on that. With respect to coffee, do we have a sense of what

01:51:20.380 component of the coffee it is? And obviously, if it's caffeine, that has one set of implications.

01:51:26.580 But if it's polyphenols or things like that, then it also has a huge implication as far as the form of

01:51:32.140 the coffee. So a highly filtered drip coffee versus a French press, you're going to have totally

01:51:37.940 different amounts of those polyphenols making their way in. So I'm sure everybody, myself included,

01:51:42.880 who loves coffee, is asking the question, what do we know about the constitutive components

01:51:48.500 responsible for that benefit? And how should that impact our coffee drinking choices?

01:51:53.600 The short answer is not enough. As I hearkened to earlier, in terms of the granularity of nutrition

01:51:59.720 detail, huge opportunity. In terms of metabolomics, caffeine is a signal that when given caffeine in

01:52:07.480 and of itself, it does not mimic some of the effects that we observe. So that's not one thing.

01:52:12.300 Like many things that we talk about with nutrition, extracting a nutrient versus taking it in its natural

01:52:18.340 form are two different components. And so the methodology of coffee extraction and the caffeine

01:52:25.980 component, the instances of tea, a lot of cultures drink much more tea than coffee, including green tea.

01:52:32.420 These are all areas for further exploration. So I wish I had a more detailed answer for you,

01:52:37.280 but we don't have that yet.

01:52:38.840 The times I've looked into this, I've come to the conclusion that the more of the coffee bean

01:52:43.980 you're ingesting, the better. And so when in doubt, I opt for a French press because it's the least

01:52:50.240 filtered and I'm kind of getting the most of everything. Again, there's no rationale to that other than kind

01:52:55.380 of my teleologic two cents. The other nutrition related question I have for you is the role of

01:53:01.240 fructose specifically. And to be more clear, what I really want to understand is at isocaloric levels,

01:53:11.420 do we believe that fructose is more injurious than glucose, i.e. two very similar molecules that happen

01:53:23.240 to have very different paths of metabolism. And there has certainly been a lot of discussion,

01:53:27.860 and I myself have largely subscribed to this, that in the case of what we historically called

01:53:34.180 NAFLD, we really want to eliminate liquid sources of fructose. So if we're trying to get patients to

01:53:41.620 change their diet, yeah, by all means, keep eating your berries and your fruit, but get rid of the

01:53:47.360 smoothies, get rid of any sugar-sweetened beverages, not just because of their caloric content, but

01:53:54.000 because of that huge bolus of fructose that is hitting the gut. And then as you described,

01:53:59.720 heading through the portal circulation to the liver. So what do we know about that today?

01:54:04.640 The evidence around fructose, it's been studied in kids and adults, specifically high fructose corn

01:54:10.780 syrup and some of the more processed forms. And again, taking something in isolation, much easier to do

01:54:16.700 in animal models than in humans. But the first thing I would say is any study that you're looking

01:54:22.280 at, most of the mechanism for any type of liver disruption comes through an insulin resistance

01:54:28.660 pathway. So you would have to tease apart the presence or absence of overweight and obesity,

01:54:34.340 and the presence or absence of insulin resistance as the mediating, the big driver of whatever you're

01:54:39.740 observing in the liver. When studies have been done looking at that, and I think there's only one or two,

01:54:44.540 there's no net difference. There's a couple of studies that have been done that look at liver

01:54:49.280 exposure from fructose, not parsing out those. And again, these are population level data type

01:54:54.660 interventions. Then you do see evidence of liver injury, more significant activity. And by that,

01:55:00.980 I mean inflammation plus or minus scar tissue. Yeah. My reading of this literature is that it has been

01:55:07.100 very difficult to disentangle the relationship between the macronutrient and, for example, weight

01:55:15.840 loss. In other words, if you look at studies that have removed all fructose from the diet and have

01:55:22.160 actually demonstrated a remarkable amelioration of what was called NAFLD, the patients still, I say

01:55:28.720 unfortunately, I say unfortunately from the scientific standpoint, they lost weight. And so even though

01:55:34.840 these were meant to be studies that were eucaloric, just taking fructose out of a person's diet

01:55:40.000 presumably led to less spontaneous consumption. I think there are lots of great mechanisms for why a

01:55:45.880 high fructose diet leads to overeating. And so while that's maybe a great outcome, A, we don't know if

01:55:51.800 that's really sustainable in the long run. B, it doesn't answer the mechanistic question, which we so badly

01:55:57.660 want to answer. And so what I'm hearing you say is you do not specifically counsel people to eliminate

01:56:05.820 fructose from their diet other than that being part of an overall general dietary pattern. In other

01:56:12.160 words, if you're advising people to eat less and move to lower glycemic foods, that often comes with a

01:56:17.940 pattern that is consistent with what I just described, that's going to be lower in all forms of fructose that

01:56:24.160 come from refined sources. So when we get into specific recommendations, it's got to be dialed

01:56:29.780 in for the individual and what they have capacity for at that time. The range of patients that I see,

01:56:34.320 some people can hire a personal chef and a personal trainer. The vast majority of my patients cannot.

01:56:38.840 So if the effort to eliminate a specific component causes so much distress to the average person,

01:56:46.480 that's a lot. That's a lot of mental work. And to isolate one particular component, it's much easier

01:56:51.760 and implementable to say avoid processed foods. So if you're buying from a podega versus buying from a

01:56:58.040 grocery store in New York City, where is your source? The best way to study this would be in

01:57:03.260 areas where the government or some regulatory body has excluded some of the high fructose corn syrup and

01:57:08.960 processed foods. There are communities that do that. So if you want to dial down on population level

01:57:14.940 effects, that's probably the best way to study it because humans doing what they do be very,

01:57:20.020 very difficult to longitudinally exclude a single component over the long haul,

01:57:25.200 just given the nature of how humans interact with their environment. Completely doable from

01:57:29.600 a mouse model perspective. But what we know about fatty liver disease, Mazel, Nafold, any way that you

01:57:35.260 study it, the translation from preclinical to clinical, let alone phase one to phase three,

01:57:39.960 does not always borne out with the biology, given the beauty of the liver and its homeostasis.

01:57:44.820 I want to talk a little bit about GLP-1 agonists, at least the two most popular ones that are out

01:57:50.800 there today. So semaglutide and trisepatide. Obviously, they have a profound impact on weight

01:57:56.240 loss. They generally tend to have a very favorable impact on insulin sensitivity as well. So it would

01:58:03.220 seem to me that one could make the case today that the most effective drug we have for treating

01:58:09.640 NAFLD, formerly NAFLD and NASH are indeed these drugs. What is your view of that and what have

01:58:16.040 you seen clinically? Let's start with my view. So in terms of when to bring in these drugs and what

01:58:22.800 you're actually treating with it, I tend to go based on published evidence and what we have data for and

01:58:29.460 what we have approvals for and anything that's not being used in that context that we're specific

01:58:34.800 about why. So if you have someone who is a known diabetic, it is low-hanging fruit to reach for one

01:58:42.580 of these agents. Again, when there is weight to be lost, a certain percentage of patients can't afford

01:58:48.780 to lose weight, especially some of the muscle loss effects that are also associated with these drugs.

01:58:53.960 So when I have the average person who's BMI 28 to 40, they have stage two estimations from

01:59:02.340 non-invasive tests. They've maximized their lifestyle modifications for their current demands

01:59:08.380 in life. What are we working with endocrinologists? Most of them have already had the discussion,

01:59:14.400 if they have diabetes, about bringing in a GLP-1 receptor agonist. If they're not, we strongly

01:59:20.720 move forward that conversation, but we don't do it outside of the context of at some point,

01:59:27.080 you will likely have to come off of this medicine. We need to talk about how many people regain the

01:59:33.600 weight afterwards and what's the longitudinal benefit for a longitudinal disease if two years

01:59:40.420 down the road you regain the weight and the injury pattern resumes. So we do take a long lens on it.

01:59:47.960 I do have very overt conversations when patients are in the stage three range,

01:59:53.180 or early cirrhosis, about bariatric surgery, metabolic and weight loss surgery, and the

01:59:59.860 involvement of some of these weight loss drugs with a clear open discussion about what happens

02:00:07.160 when you come off of the drugs and what's the longitudinal weight regain post-bariatric surgery

02:00:12.720 from some of the surgical interventions. So when to bring it in, comorbid obesity, comorbid

02:00:19.580 overweight status, comorbid diabetes, and do we use it specifically? It has clearly in the evidence

02:00:25.900 it's been tested in multiple phase two studies and recently released data in terms of the effects on

02:00:32.100 the liver. The effects on the liver are difficult to tease out in terms of how much of it is due to

02:00:37.580 overall weight loss versus a direct liver related effect. When we used to talk about NAFLD and NASH,

02:00:43.920 I assume that those were largely biopsy differentiated terms and NAFLD focused on fat

02:00:50.040 accumulation, NASH focused on the inflammation that was present, and then of course cirrhosis was the

02:00:56.720 end stage of fibrosis. Today you're talking about it in terms of staging. Does that allow us to move past

02:01:03.920 biopsies and rely on some of the elastography and ways to look at both fat and fibrosis scores? And if so,

02:01:11.360 how do you delineate the staging today?

02:01:13.920 Most of us are using non-invasive tests. So those are things that are apart from biopsy. Any of the

02:01:19.320 ones that we named before for the vast majority of our clinical patient follow-up. The time that we

02:01:25.080 bring in biopsies, usually for anything, oftentimes we'll get, especially women with a positive ANA,

02:01:32.920 smooth muscle antibodies, some indication that there may be an autoimmune component. So treatments are

02:01:38.200 very different between the two. So to exclude a biomarker of interest in a population,

02:01:43.920 about 18 to 20% of people, patients with MASL-D will have one of those positive biomarkers.

02:01:50.280 So we use it to exclude other types of diseases. We also use it for clinical trials purposes.

02:01:56.480 And then we use it oftentimes in diagnostic testing prior to a procedure, prior to an elective surgery,

02:02:02.700 prior to an intervention that may or may not result in liver, where you need to know about cirrhosis

02:02:10.000 before an abdominal surgery or a cardiothoracic surgery might be done. Those are the three

02:02:14.540 instances that we see most often. Because of the explosion of non-invasive tests, being a recipient

02:02:20.880 of all the confounders, we also help use it to delineate when there needs to be a tiebreaker.

02:02:27.200 You get one non-invasive test that suggests very advanced fibrosis. You get an MRI that suggests,

02:02:32.660 with elastography, that suggests something very different, where there's such discordance that you

02:02:37.920 need something to adjudicate the in-between area. So I'd say there's four instances.

02:02:43.080 And so what are the stages? When you talk about stage one, two, three, and four,

02:02:46.720 what makes up those stages today?

02:02:48.940 Fibrosis scores. So the way that we look at the liver, and there's different scoring systems that

02:02:53.380 are based on different types of diseases. But the way that we think about a normal liver,

02:02:58.460 assuming no genetic influences, most humans are born with a normal liver. Let me define some of

02:03:03.640 these disease processes. So we defined what steatosis development looked like in MASL-D,

02:03:09.080 and that's more than 5% fat. When you start to move into fat plus inflammation, so inflammatory

02:03:16.100 cells infiltrating the liver, plus what we call hepatocyte ballooning, that stressed out hepatocyte,

02:03:22.020 that's the definition of NASH. NASH does not necessarily mean that there's scar tissue. Oftentimes,

02:03:27.300 you will see some scar tissue, but the fibrosis component is different. Stage one scarring is

02:03:33.020 early stage scarring. It's usually, like I said, in adults around the vein. We call it chicken wire

02:03:38.260 because that's what it looks like under the microscope. And then depending on the distribution

02:03:42.780 and presence of scar tissue, we stage it stage one, stage two, stage three, stage four.

02:03:49.720 The way that the liver architecture looks under the microscope around stage three,

02:03:54.780 we start to see connections between that portal-based area and some of the central vein areas. So you'll

02:04:01.100 hear people say expansion, bridges, and then stage four scarring is what we consider cirrhosis. And that's

02:04:08.000 where you have a lot of architectural disruption, nodules forming in the liver. It looks lumpy-bumpy,

02:04:13.580 sometimes on an ultrasound, sometimes on an MRI. Our thinking around cirrhosis and reversibility has

02:04:19.400 also changed in the field. And a lot of this was learned after the potent hepatitis C cures. We

02:04:25.420 used to teach that any form of cirrhosis we thought was very, the scar tissue was very fixed and

02:04:30.560 irreversible. Now we've subdivided cirrhosis into different stages. And early cirrhosis or stage four

02:04:36.760 scarring of the liver, we've started to see evidence that even that is reversible. Time course between each of

02:04:42.540 these stages for something like Masold is five to seven years. That's largely based on European

02:04:47.740 ancestry information. And that's why it is such a hopeful disease because there's tons of time to

02:04:53.580 intervene before there's progression to the next stage. So, I mean, those are two very uplifting

02:04:58.200 pieces of information, right? The first is that you've got five to seven years between each of those

02:05:02.220 stages. And then the second is that even at least a subset of cirrhosis might be reversible.

02:05:07.940 That, again, yeah, stands in the face of the traditional teaching that we had, which was

02:05:12.440 stages one, two, three, reversible, stage four, not. Talk a little bit about the oncology risk.

02:05:18.060 You've alluded to it a couple of times now. And you've also, if I want to make sure I'm hearing

02:05:22.200 you correctly, said that, look, if you're in the early stages of Baffle D, you might say, well,

02:05:27.880 why should I care? And you're saying you should care more based on the risk to your heart and the risk

02:05:35.700 risk to cancer than you should of your immediate risk to liver disease. Because if you're in the

02:05:41.840 first stages of this disease, you're 15 to 20 years away from liver failure, but you could be

02:05:48.780 much closer to cancer or heart disease. I want to make sure that I'm representing what you said

02:05:52.640 correctly. And two, I want to particularly focus on how you would quantify the increased risk of

02:05:58.520 cancer there. Let me tackle the first portion. I think that the general community and a lot of

02:06:03.860 patients self-report this, they pick up their impressions based on how clinicians deliver the

02:06:10.180 news. And I think there's been a jadedness in terms of tackling diabetes, obesity, any type of metabolic

02:06:16.940 diseases, as if the general population will not take that information and act on it. And some of that,

02:06:24.220 I guess, is justified in the diabetes world. That said, I think we have a lot to do in terms of how we

02:06:29.940 counsel patients and whether or not they feel empowered by the information we're giving them

02:06:33.760 and if we're taking it seriously. A lot of hepatologists want to see, and we should, from a

02:06:38.740 stewardship perspective, see the more advanced perspective. But that means that we garner

02:06:42.860 understanding and support from our endocrinology, cardiology, general folks in terms of understanding

02:06:48.780 metabolic risk and how to modify that risk long-term. So for the average person, including patients that are

02:06:56.260 included in our stage one, stage two, stage three clinical trials, a main outcome is cardiac, major

02:07:01.380 adverse cardiac events. And so that's a longitudinal risk that we need to think about. When I see a

02:07:07.980 patient, I am trying to figure out what is the leading risk for their, not just mortality, but quality

02:07:14.120 of life implication. Is it something that is liver-based or is it something outside of the liver? And this is

02:07:20.300 not necessarily including malignancy risk, but sometimes does. For very early stage disease,

02:07:27.180 so not even stage one fibrosis, we talk a lot about eventual development of diabetes. A common thing that

02:07:32.840 I'll say is somebody with an elevated CAP score on a FibroScan, here's your fat score, here's your scar

02:07:38.000 score. Your scar score is normal. Your fat score is exceedingly high. It's very modifiable. Six weeks to six

02:07:45.220 months, it can be in the normal range. Unchanged, you will most likely develop diabetes in X number

02:07:51.060 of years, depending on what their insulin risk profile will be. That's not usually received in a

02:07:56.680 scary way. That's received in a, oh, I can actually change my diabetes-related risk in a meaningful way

02:08:02.060 and see an outcome in a year or two on a scan. So empowering patients with information and then also

02:08:08.380 working in partnership with endocrinology and cardiology in terms of what their cardiovascular risk

02:08:12.980 might look like and how to modify it and how to make it sustainable. I think that's the biggest

02:08:18.320 thing that we deal with when it comes to liver disease and scar. If it is five to seven years

02:08:23.440 on average to develop stages to progress, that's a lot of sustainability. And a lot of the behavior

02:08:30.160 changes that we see are related to circumstances. So how to build resilience, not just in terms of

02:08:36.620 their metabolism and their metabolic flexibility, but what their coping skills are, what they reach for

02:08:41.620 in different instances. That's early stage disease. From an oncologic risk perspective, and I'll speak

02:08:47.120 first about the liver-related oncologic risk. So our primary liver disease, our liver-related cancer

02:08:52.180 is a patocellular carcinoma. Its origin is in the liver. I'm not speaking about metastatic disease that

02:08:58.280 lands in the liver. We generally think that that occurs with cirrhosis. And for most liver diseases,

02:09:04.500 around three to five percent per year, is what we quantify risk. Highest risk, hereditary hemochromatosis.

02:09:12.780 Next, combination, hepatitis C and alcohol. This was mostly quantified before hepatitis C cures existed.

02:09:20.620 Then hepatitis C, alcohol, mazel D. Ones, and again, when you take care of the ones that escape your

02:09:28.260 escape hatch phenomenon alerts always come on, hepatitis B. And then whether or not, this is

02:09:34.540 subject of a large multidisciplinary group that we're part of, is looking at whether or not we

02:09:39.820 were getting case reports, basically, of people with stage three scar tissue from fatty liver disease,

02:09:45.940 developing cancers, really bad cancers. When liver cancers are slow growing, they're quiet,

02:09:51.380 they're silent, you have to look ahead of time. So that is a population, people with cirrhosis are a

02:09:56.740 population that we recommend looking for cancers before anyone is symptomatic. So every six months,

02:10:02.480 we recommend screening. Whether or not that needs to be done at an earlier stage in fatty liver disease

02:10:08.240 world, that mazel D world, is to be determined. There's some early evidence that around the metabolic

02:10:16.380 reprogramming that's going on in the liver, the insulin sensitization, the insulinization of the liver,

02:10:21.740 the oncologic potential is changing. Whether or not that person needs to be screened at an earlier

02:10:27.420 stage of disease is a current sort of area of interest in the field and within my group.

02:10:32.560 Yeah. I mean, that's the million dollar question, Julia, is if you quoted that three to five percent

02:10:37.240 per year increase in the risk of hepatocellular carcinoma, that's once you have stage four. Was

02:10:41.880 that what you said? Correct.

02:10:43.680 And obviously, once you're at stage four, you got a lot of problems. I mean, your risk of HCC is one of

02:10:48.140 them. But at this point, everything is a four alarm fire. But given, again, the prevalence of

02:10:54.620 MAFLD, NAFLD, NASH, whatever you want to call it along that progression, yeah, it would be really

02:10:59.420 helpful to know, is your risk of hepatocellular carcinoma 2x the normal, 3x the normal, 5x the

02:11:06.680 normal? Admittedly, it's a low baseline, even if you're at stage one or stage two. Could be a while

02:11:11.860 to answer those questions, obviously, because of the sample sizes needed. To that point, that's an

02:11:17.900 obvious opportunity to have a discussion with a patient about whether or not to involve

02:11:22.380 pharmacologic agents or surgical agents to massively decrease their risk of not just fat,

02:11:28.120 but scar tissue in their liver in a meaningfully reversible and hopefully sustainable way to

02:11:33.520 decrease potential cancer risk is a big one. And I would say a lot of patients come to us, and again,

02:11:38.780 I have a biased point of view because of my specialty, cirrhosis is not a death sentence. A lot of times we

02:11:43.740 have new diagnoses of cirrhosis in people in their 30s, 40s, because this disease starts so young.

02:11:49.880 You can live. You can have relatively good metabolic health for quite some time before

02:11:54.340 your liver falls off the curve from a dysfunction standpoint. So even with cirrhosis, you need to

02:12:00.340 undergo some appropriate screening, but the timeline for that is not you're going to need a transplant

02:12:05.380 in two years. Once you involve portal hypertension, it's a different story. Some of your listeners,

02:12:10.260 a good percentage of your listeners, might have stage three scar and not know it. And at the age of

02:12:15.580 40 might be told that they have pretty early onset stage four disease. But again, it's not like

02:12:21.540 stage four cancer. It is something that there are opportunities to do a lot of good in that

02:12:26.520 population. I want to spend a minute just talking about drugs, either currently used drugs, which

02:12:32.140 are obviously drugs that are used to treat other things. So we clearly are going to rely heavily on

02:12:37.100 drugs whose primary purpose is treating diabetes, which improve, at least in the case of metformin,

02:12:41.960 very likely improve insulin sensitivity as well. Or GLP-1 agonists that we've already discussed that

02:12:47.340 both target insulin sensitivity and appetite regulation, which then feeds back. But are there

02:12:52.800 any other drugs out there today or in what I would call kind of late stage three that are specifically

02:13:02.020 targeting fat accumulation in the liver due to metabolic consequence or even due to alcohol?

02:13:08.300 So your group might be familiar with the Resmetaram output New England Journal probably 10 days ago,

02:13:16.340 phase three. So what we have learned about the liver, whenever you have so many biological processes

02:13:21.660 that are being regulated and a lot of exogenous inputs, there's a lot of potential for therapeutics,

02:13:27.060 but that also means a lot of potential for error because of the biology of the disease.

02:13:31.320 So that's a thyroid hormone receptor agonist that has been studied and now shows very good

02:13:37.760 promise in terms of late stage efficacy, late stage by way of phase three efficacy and safety

02:13:43.860 in a population. There are a couple of limitations in terms of the population. I think it's 90%

02:13:49.460 European ancestry or self-described white with the disease prevalence in the United States and around

02:13:54.820 the world being very, very heavily diverse. So how that will play out in a different population is

02:14:01.380 one thing to be watched. But thyroid hormone signal, again, some of the omics-based studies that we do

02:14:09.400 sometimes get at the disease agnostically, which old reductionist ways of doing science

02:14:15.100 sort of were refractory to, but it's a common way to think about what does have biological plausibility

02:14:21.760 that might have an actionable effect within the liver. So when it comes to advanced scar tissue,

02:14:28.500 and this one looked, that particular study looked at agents that are stage one, stage two, stage three.

02:14:33.780 There's different forms. Tons of clinical trials have been done at various stages, including what

02:14:39.500 we call decompensated. That's when somebody with cirrhosis falls off the curve, all of a sudden their

02:14:44.220 liver stops working. So those types of agents have been studied as well. When you think about promising

02:14:49.720 agents independent of weight loss, whereas metaram is one, there are some that act on multiple types

02:14:56.160 of pathways like FGFs, FXR agonists. Different when you look at the pleiotropy of expression, of where

02:15:04.660 the injury can occur, and keeping front of mind that the liver talks to subcutaneous tissue,

02:15:11.180 subcutaneous adipose, and muscle. That's where some of the PPAR agonists come from. That's where some of

02:15:17.640 the vitamin E, the PIVNS trial. So there are different agents that have been studied depending

02:15:23.020 on the stage of disease. But what's messy about this work is that oftentimes things that show

02:15:29.060 biological activity from a histology perspective don't necessarily result in some of our endpoints

02:15:35.360 that we have as a community developed with the FDA. And that's reversal of NASH and no progression

02:15:41.940 of fibrosis. And so whether or not those histologic endpoints are representative of the disease at

02:15:47.880 large within the liver, and then also the cardiovascular and very importantly, glycemic

02:15:54.440 effects are what makes doing these trials so hard. You're looking at multiple variables, not just liver

02:16:00.540 related, but also endocrine and cardiac. So Julia, if patients come to you and say, should I be taking

02:16:06.360 choline supplements, vitamin E supplements based on the histologic changes that didn't quite meet

02:16:11.540 clinical endpoints? Do you see a downside in doing that? For choline deficiencies specifically,

02:16:17.020 you know, those are sometimes measurable. Those are things that we can do assays. We see them a lot

02:16:21.780 in people post-bypass surgery, the malnutrition form of steatotic liver disease. So I'm not terribly aware

02:16:30.040 of any downsides. I'm cautious when I say this because every day I see a patient with some sort

02:16:37.240 of new formulation that has a hyperpotent level of what we think they're getting. And so when it comes

02:16:44.420 to supplementation, quantifying exactly what's in it from a vitamin E perspective, you know, there are

02:16:48.960 some downsides, all comers, the annals, cardiovascular, longitudinal risk, and then prostate cancer,

02:16:55.880 just things to think about in terms of whether or not I would choose to use it, or at least have a

02:17:01.000 discussion with a patient. The vitamin E is very sort of low hanging fruit from a steatotic perspective,

02:17:06.920 but we do think we have additional discussions in people that have diabetes. It's generally okay.

02:17:12.900 Now there's studies have been done on people with cirrhosis, because again, there've been some studies

02:17:17.780 that indicate increased in all cause mortality, depending on the dose of vitamin E and what it's being used

02:17:23.340 for. What's in the pipeline as far as any of the mitochondrial uncoupling agents? This was sort of

02:17:28.660 talked about a lot a few years ago. I haven't been paying attention, so maybe it's still being talked

02:17:32.940 about, but is that something that is still looking promising? So I think a lot of the work that's been

02:17:39.180 done in that area, if you look at early development, again, if we go back to the de novo lipogenesis

02:17:44.660 pathways, where there's beta oxidation, where there's failures in beta oxidation, where there's overwhelm,

02:17:51.000 there's a putative mechanism there. I see most potential interventions, just like siRNA-based

02:17:58.080 agents, in combination-based therapies. And that's because for approval, you're going to have to get

02:18:04.680 at a component of fibrosis. And the most potent aspect to deal with both steatosis and fibrosis right

02:18:11.320 now are some of the blockbuster weight loss drugs. In order to have liver-specific directed therapy for

02:18:18.840 something like mitochondrial-based etiology, and we typically think of microsteotosis and development

02:18:25.340 in that way, rather than the macrosteotosis, the large flat droplets that we see with metabolic

02:18:30.380 associated steatotic liver disease. So I see them used potentially, I'm not conflicted in terms of

02:18:36.540 speaking about this, in forms of combination therapy. There are so many different agents being

02:18:42.380 talked about that are not yet public from a preclinical perspective. So I could see that,

02:18:48.940 I could envision that as a potential putative agent from a steatotic-based application,

02:18:53.260 but in combination.

02:18:55.060 Well, Julia, this has been really interesting. We've covered a lot of ground today. I've taken a lot

02:18:59.500 of notes, you probably can't tell, but that speaks to how much I've been learning and how much I think

02:19:04.600 this is going to kind of sharpen my pencil when it comes to patient management and our diagnostic

02:19:10.960 acumen within the practice. Again, I think the takeaway here is many things for me, but probably

02:19:15.760 the most important takeaways are that we need to be very thoughtful in how we make the diagnosis here,

02:19:20.520 and we need to be very thorough in evaluating the clinical history and that the overlap could be much

02:19:28.860 more significant than previously realized between metabolic dysfunction and alcohol use, and that it

02:19:34.140 doesn't take a whole lot of alcohol consumption to impact these steatohepatetic pathways. And indeed,

02:19:42.100 many patients are probably walking around with some combination of what was formerly AFLD and NAFLD.

02:19:48.260 So the other thing I've really taken away from this is that really the near-term cardiometabolic risk

02:19:53.960 and the near-term oncology risk might even outweigh the near-term hepatology risk in the early stages

02:20:01.780 of that disease. There's still a great unknown there, it sounds like, in terms of quantifying some of

02:20:07.080 those risks, but nevertheless, I was actually very taken aback by the statement you made, which was

02:20:12.420 in the stage one, two, and three clinical trials, you're using MACE, major adverse cardiac event,

02:20:19.160 as the clinical outcome. I think that speaks to the proximity of cardiovascular disease as a bad thing,

02:20:27.320 as the thing that you ought to care about. If clinical trials are looking at MACE as an outcome,

02:20:33.300 that tells you how tightly linked these conditions are with cardiovascular disease.

02:20:38.540 It's not the primary endpoint. We're still looking at liver-based endpoints. But when we look at

02:20:43.360 longitudinal clinical outcomes data, where post-approval surveillance will be and clinically

02:20:49.900 significant outcomes for the FDA for certain cardiovascular outcomes are a huge one.

02:20:55.280 Got it. Okay, thanks for clarifying that. Yeah, that was an amazing statement. If I was correct,

02:20:59.660 that it was a primary outcome, but good to hear that, maybe more logical to hear that it's not.

02:21:03.840 Anyway, thank you very much for sharing all this insight. There are literally hundreds of thousands

02:21:07.700 of people listening to us right now who are afflicted by this, some of whom know it, but I suspect many

02:21:12.400 of whom don't. And the hope is that they can get the proper diagnosis and that that diagnosis,

02:21:17.560 perhaps by itself, serves as the motivation to go after this and address it. Because,

02:21:24.080 again, the other takeaway here is imminently treatable, imminently reversible. And therefore,

02:21:31.180 there's no reason to not know that this is something going on inside your body.

02:21:35.460 Couldn't agree more.

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The Peter Attia Drive - May 20, 2024

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

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