PeterAttiaDrive #405 AMA88 Metabolic liver health FULL

Hey everyone, welcome to the member-only podcast feed for The Drive. I'm your host, Peter Attia. Welcome to Ask Me Anything AMA episode 88. Today we are talking about the liver and specifically its role in metabolic health. This is a topic that suffers from a strange mismatch. On the one hand, the liver is one of the most metabolically important organs in the body. It is the mastermind sitting at the center of how we handle glucose, fat, and cholesterol. And on the other, most of the public conversation about the liver is about detoxes, cleanses, and supplements, while the questions that actually matter go unasked. So we're going to focus on one of the liver's main functions, how it serves as the centerpiece of the whole body metabolism, and walk through how to tell whether yours is under stress, why that matters, and what actually moves the needle once you need to act. So specifically, we're going to cover why the liver is the so-called canary in the coal mine for metabolic dysfunction. The four things we're going to talk about in this episode are why the liver is the so-called canary in the coal mine for metabolic dysfunction, why normal liver enzymes can be misleading, and what we actually use to detect and stage risk, what interventions work once risk or disease is identified, plus an honest look at whether any liver supplements are worth taking. If you're a subscriber and you want to watch the full video of this podcast, you can find it on the show notes page. And if you're not a subscriber, you can watch a sneak peek of the video on the show notes page. So if you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, welcome to AMA episode 88. Peter, welcome to another AMA. How are you doing? Very good, thanks. Awesome. So today we're doing the whole episode around one topic, which is the liver and metabolic health. In the past, you've described the liver as the quote unquote canary in the coal mine for metabolic dysfunction. So I think it'd be helpful to start with a kind of talking about what you mean by that and why you think the liver is so important. Well, the liver sits sort of at the center of systemic metabolism for every macronutrient, glucose, fat, protein, as well as cholesterol. And by the way, let's not forget ethanol or alcohol there as well. So it's also one of the very first places to both promote and respond to stress from anywhere in the system. If circulating triglycerides are high, the liver gets involved. If glucose regulation is deteriorating, the liver's involved. If ApoB or LDL cholesterol is climbing, the liver made those particles. And the flip side is equally true. If we look at the liver and see that it's under stress, we know that these metabolic systems are also under stress. It's a two way mirror between systemic metabolic health and what's happening in the liver. And that's also why I think about liver disease less about a stand-alone organ problem. Dysfunction of the liver is more of a parallel expression of systemic metabolic dysfunction. The leading cause of death in people with liver disease isn't liver failure. It's cardiovascular disease. Because a liver under metabolic stress is overproducing ApoB-containing particles and amplifying the insulin resistance that drives atherosclerosis throughout the body. So that's why I think about liver disease less about a stand-alone organ problem. Dysfunction of ApoB-containing particles and amplifying the insulin resistance that drives atherosclerosis throughout the body. And so that's why this is a metabolic episode as much as a liver one. And I guess we should also name it upfront. When we're talking about fatty liver disease, we're talking about a disorder that is estimated to affect more than 38% of the world's adult population, which is hard to believe. This isn't something that happens to some unfortunate person that you'll never meet. It will happen to nearly anyone in the developed world who isn't paying some attention. And I think it's worth kind of early on talking about what the liver does, right? So I think for a lot of people, when they think of the liver, they usually think about processing alcohol. So before we get too much into metabolic disease, can you frame in a little more detail what the liver is doing in the body? Sure. And you're right. The alcohol framing dominates, and that's a bit of an undersell. As our past guest, Julia Watercheryl, says, the liver has over 300 functions, which is sort of staggering. Obviously, we're not going to talk about many of those today, but I find it useful to conceptualize all of those as fitting into four main categories. So the first is detoxification. The liver breaks down alcohol, just as it would break down virtually any toxin that makes its way into the body from food, drink, pharmaceuticals, inhalation. Any toxin that reaches the blood, the liver plays a central role in clearing it. Second, it is an immune organ. So the first place blood from the gut goes is to the liver. All blood from the gut winds its way back into the portal system to the liver. So it's one of the first responders to ingested toxins or bacterial leakage from the gut. Third is protein processing and secretion. The liver is the site of synthetization. For many of the most common proteins in our blood, something as ubiquitous as albumin and as vital as clotting and platelet stimulating factors, ApoB, peptide hormones like IGF-1. The fourth category is where we're going to spend most of our time today, and that is on energy metabolism. The liver plays a central role in the uptake and synthesis of circulating fats and cholesterol and is one of the most important organs, if not the most important organ, for the balancing act of the liver. So it's one of the most important organs for the balancing act of maintaining blood sugar. It's, you know, you can think of it as the metabolic headquarters of the body, which is why when it's harmed, the damage is not just confined to the organ itself. And so you mentioned there about the liver and blood sugar. Can you walk us through more the liver's relationship with controlling blood sugar? Yeah, it sounds simple, but the precision required to regulate blood sugar is extraordinary. And it never ceases to amaze me. It's one of my favorite things to explain to a patient. After a meal, glucose rises, the pancreas releases insulin, and insulin tells the liver to absorb glucose and store it as glycogen. Now, when you've been fasting for some period of time and glucose dips, insulin falls, and then the liver does the opposite. It breaks glycogen back down and releases glucose into the circulation. And when glucose runs really low, it can actually just manufacture glucose. So it's a very, very important thing to do. So if you're, you know, going more than a day without eating, the liver turns into a glucose-making organ. If there's too much sugar to store as glycogen, the liver converts it into triglycerides, packages it into apolipoproteins, and ships them out. So what I want people to appreciate, though, is the scale of this. So everybody, you know, think about, you go to the doctor, you get a blood draw, and it's, you know, it's a fasting blood draw, right? And you get back a number. And so let's say you're a fasting blood draw, right? And so let's say you're a let's say that number you get back says 90 milligrams per deciliter. That was your blood glucose that morning when you showed up at the lab. If that's the case, your entire bloodstream in that moment contained only about four and a half grams of glucose. That's roughly a teaspoon, not a tablespoon, just a teaspoon. Yet a single meal, especially if it's a meal that I'm eating, may contain many times that, easily 90 grams of glucose, right? So 20 times that amount in one meal. And yet, despite that, a healthy person rarely moves more than a teaspoon above baseline, right? In fact, I'm trying to think of all the times I wore a continuous glucose monitor, if I ever saw a blood glucose lever that would have been north of about 160 milligrams per deciliter. Someone with type two diabetes would rarely go above, a teaspoon and a half at fasting. And when we can go hours without eating, our glucose still stays in that range. In fact, if you go days without eating, it might only dip to say 50 milligrams per deciliter. This is a monumental homeostatic achievement. And that reserve capacity to titrate out glucose in such fine amounts is exactly why early dysfunction is very easy to miss, which is something we'll, I'm sure, talk about. Yeah. And so let's dive into more metabolic disease and how that affects the liver. And so when looking at that, is there a framework that you typically use, typically talk through with patients and explaining it? Yeah. I think the most useful framing is to consider metabolic liver disease moving through four stages. So in the first stage, the liver becomes metabolically stressed, and then the second stage in response to that, it starts storing excess, excess energy that is, as fat. And that's a condition known as steatosis. And then the third stage is steatohepatitis. And that is just a fancy word for excess fat being stored in the liver, tips the liver into inflammation, and then the liver begins to injure itself. And then the fourth stage is the response to that injury, where it starts to lay down scar tissue. And that's a term that people have probably heard called fibrosis in the liver. So those first three stages are largely reversible. It's fibrosis that is a little trickier. It is biologically reversible to varying degrees, especially if caught on the very, very early side of things. But once the scarring accumulates such that the liver's architecture is disrupted, that's the point that becomes irreversible. Now, the presence of fibrosis is what predicts the outcomes that we typically carry. Especially cardiovascular disease, cancer, and even liver-specific mortality. So as we kind of go through this exercise, I'll keep pointing back to where we are on that four-part scheme. And you've previously said that, you know, chronic calorie surplus is a primary driver of metabolic dysfunction. And so can you walk us through the chain of the events from caloric surplus to ultimately at the end, liver damage? Yeah, it starts relatively simply. If you consume more calories than you expend consistently, the body has to put that excess energy somewhere. And the liver converts much of it into triglycerides through a process of de novo lipogenesis. It packages them into these ApoB-containing particles, namely VLDLs and LDLs, and ships them to adipose tissue for long-term storage. And again, that is a normal, healthy, physiologic response. If we didn't have that capacity, we wouldn't be able to do anything. We wouldn't be here today. You and I wouldn't be talking together. Our species would have gone extinct because we had to be able to store energy when energy was abundant. And we had to be able to draw from that when energy was scarce. So, so far, this is normal. It's obviously, as you can see, it's going to become abnormal at some point. So think of a fat cell as a warehouse. For a while, they will accept every shipment. But as they become progressively overfilled, they stop responding normally to the fat cell. And so, as you can see, it's going to become abnormal at some point. But as they become progressively overfilled, they stop responding normally to insulin, which is kind of the most important hormone that's involved in this process. And one of the molecular hallmarks of that process is the accumulation of a lipid intermediate called diacylglycerol, or DAG, or DAG, which interrupts insulin signaling. So once that happens, the warehouse starts malfunctioning. Instead of simply storing fat, those particular fat cells or adipocytes begin releasing fatty acids back into the bloodstream. And so, as you can see, this is a normal, exactly what you don't want, unless you're about to use them immediately. The problem is there's already too much energy in circulation. So the last place you want more triglycerides is being released back into the bloodstream. So now the liver has to deal not only with the excess calories coming in from the diet, but also the excess fat coming back into the circulation from those defective fat cells. And what happens to the free fatty acids in the blood? So the liver picks up those fatty acids, and they're released back into the bloodstream. And so, as you can see, as well as the fats from our diet, because that's one of the primary jobs, is energy balance. But eventually, the same process develops here. So lipid intermediates begin to accumulate, insulin signaling becomes impaired, and the liver becomes insulin resistant. Now, people may recall back to the podcast that we did with Ralph DiFronzo on this, and it's one of my favorite podcasts of the time, because it's just a master class in all of the different types of insulin resistance. And insulin resistance in the muscle versus the fat cell versus the pancreas versus the liver, they all look a little bit different. I'm not going to get into that now, but if anybody wants to sort of get really brushed up on that, that's where we'll go, and we'll link to that in the podcast. But here's the part that's really important. Insulin normally tells the liver to do two things. Stop releasing glucose into the bloodstream and stop making new fat cells. Why? Because if insulin is high, you've just been fed. And if you're fed, you don't need to be putting glucose into the bloodstream or making new fat. But as insulin resistance develops, the first signal fails before the second. So the liver continues releasing glucose, even when blood sugar is already high, while the pancreas responds by making more insulin, which still drives fat production. So that's called selective hepatic insulin resistance, and it's one of the defining features of metabolic disease. At first, the liver, exports those triglycerides in these ApoB-containing particles. And again, that just means LDLs and VLDLs, which is why dyslipidemia always accompanies this. And eventually, production outpaces export. So fat accumulates inside the liver, and now we've reached stage two of our little linear progression. This is now steatosis. And so what are the liver diseases that you're concerned about as a result of that metabolic dysfunction? Well, the name changed recently, updated to reference the cause of the disease and move away from the fat in the name, because fat is basically the end result of caloric excess. But that excess isn't usually fat itself. So excess calories are often in the form of anything. It doesn't always depend on the type of food that you're eating, but it does depend on the type of food that you're eating. But that excess calories are often in the form of anything. So for example, if you're eating a non-alcoholic fatty liver disease and then if it progressed to the inflammation damage stage, it was NASH, which just stood for non-alcoholic steatohepatitis. By the way, the NA in both of those non-alcoholic is just so that we try to understand that this was driven more through excess energy, but not through the damage specifically of alcohol, because you can also get alcoholic fatty liver disease and alcoholic fatty liver disease. By the way, the NA in both of those non-alcoholic fatty liver disease and alcoholic fatty liver disease are driven more through excess energy, but not through the damage specifically of alcohol, because you can also get alcoholic fatty liver disease. durable clinical risk lives. And when talking about metabolic dysfunction, we often hear visceral fat as well. So what do we know about visceral fat in the liver? Does visceral fat affect the liver specifically? Yes, it's one of the most significant modifiers of liver risk. Not all fat is meaning or metabolically equal. Fat stored around your organs is actually more prone to releasing fatty acids even at baseline. But the bigger factor is definitely location. So visceral fat, fat around the abdominal organs, drains directly into the portal vein, which is one of the two blood supplies that goes to the liver. It's the one that drains the GI tract, so all of the gut and all of the metabolites that come from digestion. So subcutaneous fat releases fatty acids that diffuse through the entire circulation first. So it's just far less concentrated. In terms of a shot directly into the liver, visceral fat bypasses all of that. And so it's the difference between, you know, someone yelling at you from across the house versus like shouting directly into your ear. Same signal, but just much higher intensity because of where it's coming from. And the data bear this out. So in one cohort, visceral fat area, which could be estimated by CT scans, predicted steatosis independent of BMI and liver enzymes. So patients with greater than 200 centimeters squared of visceral fat had a seven and a half fold greater increase of liver steatosis when compared to people below 100 centimeters squared. And if you looked at the NHANES database among people with diagnosed muscle D, the all-cause mortality ratio in the top quartile of visceral adiposity was nearly three and a half times that. So that's the difference between visceral fat and liver steatosis. The difference is that visceral fat predicts liver pathology. And in the people who already have liver disease, visceral fat predicts a dramatically higher risk of death. And in the past, when talking about metabolic health, you've often talked about the importance of resistance training. So what do we know about how does resistance training interact with the role of the liver in metabolic dysfunction? Well, even more so than the liver, skeletal muscle is a major glucose sink in the body. In fact, it is hands down the largest sink of glucose in the body. So it pulls blood sugar out of circulation and stores it as glycogen. So roughly speaking, about three quarters of your total capacity to store glucose is in your muscle and about a quarter of it's in your liver. And that's again, storing it as glycogen. So less muscle means what? Therefore means less capacity to buffer glucose. So more of that burden lands on your liver. It's why you see metabolic liver disease in your liver. And that's why you see metabolic liver disease in your liver. So what do we know about muscle mass? Well, there are many studies in people that actually have normal BMI, but are very low in muscle mass. Sarcopenic obesity is the technical term for that, or what people call skinny fat. And multiple longitudinal cohorts point the same thing out. More muscle predicts both fewer new cases of Masl-D and higher rates of resolution. The single most striking figure comes from a large seven-year Korean cohort. People who gained the most muscle over the study resolved their Masl-D at more than four times the rate of those who gained the least muscle. We'll include all of this in the show notes. So whether it's prevention or reversal, the direction here is pretty unambiguous, which is why resistance training is kind of a non-negotiable if you're trying to address metabolic dysfunction. And do we know anything about if fructose may be more harmful than glucose? This is a very interesting question. And one that it's very easy to get wrapped around the axle on this one. The cleanest human experiment, and I only want to focus on the human experiments because we could spend the entire day on this question, Nick, if we wanted to talk about all of the animal stuff. But the cleanest human experiment is a randomized trial in 94 healthy men who drank moderate amounts of fructose, which is, again, just the pure sweet enantiomer, sucrose, which is the 50-50 mix of fructose and glucose, or glucose-sweetened beverages, for seven weeks at weight stability. So it's very important when you do these studies that you have to keep the subject's weight stable, because if you don't, it confounds everything. In this study, fructose and sucrose roughly doubled the liver's baseline fat-making machinery, this so-called de novo lipogenesis pathway. De novo just means new, and lipogenesis means fat-creating. While glucose did not. So at least in this study, fructose can behave differently from glucose in the human liver. And where that shows up most cleanly is in these measurements of de novo lipogenesis. But on the harder outcome, actual steatosis, controlled feeding studies show the dominant driver is excess calories and not fructose itself. So if you swap fructose and fructose isocalorically for other carbohydrates, liver fat barely moves. So calorie for calorie, the honest fructose-specific signal is on lipogenesis, which is an intermediate measure, but not the final outcome. Where fructose earns its reputation is in the form that it arrives in. Liquid sugar, in soda, for example, or other high-fructose corn syrup-laden beverages, which are very calorie-dense, don't make you feel full and are trivially easy to consume. And the cohort data do link sugar-sweetened beverages to higher NAFLD risk or MAZLD risk. So the practical advice holds cutting sugar-sweetened beverages is absolutely one of the higher-yield dietary moves for someone with insulin resistance or liver disease. But it's really the chief reason for that is that it's going to have its downstream effect on less calorie reduction. So one of the things I absolutely would counsel somebody on who has fatty liver disease is don't drink calories at all, and especially don't drink carbohydrate calories, and especially don't drink fructose-containing calories. A lot of especiallys there in that statement. Sounds like it was super important. All right. So going now to what we talked about earlier on, which is when people think about the liver, they think about alcohol. So how should we think about alcohol here as it relates to the liver? Yeah, alcohol is a pretty clean story. You'll recall a second ago, I said that the reason we have to put the N-A, non-alcoholic or whatever, in front of those is to differentiate it. It can cause fatty liver on its own. So alcohol-associated liver disease, which by the way, is more common than we give it credit for. It's very easy to just focus on the non-alcoholic metabolic versions. But if you actually look at the people requiring liver transplants, I don't remember the latest numbers, but the last time I looked at it, I was like, oh, I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't know. I don't I was very surprised at how many, I think more of those came from alcohol consumption than non-alcoholic consumption. Again, I could be off on that, but I just remember being sort of surprised. Now that said, it works through a different mechanism than caloric excess, but it turns out the outcome is almost the same. You pass through these categories of steatosis, insulin resistance, fibrosis, ultimately cirrhosis. Different mechanism, which is why it's very harmful if you combine it with metabolic dysfunction, as is often the case. So now you're getting basically a two-pronged synergistic attack when you have calorie excess and alcohol co-occurring. The combination of metabolic dysfunction and alcohol consumption recently earned its own designation, which I, frankly, I think we're getting a little ahead of ourselves, which is metabolic and alcohol-associated liver disease, or METLD. I'm not going to say that ever again. There's a very telling cohort study from the NHANES database in patients with existing cardiometabolic risk factors. If you already had a risk factor, steatosis alone wasn't associated with increased all-cause mortality, but steatosis plus what they described as moderate, and I might call moderate plus alcohol consumption, produced hazard ratios of 1.4% for all-cause mortality, 2.35 for cancer mortality, and a whopping 15, please check that number again, yes, 15x for liver-specific mortality versus people with no steatotic liver disease. So to put those into actual relative risks, that's a cause of death from anything is up 40%, death from cancer is up 135%, and from liver-specific disease, death is up 1,400%. So again, the purpose of me sharing this is not to tell you never to have another drink. It's to explain that when you add alcohol to liver disease, it gets really bad. Now, if we look at the pattern of drinking, there might be some, again, something to glean here. So acetyl aldehyde is the primary driver of alcohol's harm on the liver, and it accumulates faster the more you exceed about one drink per hour. therefore mechanistically I get asked this question all the time but I think what we could say is seven drinks in one evening is probably worse for you than one drink per night seven you know consecutive nights again I haven't seen the data for that but when you understand the mechanism of action I think that makes sense but that's basically I think the point here is that you know human data directly comparing binge versus daily drinking don't exist for the metabolic disease and I suspect we're not going to have an RCT for that but but that's kind of the point on alcohol and metabolic liver disease and to follow up on the NHANES study do we know how much alcohol they were actually drinking yeah again everything is self-reported so it's possible that this is what they were drinking it's also possible this is a slight underestimate I believe the men were drinking alcohol and they were drinking alcohol and they were drinking alcohol something to the tune of 40 to 60 grams a day and the women would have needed to be a bit less than that we'll put the exact numbers in the show notes page but that means that these are people that are self-reporting three at least three drinks a day maybe four drinks a day because again 60 grams of ethanol is technically for normal sized drinks or potentially less if you're drinking you know if you're pouring it yourself the point I would also add to that Nick is there are lots of people who can drink that amount and they're totally functional so I don't want the interpretation to be this is only for people you know who are rampant alcoholics because lots of people can be drinking three drinks a day and obviously have you know no obvious side effects of that and so moving beyond just lifestyle factors so when looking at the liver are there any people who are at greater risk at the baseline whether that's from genetics hormones or something else yep I would put these into two buckets the inherited genetic piece and then obviously the hormonal piece which can fluctuate over time so on the inherited side the most important single gene variant here is something called pnpla3 and people who carry two copies of a particular variant here tend to have about 2x the risk of or the the likelihood of accumulating liver fat and then with that comes the elevating risk of the risk of the risk of inflammation and fibrosis even after accounting for standard metabolic risk factors there are also variants that appear protective especially a loss of function variant in a gene called hsd17b13 which is associated with lower liver enzymes and fibrosis risk and it may actually partially offset the pnpla3 associated risk there are other variants as well again we'll kind of go into that in a bit but the larger point here is that there is an absolute genetic predisposition and even some protection that we see and it I mean I think any clinician can attest to this right you've got that patient who for whatever reason two people doing the exact same things and they have completely different liver health it's also why ancestry can show up in population level risk though you know we have to be careful not to overstate it so the pnpla3 risk variant is much more common than the pnpla3 risk variant and it's a very common variant and it's a very common in people with hispanic ancestry so that's why at the population level we know that hispanics are much more sensitive to and therefore susceptible to mazaldi and mash and it's actually the exact opposite in people of african ancestry so that likely contributes to what we see clinically but again that doesn't mean at the individual level that's always the case so I don't want someone who's listening to this who's black to think great I can't get mazaldi you know away I go and I don't want someone who's hispanic to listen to this and say oh well great this is my destiny it's just again it's a predisposition but it's it's you know it's not destiny so I mean there are also now body composition differences that standard labs and bmi stuff can always miss so for example many people who are of asian ancestry develop metabolic risk at lower and normal bmis in part again because visceral adiposity can be higher at a given body weight in a in a group of people who otherwise don't have a body weight and they can't have a body weight and they can't have a body weight and they don't genetically accumulate much subcutaneous fat so again this is why I think body weight and bmi while at the population level are useful tools at the individual level offer nothing I wouldn't be able to tell you the bmi of one of my patients but I can tell you virtually every one of their total body fat visceral fat and other measurements that are more nuanced so that's what really matters the other major baseline modifier is menopause so pre-menopausal women are the most likely to have menopause and the net effect of estrogen here appears to be restraining visceral and hepatic fat accumulation of course after menopause that protection starts to fade and it can do so quite quickly and then fatty liver becomes more common and can progress actually more aggressively so again all of these things ancestry family history genotype all menopause status all of these things belong in the risk assessment but again none of them replaces the core question which is the metabolic phenotype so I don't want to get too hung up on knowing what increases or decreases risk beyond you know what I just said I think what we really want to focus on is how do you actually measure it objectively in yourself unambiguously Peter let's move into that which is how people figure out kind of their liver health in a way so I think if you ask most people they would assume that if they go get annual blood work done and their liver enzymes come back normal everything is fine with their liver so first and foremost would you say that that's true no not really and this is one of the most important blind spots I think in standard care so think of the next few minutes as kind of a workflow what the routine labs can and can't tell you and how we stratify risk from there and and then what we reach for if we indeed turn to imaging so ALT and AST which just stand for alanine aminotransferase and aspartate aminotransferase are liver enzymes on a standard panel and we are just as guilty of this as every other doctor out there we often refer to these as liver function tests but that's actually not true at all they're not tests of liver function they are liver enzymes which again appear on a standard panel and it's actually better to understand them as markers of active liver cell damage so they're very good for telling you if there's damage that's occurring acutely like hepatitis drug injury or alcohol related damage but they require inflammation so liver fat early mazaldi and sometimes even early mash develop almost entirely before those enzymes rise so you can have 15 to 20 percent of the liver containing fat the hepatocytes while AST and ALT still appear normal and when I say normal there's also a reference range problem here which we've talked about in the past the typical norm is up to 40 and these norms were derived from populations that obviously included large proportions of people with undetected metabolic dysfunction think back to what I said at the outset right of what the the you know how common the prevalence of this is so if over a third of Americans have mazaldi using that population to define normal points your compass at the wrong target we and I we've talked about this Nick many times in the practice we use different numbers we we typically look to see AST below 30 and ALT below 25 and that's that's kind of what we hold up as as normal in that sense so the best early warning lives in the metabolic panel where you're looking at things like insulin glucose even other things like potentially uric acid homocysteine triglycerides HDL cholesterol and not in the liver panel so those reflect insulin resistance and dyslipidemia that are actually going to precede the the liver disease and if those things are trending in the wrong way the liver is already under stress even if the AST and the ALT are quote-unquote normal also it's worth pointing out in the extreme case that these enzymes actually start to decline when the liver gets really really damaged again we're not really talking about that here today but at some point AST and ALT will decline as you know at the at the end stages of liver destruction so then let's double click on that when you're ordering labs around this what are you actually looking for well again we're really focusing mostly on the the earliest side of this which is the signature of insulin resistance so triglycerides particularly that what the triglyceride to HDL cholesterol ratio is LDL changes APOB changes insulin we do of course the oral glucose tolerance test which is really the gold standard for measuring insulin resistance and again we we just don't rely on any one metric you're really looking at an entire pattern and you're looking at how it sustains over time so we'll we'll kind of include in the show notes a table for what we would consider low borderline and high risk across all of these beyond the standard panel I think probably fasting insulin is a very good test. Again, it should be part of a standard blood draw. It's typically not. We, again, we want patients to be below six. And if they're in the six to nine repeatedly, we start to have concern. And if they're above 10, we're definitely concerned regardless of what the hemoglobin A1C is or the fasting glucose level. So again, these are just things that we're looking at in the blood. The other thing we're looking at is in the DEXA. So it's a different test, obviously, but at least once a year, we would like to be able to track a person's visceral fat. But we're also, of course, looking at muscle mass and total body fat. So we basically think that, I mean, we're always comparing people across a nomogram, but visceral fat level above about 800 grams in a woman or about 1,000 grams in a man is very highly correlated with insulin resistance. And quite frankly, we choose to see people as close to zero as possible. So we're pretty happy when a person shows up with a visceral fat level. And we're also looking at 1 to 200 grams of visceral fat. But basically, anytime they're over about 500 grams of visceral fat, we start to think of that as a warning sign. I talked about the oral glucose tolerance test in the past, but we still believe that despite how cumbersome that test is, and we understand why it's not kind of a mainstay of testing, that it provides extraordinary yield. And it doesn't need to be done often. I mean, you could do it every couple of years. But it really gives you a lot of a wonderful picture of what's going on. The continuous glucose monitors are also an option. They do give you a sense of how glucose is managed. They obviously aren't telling you how much insulin is being required to do it. For whatever reason, we have not found the CGMs to be as reliable lately as they once were. The options around calibrating them have become more difficult, and we have relied on them. Much less recently than we had in the past. And so, let's say someone is getting some of this work done, and their blood work raises a flag. How are you then stratifying liver risk from there? Well, ALT, the alanine aminotransferase, is the more specific of the two liver enzymes. So, whenever we see something, we're trying to make sense of the two. AST elevations can be driven by muscle. So, intense exercise and things like that. And then, of course, alkaline phosphatase can come from the liver or from the bone. So, to resolve the ambiguity around these things, we can add another enzyme to the panel called GGT, which rises with liver inflammation and oxidative stress. So, if elevated AST or ALK-FOS with a normal GGT is what we see, we tend to read those as probably not coming from the liver. Whereas elevated GGT would raise our suspicion of liver origin. Again, not a hard and fast rule, but a two-to-one ratio of AST to ALT with an elevated GGT could also flag more of an alcohol-driven component as opposed to a calorically-driven etiology. But even with enzymes in range, the main thing we're worried about is sustained metabolic dysfunction. And when we see years of it, we calculate something called a FIB4. Which is a proxy for fibrosis risk. It combines age, platelet count, AST, and ALT. And again, by including platelets, it accounts for the loss of liver secretory function that occurs during that development of fibrosis. It's cheap, meaning it's free. The formula is simple. It can be found in the show notes or online. And what it resolves for us is whether or not we need imaging. That's what we're basically using it for. So, intermediate and high-level FIB4. High scores proceed to imaging. And we're very aggressive here. We don't recommend using the age adjustment. And basically, if we see a FIB4 greater than about 1.3 and or other signs that are concerning to us, we're going to follow up with an ultrasound. We think that raising that threshold for identifying at-risk older patients means potentially missing people with real liver pathology. We kind of want to hold everybody to a high standard. And it's, frankly, given the cost and non-invasive nature of the follow-up imaging, we think it's better to err on the side of probably more imaging than less. So, that's how we think about making that transition diagnostically. And so, let's jump into that. So, if you're looking to characterize Masl-D or MASH, what imaging are you using? So, the main tool is a vibration-controlled transient elastography, or VCTE. And it's commonly referred to by a trade name. It's a VCTE. And it's a VCTE. And it's a VCTE. FibroScan. I had one two years ago just because I wanted to know what it was I was subjecting patients to. Takes 10 minutes. It's an outpatient test. Gives you two numbers, a score for liver fat and then a stiffness score for fibrosis. And these are the two things you care about, right? Because they're the hallmarks of stages two and stage four. Accessible, reasonably priced. I think it's like a couple hundred dollars out of pocket or maybe a small copay. And it gives you data that it's a blood test. MRI is the gold standard, but I don't, we typically wouldn't progress to an MRI without getting the FibroScan to start. Once you're doing the MRI, of course, you start to look at different sequences that are understanding how to selectively identify for proton density and fat fraction in the liver. And then for fibrosis, they're looking at a different magnetic resonance elastography sequence. So, again, there are more and more accurate ways to do this with MRI. MRI is not quantifiable. It's more expensive. A lot of patients don't like to get an MRI. So we can, we can, we can do a lot with the FibroScan. Obviously, the gold standard here is a liver biopsy, which gives the most information and it's unambiguous. But truthfully, I, I think I've only ever sent a patient for a liver biopsy once in the last 10 years when there, when there was so much ambiguity from all of the non-invasive testing. So really outside of clinical trials or staging significant fibrosis, that's, that's almost something that, you know, that a lot of physicians I don't think, or hopefully people listening won't have to deal with. Now, one thing just for the purists out there, MASH is technically defined by histology, which means you would need a biopsy. So it's hepatocyte ballooning and immune cell inflammation. But the clinical practice of doing that has receded greatly. So, um, I throw that in there just for the sake of completeness, that technically you do need a biopsy to diagnose MASH. Although practically speaking, that's just not what's done today. And before we move on to questions around treatment, I think one of the things that'd be worth talking about here is you've often talked in the past that the liver is an organ that can really heal itself. And so I think that's also a really positive thing for people to hear about when they're looking at their metrics and when they're looking at maybe where they're at. So do you want to spend a few minutes talking about that? Yeah, I'm glad you brought it up. I think it's worth sitting with because everything I've talked about sounds like a lot of doom and gloom, the sort of unstoppable cascade, but that's, that's actually not the case. The liver is, you know, as far as I can tell, probably the most remarkable organ in the body from a regenerative standpoint. You know, it's certainly the OG Wolverine of the body and that's reflected in how long I think it takes to injure. The transition from Masldy to MASH typically takes a decade, if not a little bit more, and each of the fibrosis stages can take, you know, another five to seven years. So that's not sort of a passive rate. That's a reflection of how hard the liver is fighting back on this damage. So it's true that at the very end of the line, you know, the only treatment is going to be liver transplant and liver transplant requirements are on the rise. But the disease can be reversible and that's why we make so much hay about intervening early. We address the metabolic drivers and we see that steatosis and fibrosis in the earliest stages can regress, especially the earlier the fibrosis is caught. Again, this is not an argument for procrastination. Advanced cirrhosis is going to be a permanent impairment, even if the patient survives the liver insult. The ancillary damage across the cardiovascular system, the pancreas are devastating. So we just don't want anybody getting anywhere near cirrhosis. I don't want somebody being in the same zip code. But if you're listening to this and you're 55 years old and you've been living with untreated metabolic disease for years and you managed to get a fiber scan and it shows that your liver is full of fat, this is not too late to intervene. So I would, I would take comfort in that. And then when talking about these metabolic liver diseases, what do you think is the most important thing to do? I think the most important thing to do is to what do you think drives the risk that you care about the most and kind of how big is that risk that people should be thinking about? Well, that's, I think the payoff of this four stage map, right? So stage two and three, which are steatosis and early inflammation, mostly track your broader metabolic risk. And as serious as that is, we don't worry about the liver pathology separately from everything else that disrupted metabolism predicts. Now, fibrosis is different, which is the fourth stage. So liver fibrosis is different, which is the fourth stage. So liver fibrosis carries risk that's independent of the other metabolic factors. And that's why I don't want anybody getting anywhere, anywhere new. near that stage. And the numbers are worth sitting with as we move from fibrosis stage 0, which we call F0, up to fibrosis stage 4, which is F4. That's defined as cirrhosis. So let's just start with all-cause mortality. Compared to F0, the hazard ratio for all-cause mortality is 1.5 at F2, at F3, and 3.7 at F4. And in the study that identified that, the 10-year mortality was 7.7% for people in the F0, 1, and 2 category versus 41.5% for people at F4. So fibrosis stage predicts death from any cause, with risk increasing non-linearly as fibrosis becomes more and more severe. For cause-specific death, a few things can be seen. For example, if you have a fibrosis stage, you can see that the risk of death from any cause is increasing non-linearly as fibrosis becomes more and more severe. For cause-specific that cancer isn't confined to the liver. If you stratify the fib 4s, they're going to have a 14-fold higher odds ratio of hepatocellular carcinoma at 10 years, but also a 2- to 3-fold increase in other common cancers like lung, colon, and breast, along with a 5-fold increase in pancreatic and more than a 6-fold increase for the diagnosis of any metastatic cancer that shows up. So again, liver fibrosis isn't just a problem for the liver. It's basically a problem for the whole body, and I could go on and on about what the effects are on cardiovascular disease, kidney disease, and everything else. I don't think I need to. You get the point, and that's why we just don't want anybody getting near it. And let's say someone is near it. So let's say someone has Masl-D, or they're headed in that direction. They come to you and say, what should I do about this? What are you recommending? Where should they start? Well, when I said anywhere near it, I meant fibrosis. So there's lots of people that are going to be listening to us that are in Masl-D or heading to it, and I'm not as worried about that. We can intervene here. And the primary tool is weight loss and body recomposition, right? We want more muscle, less fat. And that's basically the answer. Everything else is going to be in service to that or an adjunct to it. The data are consistent, and they're dose-dependent. While the exact percentages vary with starting weight, on average, the lay of the land is this. If you lose 5% or more of your body weight, steatosis will start to drop. You're going to start losing liver fat. If you hit that sort of 7% to 10% range, inflammation will actually start to resolve. And if you get above 10% weight loss, you start to see actual reductions in early stages of fibrosis. So what does that mean? That basically means caloric deficit. The data here do not point to any specific diet, like Mediterranean, low-carb, high-protein. It's basically lots of trials have tried to find out if there's any benefits in one over the other, but it's not. The unifying thread is that calories below expenditure sustained over enough time is what does it. Again, that's the overall objective. How you do that strategically, there are lots of ways. We've already talked about this idea of cutting sugars, especially drinking any sugar, and then focusing maybe on very high-calorie foods can help at the margins. But if you're looking for the answer, I think you want to revert back to our old playbook, which is CRDRTR. You're restricting calories, you're restricting time, you're restricting specific nutrients, all of which force you into a reduction of calorie. Now, if I were giving this discussion 10 years ago or 8 years ago, I wouldn't be able to say what I'm about to say now, which is that the recent foray into weight loss has really expanded what we can do here. It's interesting because they're doubling on both the metabolic health and the weight loss. I think it would be crazy today to not acknowledge that in addition to fixing diet and exercising more, we have to really consider the impact of pharmaceutical agents that can help many individuals. Dr. So, Peter, on that, that is a question we get asked a lot, which is, what is the role of GLP-1 medications for liver metabolic health? What do we know about it? Well, as of today, GLP-1 receptor agonists are indeed first line. Some of the most impactful pharmacologic tools we have for metabolic liver disease, particularly in patients who are significantly overweight or those who have considerable visceral adiposity on dexa. Again, the logic is pretty straightforward and we understand why. So, it's the combination of insulin sensitivity, appetite suppression, slower gastric emptying, the effects on the brain's food reward signaling system. All of these things are going to move a patient in the right direction. Now, semaglutide is currently the only GLP-1 agonist with a formal MASH approval, specifically for stage 2 or stage 3 fibrosis, with strong phase 3 clinical trial data. They found, resolution of steatohepatitis without worsening fibrosis in 63% of patients and a reduction in fibrosis in 37% of patients compared to 34% and 22% in the placebo arm. Now, trisepatide, which adds GIP agonism to the GLP-1 agonism of semaglutide, was cleared for phase 2, but it is still waiting on phase 3. So, as of this time, we don't yet have at least approval for that. I don't think that that means that trisepatide wouldn't be a good choice here. It's really just about payers and reimbursements on that. Now, here's what's interesting. If you're thinking through this mechanistically, the question is, is all of the effect and the success that I, not only did we see in semaglutide, but I suspect we'll see in trisepatide, is it all due to weight loss or is there something beyond weight management? And the short answer is, we don't know, but right now it looks like it's being driven by weight loss and not something beyond that. And then looking beyond GLP-1s, do we know anything about, are there other medications that can come into play here? Resmaterin is the other drug with specific MASH approval. It's actually a thyroid hormone receptor beta agonist. It essentially tells liver cell mitochondria to burn stored fat rather than accumulate it. So it's that impairment of fat burning that I talked about being targeted by this drug specifically. The beta selectivity matters. So broad thyroid activation would hit the heart, but this preferentially targets the liver. And this medication allows it to drive down steatosis in the liver specifically, but can also work synergistically with caloric restriction. And again, the patient can also be adding lean mass. All of that would be great. Piaglitazone is another drug that can be used here, usually paired with a GLP-1 agonist. It acts on PPAR gamma in fat cells, increasing fat uptake and beta oxidation, and importantly, redistributing fat from visceral depots towards subcutaneous ones. Again, this is a drug that has largely fallen out of favor in the treatment of type 2 diabetes. But again, as discussed on the podcast with Ralph DiFronzo, it is probably one of the best insulin sensitizing drugs out there. And I think its side effects are very misunderstood and misrepresented. And pairing it with either an SGLT2 inhibitor or a GLP-1 agonist will often mitigate any of the edema or side effects that can be seen with it. Bariatric surgery has obviously been demonstrated to be highly effective in patients who are morbidly or what we call super morbidly obese. So these are patients with BMI above 50. But the reality of it is that with the success of the most recent generations of GLP-1 agonists, it's not even clear that that would be first line anymore. So it's fallen down the priority chain as people look to the GLP-1s first. Talked about SGLT2s in combination with piaglitazone, but also by themselves. They're a fantastic class of drugs, especially if a person has some coexisting hypertension, kidney disease, obviously T2D, or any risks for cardiovascular disease. So again, really, we're living in a time when pharmacology is able to do much more than it did 10 or 20 years ago. It's interesting, metformin, I wouldn't really put on this list, and you might think it should be, but it has failed consistently to show histologic improvement in Masl-D or MASH. And the trials that it's been included in have failed to show any meaningful changes in steatosis, inflammation, or fibrosis. So for whatever reason, even though metformin appears to have some benefits, it doesn't appear to have any liver-specific benefits the way some of these other tools do. So I think it's a great question. And what about exercise? What's the role of exercise in this? Exercise has kind of two jobs here. The first is helping create and maintaining that caloric deficit, though obviously the intake side is more important when it comes to weight loss, although again, exercise does become an important part of appetite regulation. The second and arguably more important is the one we talked about earlier about preserving and even building lean or skeletal muscle specifically, because again, that's the body's main glucose sink. So resistance training is very important because remember, every treatment that is aimed at reversing Masl-D and MASH involves some amount of caloric restriction. And so we have to be careful when people are restricting calories, that they're preserving as much lean tissue as possible. So if someone with Masl-D says they're going to exercise more, the first thing you really want to understand is what does their resistance training program look like? Because if they're only going to be doing cardio, while that's certainly better than doing nothing, they run the risk of giving up lean. mass, especially if they're accompanying that with drugs like GLP-1 agonists, which can disproportionately reduce muscle mass. So again, the goal in metabolic liver disease, whether through diet and exercise alone or paired with drugs is to lose as much fat and as little muscle as possible. And now let's look to supplements, whether detoxes, cleanses, liver support products, everyone's kind of seen them. So what do you think around liver support, liver detox supplements? You know, I think my view is that the framing is a bit philosophically backwards. Your liver is a detox organ. Liver driven processes are quite literally what detoxification means in a vertebrate body. So detoxification is a very sophisticated two-phase enzymatic process for neutralizing and excreting harmful molecules, which is primarily performed in and by the liver. So when I say detoxing, I'm not saying that I'm saying that you need to do a liver detox. I'm saying that you need to do a liver detox, because if you do, you need to do a liver detox. And of course, the irony cuts deeper. If a liver detox contains anything biologically active, there's a good chance your liver has to detox the detox. During phase one metabolism, liver cells are directly exposed to high concentrations of whatever they're processing. If it's toxic, then the liver is actually the thing that takes that first hit. And this is exactly why supplements are so important. Supplements now account for roughly 20% of acute liver injury cases reported to the drug-induced liver injury network, up from 7% in the early 2000s. In the transplant registry, the share of non-acetaminophen, non-tylenol drug-induced injuries attributable to supplements rose from under 3% in 1995 to almost 20%. And so, do you think there's any supplements that are actually worth taking around the liver? Well, I think a few things have real signal, but the list is shorter and more qualified than the marketing would certainly have you believe. So, I'll kind of go through them here. We'll provide a link to the European Masel-D guidelines that actually cover the data for many of these supplements specifically. So, vitamin E has the best trial data, RCTs show meaningful benefit, specifically in confirmed MASH. The effect, of course, is modest compared to GLP-1s or actual caloric deficit that you could get through any dietary means. And there are concerns with high-dose long-term use. So, it's not a prophylactic. But in confirmed MASH, it's worth a conversation with your doc. Hey, is this something that would add to what I'm doing? Believe it or not, coffee has a reasonably consistent effect on the liver. So, it's not a prophylaxis. It's not a prophylaxis. It's a consistent beneficial signal in observational studies, particularly for fibrosis. And an analysis of the UK Biobank found similar associations for decaf, which suggests that the caffeine isn't the only active ingredient. The observational data are strong enough that I'd say coffee may be genuinely protective, and it's unlikely to cause liver harm. But because they're observational, I don't think that you should just start drinking coffee to protect your liver if you're not otherwise interested in drinking. Coffee. And the effects are only observed at three or more cups per day. So, the problem with that approach is if you're not a particularly fast metabolizer of caffeine, the small benefits you get from that could easily be offset by the disruption to your sleep. Technically, a lot of people are going to have a hard time drinking three cups of coffee a day and still managing a good night's sleep. Interestingly, omega-3s show no liver-specific histological benefit in MASH trials. So, for many people, they're probably worth taking for two weeks. So, if you're not triglyceride management and cardiovascular risk, but they don't appear to do anything for liver disease pathology alone, despite what some might have you believe. And what about some other common recommendations people may have seen online? Things like NAC, specific kinds of tea. Do we know anything about that? NAC or N-acetylcysteine has a legitimate life-saving base when it comes to something like acetaminophen toxicity, but that pathway is actually pretty different from the metabolic liver disease pathway. So there is a real benefit to the liver. It just isn't in the context of which most people would ever be thinking about taking it. So I would actually say it's pretty unwise and unearned extrapolation to suggest that the data from using NAC to treat a Tylenol overdose means it's a good drug to be taking just to support overall liver health. Choline actually matters. And we know that in choline deficiency, replacing choline can actually have a big difference in liver fat. But again, it's tempting to make the extrapolation that says, well, then I should be mainlining choline, when in reality there aren't data to support that. So there's nothing to suggest that surplus supplementation of choline in a choline replete individual has a benefit. Milk thistle tea and its extract have plausible preclinical mechanisms, but the human data are quite conflicted. And I think therefore wouldn't really support routine use. In RCT of 99 adults with biopsy proven mash, silymarin, which is the active ingredient in milk thistle, taken three times daily for a year, didn't meet its primary endpoint on histologic activity score improvement. It's also important to separate brewed green tea from green tea extract, brewed teas look safe, but the trial data failed to show any benefit worth endorsing. So it's worth emphasizing, I think, that supplements marketed as containing green tea extract are a documented cause of clinically apparent liver injury. The NCBI's liver talks repository lists more than 100 cases, including acute liver failure leading to transplant or death. So while I think green tea is obviously harmless, but not necessarily useful, the supplements with green tea extract should really be avoided. They're probably more likely to cause you any harm than benefit. So on the whole, I would say the thesis for liver supplements is that it's a best, you know, at best, it's a tool for people who are deficient in something. Again, choline would be an example. But other than that, I wouldn't touch a liver supplement. So I would say I would never recommend it to a patient. So as we kind of land this plane, you know, how would you frame what a person listening or watching should be thinking about around their liver health? Okay. So first and foremost, figure out where you are on the four stage map, if you will, and then act to stop moving up. And if necessary, start moving down. So again, this begins with the assessment. So if you're a liver supplement, you should be thinking about where you are on the four stage map. So metabolic panel, fasting insulin, DEXA, specifically to look at visceral fat. If risk is sustained and the GGT and the FIB4 score are indicative, again, just look at all that stuff. If the FIB4 score is 1.3 or more, or you're persistently finding insulin resistance signals across, I think a FibroScan is an appropriate next step. If you already have steatosis or MaslD, that means probably doing an annual FibroScan and DEXA to see whether the interventions you're undertaking to move down and normalize the liver are working. And then basically it's what are the levers that you pull? And they're frankly the same, whether you're healthy and wanting to stay healthy, or whether you already have liver fat and liver disease, and you're trying to heal yourself. So again, you want to eat to match your energy expenditure. You can maintain muscle, and you want to use something like visceral fat as one of your metrics and keep it as low as possible. Again, it's much more important than subcutaneous body fat. Subcutaneous body fat might be the one that we aesthetically care about, but it's that visceral fat inside that is the one we should be managing to. And fortunately, it's an early responder to caloric deficit. You'll recall the data I shared earlier. 5% to 10% body weight loss can have a meaningful impact on both visceral fat, and ultimately liver fat. Now, if you're already in the stages of dysfunction, I hate to say this because I know alcohol is enjoyable for many reasons, But it becomes very difficult to justify drinking alcohol if you have Masl-D, let alone mash. And the reason, again, we go back to what we talked about, once you already have liver disease and metabolic liver disease and you add alcohol to it, the impact increases non-linearly. The other thing that I think is really just kind of a non-negotiable once you're in the Masl-D mash category is I just pull all calories out of beverages, especially sort of anything sugary and high in fructose. So if you're going to drink a protein shake, maybe that's fine, but I wouldn't be consuming calories in liquid. So I think those become both better ways to reduce calories, but also it puts less stress on the liver and the de novo lipogenic pathways. On the supplements, I would say I just wouldn't turn to these things unless you really felt you had a choline deficiency and that maybe taking that could help or vitamin E could provide some marginal benefit. But again, I'd be very cautious in opting for what sometimes appears as an easier way out. Again, we don't want to be afraid of pharmacology here. So this is an area where, first and foremost, the drugs that help with weight loss, which right now the GLP-1 agonists are probably best in class at that, but also drugs that are targeting metabolic health. So that includes everything that we talked about from pioglitazone to SGLT2 inhibitors and, of course, the GLP-1 agonists for that purpose. Again, the guiding principles here are simple. The interventions that heal the liver are the same ones that protect it. So the remarkable thing about the liver is that it spends years protecting you from metabolic dysfunction before it itself finally becomes a victim of it. And again, fortunately, that means you have lots of time to course correct and make changes. I think that wraps this conversation around the liver. Anything you want to add before? We let people go? No. I mean, what's interesting is we spent, I don't know how long we were talking there, but it was probably at least an hour, an hour and a half. And we really didn't touch on so much of the liver, right? I mean, we didn't talk about, you know, we didn't talk about the diseases like hepatitis and the primary sclerosing, cholangitis, and biliary stroke. I mean, there's so many other branches you can go down into liver health. And again, I think it is, it's a remarkable organ. And I think. And you know, any of the hepatologists around the world listening to this can, can, can speak to it more eloquently than I did, but, but probably appreciate, uh, things that, that I certainly don't. All right. Until next time, Peter. Have a good one. Thank you. Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com/shownotes. If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter. All with the handle peteratiamd.com/shownotes. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. 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