#405 ‒ AMA #88: Metabolic liver health: how to assess risk, catch dysfunction early, and prevent or reverse liver disease

0:10Peter Attia:Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast. I'm your host, Peter Attia. At the end of this short episode, I'll explain how you can access the AMA episodes in full, along with a ton of other membership benefits we've created, Or you can learn more now by going to peteratiyamd.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode.

0:38Peter 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.

1:33Peter Attia:So specifically, we're going to cover why the liver is the so-called canary in the coal mine for metabolic dysfunction, the four stages of progression from metabolic stress to fibrosis, and which stages are reversible, 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 our YouTube page.

2:17Peter Attia:So without further delay, welcome to AMA episode 88.

2:27Peter, 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 coalmine for metabolic dysfunction. So I think it'd be helpful to start with kind of talking about what you mean by that and why you think the liver is so important.

2:51Peter Attia: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 is 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.

3:35Peter Attia: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 standalone 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. And so that's why this is a metabolic episode as much as a liver one.

4:18Peter Attia:And I guess we should also name it up front. 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?

5:03Peter Attia: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.

5:44Peter Attia: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 synthesis 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.

6:27Peter Attia: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 maintaining blood sugar. It's, you know, you could 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.

7:07Peter Attia: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 in 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 on its own. 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.

7:54Peter Attia: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 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?

8:36Peter Attia: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 2 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.

9:26Peter Attia: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.

10:12Peter Attia: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.

10:57Peter Attia:But once the scarring accumulates into 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 care about, especially cardiovascular vascular 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 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?

11:41Peter Attia: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 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.

12:22Peter Attia: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 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.

13:05Peter Attia:Instead of simply storing fat, those particular fat cells or adipocytes begin releasing fatty acids back into the bloodstream. 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 as well as the fats from our diet, because that's one of the primary jobs is energy balance.

13:49Peter Attia: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 DeFranco on this, and it's one of my favorite podcasts of the past year or two 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.

14:30Peter Attia: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.

15:12Peter Attia: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.

16:02Peter Attia:So excess calories are often in the form of anything. It could be carbohydrates, glucose, fructose. So basically earlier we called this disease NAFLD, 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 steatohepatitis. Okay, now these things are called MASLD, M-A-S-L-D, and MASH, not the TV show.

16:51Peter Attia:And what does that stand for? That stands for metabolic dysfunction-associated steatotic liver disease and steatohepatitis. So basically it's the same disease, just new names. And I'm going to apologize in advance. I will occasionally still refer to these as Nafldi and Nash as opposed to Masldi and Mash. Again, apologies in advance for that, but please understand it's just new nomenclature to try to more accurately reflect the process of the disease. And on that, so once fat is built up, is that the point at which the liver starts to suffer actual damage? Well, steatosis is a giant warning sign.

17:29Peter Attia:It's not liver damage yet though, but you're sort of now on the path. to liver damage. So think of it as the liver stuffing excess energy inventory into the manager's office because the shelves are full. Something is clearly wrong, but at the packaging facility, nothing is breaking yet. If that analogy helps, it might not. Masal-D is diagnosed when that steatosis is accompanied by another cardiometabolic risk factor, such as hypertension, pre-diabetes defined by hemoglobin A1c, or even just type 2 diabetes itself, dyslipidemia, elevated BMI or obesity. Again, these are just sort of poor man's proxies.

18:14Peter Attia:But you get the point, which is liver fat accompanied by some other metabolic dysfunction is what we're looking for. And so that's our second stage, both metabolic stress as well as fat in the liver. The real damage begins when that fat burden triggers inflammation. Hepatocytes loaded past their limit actually start to die. Hepatocytes are just the cells that make up the liver. Their death recruits immune cells, which release inflammatory signals that spread to neighboring cells. And it's that inflammation that starts to disable insulin signaling through a second separate pathway. So the resistance is now coming from two directions at once.

19:01Peter Attia:With even more insulin resistance, the neighboring cells now accumulate more fat and die too. And then you get a spreading wave where each cell death drives the next. So as you can see, this becomes a feed forward kind of amplified loop. That transition, fat accumulating to active inflammation, is the move from stage two to stage three, what we call mash. And the liver responds to dying cells the way any tissue does. It lays down scar tissue. That's called fibrosis. It's our final stage of thinking about metabolic disease in the liver. As fibrosis accumulates, the liver moves towards cirrhosis.

19:52Peter Attia:That's the end stage scarring where so much functioning tissue has been replaced that the liver can't even do its job anymore. And you have to think back to all those other things I talked about, making proteins and clotting factors and doing detoxification, all that stuff starts to go out the window. This is also where cancer risk starts to climb dramatically. Fibrosis is where the really 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?

20:30Yes.

20:31Peter Attia:It's one of the most significant modifiers of liver risk. Not all fat is 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.

21:16Peter Attia: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 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.

21:59Peter Attia:And if you looked at the NHANES database, among people with diagnosed Mastel D, the all-cause mortality ratio in the top quartile of visceral adiposity was nearly three and a half times that in the lowest quartile. So 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?

22:40Peter Attia: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 people that actually have normal BMI, but are very low in muscle mass.

23:18Peter Attia: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.

24:04And do we know anything about if fructose may be more harmful than glucose?

24:11Peter Attia: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 enantomer, 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.

24:58Peter Attia: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 isocalorically for other carbohydrates, liver fat barely moves.

25:48Peter Attia: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 MASLD 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.

26:35Peter Attia: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 especially is 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?