The Peter Attia Drive - August 24, 2026


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


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39 minutes

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1

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5

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Transcript

Transcript generated with Whisper (turbo).
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00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.
00:00:15.820 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access
00:00:20.280 the AMA episodes in full, along with a ton of other membership benefits we've created,
00:00:24.900 Or you can learn more now by going to peteratiyamd.com forward slash subscribe.
00:00:30.600 So without further delay, here's today's sneak peek of the Ask Me Anything episode.
00:00:38.820 Welcome to Ask Me Anything AMA episode 88.
00:00:42.700 Today we are talking about the liver and specifically its role in metabolic health.
00:00:48.160 This is a topic that suffers from a strange mismatch.
00:00:52.380 On the one hand, the liver is one of the most metabolically important organs in the body.
00:00:57.800 It is the mastermind sitting at the center of how we handle glucose, fat, and cholesterol.
00:01:03.820 And on the other, most of the public conversation about the liver is about detoxes, cleanses,
00:01:09.460 and supplements, while the questions that actually matter go unasked.
00:01:13.840 So we're going to focus on one of the liver's main functions, how it serves as the centerpiece
00:01:21.160 of the whole body metabolism and walk through how to tell whether yours is under stress,
00:01:28.880 why that matters, and what actually moves the needle once you need to act. So specifically,
00:01:34.520 we're going to cover why the liver is the so-called canary in the coal mine for metabolic dysfunction,
00:01:40.800 the four stages of progression from metabolic stress to fibrosis, and which stages are reversible,
00:01:48.820 why normal liver enzymes can be misleading and what we actually use to detect and stage risk
00:01:55.920 what interventions work once risk or disease is identified plus an honest look at whether any
00:02:03.920 liver supplements are worth taking if you're a subscriber and you want to watch the full video
00:02:08.980 of this podcast you can find it on the show notes page and if you're not a subscriber you can watch
00:02:13.820 a sneak peek of the video on our YouTube page. So without further delay, welcome to AMA episode 88.
00:02:27.320 Peter, welcome to another AMA. How are you doing? Very good, thanks. Awesome. So today we're doing
00:02:33.500 the whole episode around one topic, which is the liver and metabolic health. In the past,
00:02:38.900 you've described the liver as the quote-unquote canary in the coal mine for metabolic dysfunction.
00:02:43.820 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.
00:02:51.500 Well, the liver sits sort of at the center of systemic metabolism for every macronutrient, glucose, fat, protein, as well as cholesterol.
00:03:03.220 And by the way, let's not forget ethanol or alcohol there as well.
00:03:06.560 So it's also one of the very first places to both promote and respond to stress from anywhere in
00:03:13.760 the system. If circulating triglycerides are high, the liver gets involved. If glucose regulation is
00:03:19.560 deteriorating, the liver is involved. If ApoB or LDL cholesterol is climbing, the liver made those
00:03:26.320 particles. And the flip side is equally true. If we look at the liver and see that it's under stress,
00:03:31.560 we know that these metabolic systems are also under stress. It's a two-way mirror between
00:03:37.360 systemic metabolic health and what's happening in the liver. And that's also why I think about
00:03:43.220 liver disease less about a standalone organ problem. Dysfunction of the liver is more of
00:03:49.740 a parallel expression of systemic metabolic dysfunction. The leading cause of death in
00:03:56.280 people with liver disease isn't liver failure. It's cardiovascular disease because a liver under
00:04:02.800 metabolic stress is overproducing ApoB-containing particles and amplifying the insulin resistance
00:04:09.300 that drives atherosclerosis throughout the body. And so that's why this is a metabolic episode as
00:04:16.520 much as a liver one. And I guess we should also name it up front. When we're talking about fatty
00:04:21.580 liver disease. We're talking about a disorder that is estimated to affect more than 38% of the
00:04:28.620 world's adult population, which is hard to believe. This isn't something that happens to some
00:04:35.440 unfortunate person that you'll never meet. It will happen to nearly anyone in the developed world who
00:04:43.140 isn't paying some attention. And I think it's worth kind of early on talking about what the
00:04:49.680 liver does, right? So I think for a lot of people, when they think of the liver, they usually think
00:04:54.260 about processing alcohol. So before we get too much into metabolic disease, can you frame in
00:05:00.300 a little more detail what the liver is doing in the body? Sure. And you're right. The alcohol
00:05:05.560 framing dominates, and that's a bit of an undersell. As our past guest, Julia Watercheryl
00:05:13.040 says the liver has over 300 functions, which is sort of staggering. Obviously, we're not going to
00:05:20.780 talk about many of those today, but I find it useful to conceptualize all of those as fitting
00:05:26.440 into four main categories. So the first is detoxification. The liver breaks down alcohol,
00:05:32.360 just as it would break down virtually any toxin that makes its way into the body from food,
00:05:37.200 drink, pharmaceuticals, inhalation, any toxin that reaches the blood, the liver plays a central
00:05:42.800 role in clearing it. Second, it is an immune organ. So the first place blood from the gut goes
00:05:50.480 is to the liver. All blood from the gut winds its way back into the portal system to the liver.
00:05:56.580 So it's one of the first responders to ingested toxins or bacterial leakage from the gut.
00:06:02.800 Third is protein processing and secretion. The liver is the site of synthesis for many of the
00:06:09.680 most common proteins in our blood, something as ubiquitous as albumin and as vital as clotting
00:06:16.880 and platelet-stimulating factors, ApoB, peptide hormones like IGF-1. The fourth category is where
00:06:23.120 we're going to spend most of our time today, and that is on energy metabolism. The liver plays a
00:06:28.500 central role in the uptake and synthesis of circulating fats and cholesterol and is one of
00:06:33.220 the most important organs, if not the most important organ, for the balancing act of
00:06:38.440 maintaining blood sugar. It's, you know, you could think of it as the metabolic headquarters
00:06:43.120 of the body, which is why when it's harmed, the damage is not just confined to the organ itself.
00:06:50.840 And so you mentioned there about the liver and blood sugar. Can you walk us through more
00:06:55.420 the liver's relationship with controlling blood sugar?
00:06:59.260 Yeah, it sounds simple, but the precision required to regulate blood sugar is extraordinary.
00:07:05.200 and it never ceases to amaze me.
00:07:07.320 It's one of my favorite things to explain to a patient.
00:07:10.280 After a meal, glucose rises.
00:07:12.780 The pancreas releases insulin
00:07:14.380 and insulin tells the liver to absorb glucose
00:07:17.560 and store it as glycogen.
00:07:19.540 Now, when you've been fasting for some period of time
00:07:22.040 and glucose dips, insulin falls
00:07:24.580 and then the liver does the opposite.
00:07:26.300 It breaks glycogen back down
00:07:29.180 and releases glucose into the circulation.
00:07:33.520 And when glucose runs really low, it can actually just manufacture glucose on its own.
00:07:38.840 So if you're, you know, going more than a day without eating, the liver turns into a
00:07:43.500 glucose-making organ.
00:07:45.760 If there's too much sugar to store as glycogen, the liver converts it into triglycerides,
00:07:50.080 packages it into apolipoproteins, and ships them out.
00:07:54.200 So what I want people to appreciate, though, is the scale of this.
00:07:57.840 So everybody, you know, think about, you go to the doctor, you get a blood draw, and it's,
00:08:01.960 you know, it's a fasting blood draw, right? And you get back a number. And so let's say that
00:08:07.340 number you get back says 90 milligrams per deciliter. That was your blood glucose that
00:08:12.280 morning when you showed up at the lab. If that's the case, your entire bloodstream in that moment
00:08:18.420 contained only about four and a half grams of glucose. That's roughly a teaspoon, not a tablespoon,
00:08:25.400 just a teaspoon. Yet a single meal, especially if it's a meal that I'm eating, may contain many
00:08:32.300 times that, easily 90 grams of glucose, right? So 20 times that amount in one meal. And yet despite
00:08:41.180 that, a healthy person rarely moves more than a teaspoon above baseline, right? In fact, I'm trying
00:08:49.940 to think of all the times I wore a continuous glucose monitor, if I ever saw a blood glucose
00:08:55.780 lever that would have been north of about 160 milligrams per deciliter. Someone with type 2
00:09:02.860 diabetes would rarely go above a teaspoon and a half at fasting. And when we can go hours without
00:09:12.840 eating, our glucose still stays in that range. In fact, if you go days without eating, it might
00:09:18.860 only dip to, say, 50 milligrams per deciliter. This is a monumental homeostatic achievement.
00:09:26.840 And that reserve capacity to titrate out glucose in such fine amounts is exactly why early
00:09:34.920 dysfunction is very easy to miss, which is something we'll, I'm sure, talk about.
00:09:40.300 Yeah. And so let's dive into more metabolic disease and how that affects the liver. And so
00:09:45.440 when looking at that, is there a framework that you typically use, typically talk through with
00:09:50.280 patients in explaining it? Yeah. I think the most useful framing is to consider metabolic liver
00:09:57.780 disease moving through four stages. So in the first stage, the liver becomes metabolically
00:10:04.200 stressed. And then the second stage in response to that, it starts storing excess, excess energy
00:10:11.400 that is as fat. And that's a condition known as steatosis. And then the third stage is
00:10:18.200 steatohepatitis. And that is just a fancy word for excess fat being stored in the liver, tips
00:10:24.580 the liver into inflammation, and then the liver begins to injure itself. And then the fourth
00:10:31.080 stage is the response to that injury, where it starts to lay down scar tissue. And that's a term
00:10:38.200 that people have probably heard called fibrosis in the liver. So those first three stages are
00:10:44.820 largely reversible. It's fibrosis that is a little trickier. It is biologically reversible to varying
00:10:53.020 degrees, especially if caught on the very, very early side of things. But once the scarring
00:10:59.600 accumulates into such that the liver's architecture is disrupted, that's the point that becomes
00:11:07.060 irreversible. Now, the presence of fibrosis is what predicts the outcomes that we typically care
00:11:13.440 about, especially cardiovascular disease, cancer, and even liver-specific mortality. So as we kind
00:11:19.060 of go through this exercise, I'll keep pointing back to where we are on that four-part scheme.
00:11:25.420 And you previously said that, you know, chronic calorie surplus is a primary driver of metabolic
00:11:32.280 dysfunction. And so can you walk us through the chain of the events from caloric surplus to
00:11:38.700 ultimately at the end, liver damage? Yeah, it starts relatively simply. If you consume more
00:11:45.180 calories than you expend consistently, the body has to put that excess energy somewhere. And the
00:11:51.740 liver converts much of it into triglycerides through a process of de novo lipogenesis.
00:11:57.680 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, and we had to be able to draw from that when energy was scarce.
00:12:26.280 So, so far, this is normal.
00:12:28.620 It's obviously, as you can see, it's going to become abnormal at some point.
00:12:32.080 So think of a fat cell as a warehouse.
00:12:34.440 For a while, they will accept every shipment.
00:12:37.260 But as they become progressively overfilled, they stop responding normally to insulin,
00:12:44.060 which is kind of the most important hormone that's involved in this process.
00:12:47.220 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.
00:13:00.840 So once that happens, the warehouse starts malfunctioning.
00:13:04.980 Instead of simply storing fat, those particular fat cells or adipocytes begin releasing fatty acids back into the bloodstream.
00:13:13.280 exactly what you don't want unless you're about to use them immediately. The problem is there's
00:13:19.200 already too much energy in circulation. So the last place you want more triglycerides is being
00:13:24.100 released back into the bloodstream. So now the liver has to deal not only with the excess calories
00:13:28.820 coming in from the diet, but also the excess fat coming back into the circulation from those
00:13:34.300 defective fat cells. And what happens to the free fatty acids in the blood?
00:13:39.900 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. But eventually the same process develops here. So lipid intermediates begin to accumulate, insulin signaling becomes impaired, and the liver becomes insulin resistant.
00:14:03.440 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.
00:14:18.880 And insulin resistance in the muscle versus the fat cell versus the pancreas versus the liver, they all look a little bit different.
00:14:23.900 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.
00:14:31.020 But here's the part that's really important.
00:14:32.940 Insulin normally tells the liver to do two things.
00:14:36.960 Stop releasing glucose into the bloodstream
00:14:39.700 and stop making new fat cells.
00:14:42.580 Why?
00:14:43.040 Because if insulin is high, you've just been fed.
00:14:45.460 And if you're fed, you don't need to be putting glucose
00:14:47.620 into the bloodstream or making new fat.
00:14:49.880 But as insulin resistance develops,
00:14:53.020 the first signal fails before the second.
00:14:56.220 So the liver continues releasing glucose
00:14:58.220 even when blood sugar is already high.
00:15:00.500 while the pancreas responds by making more insulin, which still drives fat production.
00:15:05.540 So that's called selective hepatic insulin resistance, and it's one of the defining
00:15:09.860 features of metabolic disease. At first, the liver exports those triglycerides in these
00:15:15.280 ApoB-containing particles, and again, that just means LDLs and VLDLs, which is why dyslipidemia
00:15:20.780 always accompanies this. And eventually, production outpaces exports. So fat accumulates
00:15:26.900 inside the liver. And now we've reached stage two of our little linear progression. This is now
00:15:33.820 steatosis. And so what are the liver diseases that you're concerned about as a result of that
00:15:40.520 metabolic dysfunction? Well, the name changed recently, updated to reference the cause of the
00:15:49.980 disease and move away from the fat in the name because fat is basically the end result of
00:15:57.860 caloric excess, but that excess isn't usually fat itself. So excess calories are often in the form
00:16:05.820 of anything. It could be carbohydrates, glucose, fructose. So basically earlier we called this
00:16:12.380 disease NAFLD, non-alcoholic fatty liver disease. And then if it progressed to the inflammation
00:16:20.680 damage stage, it was NASH, which just stood for non-alcoholic steatohepatitis. By the way,
00:16:27.600 the NA in both of those non-alcoholic is just so that we try to understand that this was
00:16:33.820 driven more through excess energy, but not through the damage specifically of alcohol,
00:16:39.940 because you can also get alcoholic fatty liver disease and alcoholic steatohepatitis.
00:16:45.520 Okay, now these things are called MASLD, M-A-S-L-D, and MASH, not the TV show. And what does
00:16:52.460 that stand for? That stands for metabolic dysfunction associated steatotic liver disease
00:16:59.160 and steatohepatitis. So basically it's the same disease, just new names. And I'm going to apologize
00:17:04.300 in advance. I will occasionally still refer to these as NAFLD and NASH as opposed to MASLD
00:17:09.860 and mash. Again, apologies in advance for that, but please understand it's just new nomenclature
00:17:14.920 to try to more accurately reflect the process of the disease. And on that, so once fat is built up,
00:17:21.220 is that the point at which the liver starts to suffer actual damage?
00:17:26.460 Well, steatosis is a giant warning sign. It's not liver damage yet though, but you're sort of now on
00:17:33.740 the path to liver damage. So think of it as the liver stuffing excess energy inventory into the
00:17:42.120 manager's office because the shelves are full. Something is clearly wrong, but at the packaging
00:17:48.520 facility, nothing is breaking yet. If that analogy helps, it might not. Mazel-D is diagnosed when
00:17:55.820 that steatosis is accompanied by another cardiometabolic risk factor, such as hypertension,
00:18:02.860 pre-diabetes defined by hemoglobin A1c, or even just type 2 diabetes itself, dyslipidemia,
00:18:09.040 elevated BMI or obesity. Again, these are just sort of poor man's proxies. But you get the point,
00:18:15.080 which is liver fat accompanied by some other metabolic dysfunction is what we're looking for.
00:18:22.500 And so that's our second stage, both metabolic stress as well as fat in the liver. The real
00:18:27.600 damage begins when that fat burden triggers inflammation. Hepatocytes loaded past their
00:18:35.340 limit actually start to die. Hepatocytes are just the cells that make up the liver. Their death
00:18:40.240 recruits immune cells, which release inflammatory signals that spread to neighboring cells.
00:18:46.840 And it's that inflammation that starts to disable insulin signaling through a second
00:18:54.140 separate pathway. So the resistance is now coming from two directions at once. With even more
00:19:02.940 insulin resistance, the neighboring cells now accumulate more fat and die too. And then you
00:19:10.440 get a spreading wave where each cell death drives the next. So as you can see, this becomes a feed
00:19:18.400 forward kind of amplified loop. That transition, fat accumulating to active inflammation, is the
00:19:27.960 move from stage two to stage three, what we call mash. And the liver responds to dying cells the
00:19:36.800 way any tissue does. It lays down scar tissue. That's called fibrosis. It's our final stage of
00:19:44.620 thinking about metabolic disease in the liver. As fibrosis accumulates, the liver moves towards
00:19:51.520 cirrhosis. That's the end stage scarring where so much functioning tissue has been replaced
00:19:58.180 that the liver can't even do its job anymore. And you have to think back to all those other
00:20:02.440 things I talked about, making proteins and clotting factors and doing detoxification,
00:20:06.440 all that stuff starts to go out the window. This is also where cancer risk starts to climb
00:20:11.360 dramatically. Fibrosis is where the really durable clinical risk lives.
00:20:19.340 And when talking about metabolic dysfunction, we often hear visceral fat as well. So what do we
00:20:24.300 know about visceral fat in the liver? Does visceral fat affect the liver specifically?
00:20:30.520 Yes. It's one of the most significant modifiers of liver risk. Not all fat is metabolically equal.
00:20:38.360 fat stored around your organs is actually more prone to releasing fatty acids even at baseline.
00:20:44.820 But the bigger factor is definitely location. So visceral fat, fat around the abdominal organs
00:20:51.700 drains directly into the portal vein, which is one of the two blood supplies that goes to the
00:20:57.840 liver. It's the one that drains the GI tract, so all of the gut and all of the metabolites that
00:21:04.120 come from digestion. So subcutaneous fat releases fatty acids that diffuse through the entire
00:21:10.640 circulation first. So it's just far less concentrated in terms of a shot directly into the
00:21:15.820 liver. Visceral fat bypasses all of that. And so it's the difference between, you know, someone
00:21:20.640 yelling at you from across the house versus like shouting directly into your ear. Same signal,
00:21:26.200 but just much higher intensity because of where it's coming from. And the data bear this out. So
00:21:31.640 in one cohort, visceral fat area, which could be estimated by CT scans, predicted steatosis
00:21:39.880 independent of BMI and liver enzymes. So patients with greater than 200 centimeters squared of
00:21:48.900 visceral fat had a seven and a half fold greater increase of liver steatosis when compared to
00:21:56.160 people below 100 centimeters squared.
00:22:00.220 And if you looked at the NHANES database, among people with diagnosed
00:22:04.800 Massel D, the all-cause mortality ratio in the top quartile of visceral
00:22:10.560 adiposity was nearly three and a half times that in the lowest quartile.
00:22:15.840 So visceral fat predicts liver pathology and in the people who already
00:22:21.360 have liver disease, visceral fat predicts a dramatically higher risk of death.
00:22:26.160 And in the past, when talking about metabolic health, you've often talked about the importance
00:22:30.640 of resistance training. So what do we know about how does resistance training interact with the
00:22:35.980 role of the liver in metabolic dysfunction? Well, even more so than the liver, skeletal
00:22:42.620 muscle is a major glucose sink in the body. In fact, it is hands down the largest sink of glucose
00:22:47.300 in the body. So it pulls blood sugar out of circulation and stores it as glycogen. So
00:22:51.840 roughly speaking, about three quarters of your total capacity to store glucose is in your muscle
00:22:58.740 and about a quarter of it's in your liver. And that's again, storing it as glycogen. So less
00:23:03.500 muscle means what? Therefore means less capacity to buffer glucose. So more of that burden lands
00:23:09.180 on your liver. It's why you see metabolic liver disease in people that actually have normal BMI,
00:23:15.480 but are very low in muscle mass. Sarcopenic obesity is the technical term for that,
00:23:21.440 what people call skinny fat. And multiple longitudinal cohorts point the same thing
00:23:26.740 out. More muscle predicts both fewer new cases of Masl-D and higher rates of resolution.
00:23:32.680 The single most striking figure comes from a large seven-year Korean cohort. People who gained
00:23:42.160 the most muscle over the study resolved their Masl-D at more than four times the rate of those
00:23:48.920 who gained the least muscle. We'll include all of this in the show notes. So whether it's prevention
00:23:54.180 or reversal, the direction here is pretty unambiguous, which is why resistance training
00:23:58.940 is kind of a non-negotiable if you're trying to address metabolic dysfunction.
00:24:05.340 And do we know anything about if fructose may be more harmful than glucose?
00:24:11.040 This is a very interesting question and one that it's very easy to get wrapped around the axle on
00:24:16.900 this one. The cleanest human experiment, and I only want to focus on the human experiments because
00:24:23.160 we could spend the entire day on this question, Nick, if we wanted to talk about all of the animal
00:24:27.880 stuff. But the cleanest human experiment is a randomized trial in 94 healthy men who drank
00:24:33.940 moderate amounts of fructose, which is again, just the pure sweet enantomer, sucrose, which is the
00:24:43.040 50-50 mix of fructose and glucose or glucose sweetened beverages for seven weeks at weight
00:24:50.520 stability. So it's very important when you do these studies that you have to keep the subject's
00:24:54.840 weight stable because if you don't, it confounds everything. In this study, fructose and sucrose
00:25:01.340 roughly doubled the liver's baseline fat-making machinery, this so-called de novo lipogenesis
00:25:08.780 pathway. De novo just means new, and lipogenesis means fat-creating, while glucose did not. So at
00:25:15.480 least in this study, fructose can behave differently from glucose in the human liver,
00:25:20.940 and where that shows up most cleanly is in these measurements of de novo lipogenesis.
00:25:28.480 But on the harder outcome, actual steatosis, controlled feeding studies show the dominant
00:25:35.680 driver is excess calories and not fructose itself. So if you swap fructose isocalorically for other
00:25:45.220 carbohydrates, liver fat barely moves. So calorie for calorie, the honest fructose-specific signal
00:25:54.000 is on lipogenesis, which is an intermediate measure but not the final outcome. Where fructose
00:26:00.440 earns its reputation is in the form that it arrives in. Liquid sugar in soda, for example,
00:26:07.420 or other, you know, high fructose corn syrup laden beverages, which are very calorie dense,
00:26:12.640 don't make you feel full and are trivially easy to consume. And the cohort data do link
00:26:19.040 sugar sweetened beverages to higher NAFLD risk or MASLD risk. So the practical advice holds
00:26:26.400 cutting sugar-sweetened beverages is absolutely one of the higher-yield dietary moves for someone
00:26:32.900 with insulin resistance or liver disease. But it's really the chief reason for that is that it's
00:26:40.740 going to have its downstream effect on less calorie reduction. So one of the things I absolutely
00:26:45.940 would counsel somebody on who has fatty liver disease is don't drink calories at all, and
00:26:51.100 especially don't drink carbohydrate calories and especially don't drink fructose containing
00:26:55.980 calories. A lot of especially is there in that statement. Sounds like it was super important.
00:27:02.160 All right. So going now to what we talked about earlier on, which is when people think about the
00:27:05.680 liver, they think about alcohol. So how should we think about alcohol here as it relates to the
00:27:11.960 liver? Yeah. Alcohol is a pretty clean story. You'll recall a second ago, I said that the reason
00:27:16.140 we have to put the NA non-alcoholic or, you know, whatever in front of those is to differentiate
00:27:22.500 it. It can cause fatty liver on its own. So alcohol associated liver disease, which by the
00:27:28.340 way is more common than, than we give it credit for. It's very easy to just focus on the non-alcoholic
00:27:34.900 metabolic versions. But if you actually look at the people requiring liver transplants,
00:27:39.620 I don't remember the latest numbers, but the last time I looked, I was very surprised
00:27:43.800 at how many, I think more of those came from alcohol consumption than non-alcoholic consumption.
00:27:52.040 Again, I could be off on that, but I just remember being sort of surprised. Now that said,
00:27:56.600 it works through a different mechanism than caloric excess, but it turns out the outcome is
00:28:01.300 almost the same. You pass through these categories of steatosis, insulin resistance, fibrosis,
00:28:08.780 ultimately cirrhosis. Different mechanism, which is why it's very harmful if you combine it with
00:28:16.440 metabolic dysfunction, as is often the case. So now you're getting basically a two-pronged
00:28:22.560 synergistic attack when you have calorie excess and alcohol co-occurring. The combination of
00:28:29.840 metabolic dysfunction and alcohol consumption recently earned its own designation, which I,
00:28:35.860 frankly, I think we're getting a little ahead of ourselves, which is metabolic and alcohol-associated
00:28:40.900 liver disease, or METOLD. I'm not going to say that ever again. There's a very telling cohort
00:28:49.020 study from the NHANES database in patients with existing cardiometabolic risk factors.
00:28:55.240 If you already had a risk factor, steatosis alone wasn't associated with increased all-cause
00:29:01.140 mortality. But steatosis plus what they described as moderate, and I might call moderate plus
00:29:07.920 alcohol consumption, produced hazard ratios of 1.4 for all-cause mortality, 2.35 for cancer
00:29:16.340 mortality, and a whopping 15, please check that number again, yes, 15X for liver-specific mortality
00:29:26.040 versus people with no steatotic liver disease.
00:29:29.120 So to put those into actual relative risks,
00:29:32.760 that's a cause of death from anything is up 40%.
00:29:36.720 Death from cancer is up 135%.
00:29:40.480 And from liver-specific disease, death is up 1,400%.
00:29:47.420 So again, the purpose of me sharing this
00:29:51.260 is not to tell you never to have another drink.
00:29:53.460 it's to explain that when you add alcohol to liver disease, it gets really bad. Now, if we look at the
00:30:00.520 pattern of drinking, there might be some, again, something to glean here. So, acetyl aldehyde is
00:30:08.160 the primary driver of alcohol's harm on the liver, and it accumulates faster the more you exceed
00:30:16.720 about one drink per hour. Therefore, mechanistically, I get asked this question all the time,
00:30:23.640 but I think what we could say is seven drinks in one evening is probably worse for you than
00:30:32.720 one drink per night, seven consecutive nights. Again, I haven't seen the data for that, but
00:30:40.040 when you understand the mechanism of action, I think that makes sense. But that's basically,
00:30:43.820 I think the point here is that, you know, human data directly comparing binge versus daily
00:30:49.980 drinking don't exist for the metabolic disease. And I suspect we're not going to have an RCT for
00:30:55.020 that, but that's kind of the point on alcohol and metabolic liver disease.
00:30:59.980 And to follow up on the NHANES study, do we know how much alcohol they were actually drinking?
00:31:07.600 Yeah. Again, everything is self-reported. So it's possible that this is what they were drinking.
00:31:12.280 It's also possible this is a slight underestimate. I believe the men were drinking 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.
00:31:32.580 because again 60 grams of ethanol is technically for normal sized drinks or potentially less if
00:31:40.340 you're drinking you know if you're pouring it yourself the point i would also add to that nick
00:31:45.200 is there are lots of people who can drink that amount and they're totally functional so i don't
00:31:49.200 want the interpretation to be this is only for people you know who are rampant alcoholics because
00:31:56.680 Lots of people can be drinking three drinks a day and obviously have no obvious side effects of that.
00:32:04.340 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?
00:32:18.140 Yep. I would put these into two buckets, the inherited genetic piece and then obviously the hormonal piece, which can fluctuate over time.
00:32:24.500 So on the inherited side, the most important single gene variant here is something called PNPLA3.
00:32:32.500 And people who carry two copies of a particular variant here tend to have about 2x the risk of, or the likelihood of accumulating liver fat.
00:32:43.340 And then with that comes the elevated risk of inflammation and fibrosis, even after accounting for standard metabolic risk factors.
00:32:50.380 There are also variants that appear protective, especially a loss of function variant in a gene
00:32:58.100 called HSD17b13, which is associated with lower liver enzymes and fibrosis risk. And it may
00:33:05.740 actually partially offset the PNPLA3 associated risk. There are other variants as well. Again,
00:33:11.880 we'll kind of list them in the show notes for completeness. But I think the larger point here
00:33:16.060 is that there is an absolute genetic predisposition and even some protection that we see. And it,
00:33:24.400 I mean, I think any clinician can attest to this, right? You've got that patient who,
00:33:29.180 for whatever reason, two people doing the exact same things and they have completely different
00:33:33.900 liver health. It's also why ancestry can show up in population level risk, though, you know,
00:33:39.700 we have to be careful not to overstate it. So the PNPLA3 risk variant is much more common in people
00:33:45.740 with Hispanic ancestry. So that's why at the population level, we know that Hispanics are 0.99
00:33:50.340 much more sensitive to, and therefore susceptible to Masldi and MASH. And it's actually the exact 0.97
00:33:58.040 opposite in people of African ancestry. So that likely contributes to what we see clinically.
00:34:05.480 But again, that doesn't mean at the individual level, that's always the case. So I don't want
00:34:09.540 someone who's listening to this, who's black to think, great, I can't get Masldi, you know, 1.00
00:34:14.420 away I go. And I don't want someone who's Hispanic to listen to this and say, oh, well, 1.00
00:34:18.240 great. This is my destiny. It's just, again, it's a predisposition, but it's, it's, you know,
00:34:22.980 it's not destiny. So, I mean, there are also now body composition differences that standard labs
00:34:28.680 and BMI stuff can always miss. So for example, many people who are of Asian ancestry develop
00:34:34.920 metabolic risk at lower and normal BMIs in part, again, because visceral adiposity can be higher
00:34:41.120 at a given body weight in a group of people who otherwise don't genetically accumulate much
00:34:46.660 subcutaneous fat. So again, this is why I think body weight and BMI, while at the population
00:34:52.340 level are useful tools, at the individual level offer nothing. I wouldn't be able to tell you
00:34:57.200 the BMI of one of my patients, but I can tell you virtually every one of their total body fat,
00:35:02.260 visceral fat, and other measurements that are more nuanced. So that's what really matters.
00:35:06.460 The other major baseline modifier is menopause. So premenopausal women are relatively protected. 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. 0.99
00:35:31.900 So again, all of these things, ancestry, family history, genotype, menopause status, all of these things belong in the risk assessment. But again, none of them replaces the core question, which is what is the person's actual metabolic phenotype? So I don't want to get too hung up on knowing what increases or decreases risk beyond what I just said. I think what we really want to focus on is how do you actually measure it objectively in yourself unambiguously.
00:35:58.600 Peter, let's move into that, which is how people figure out kind of their liver health in a way.
00:36:04.500 So I think if you ask most people, they would assume that if they go get annual blood work done
00:36:08.880 and their liver enzymes come back normal, everything is fine with their liver. So first
00:36:13.480 and foremost, would you say that is true? Thank you for listening to today's sneak peek
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