Peter's takeaways on liver health, heart rate variability, AI in medicine & more (PS 2 sneak peek)

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 0:10 – 2:28

   Overview of topics, and the positive feedback on the quarterly podcast summary format

   1. SPSpeaker0:11

      Peter, welcome to another AMA. How you doing?

   2. PAPeter Attia0:13

      Good. Thanks for having me back.

   3. SPSpeaker0:14

      [chuckles] You're always welcome. Um, so this will be the second episode that we've done like this, which is kind of our quarterly podcast summary. We released the first one back in June, received really positive feedback. People really liked it, wanted us to continue to do it. And so today, we're gonna look at previous and recent episodes of "The Drive." And as we look at them, we'll kind of look at what your key takeaways are from the episode, along with anything you changed as a result, whether behavior, whether your mind, whether how you're thinking about things, anything of that nature. And so today's episode, if all goes well, will cover topics such as the liver, liver health, heart rate variability and training, AI in medicine, klotho and Alzheimer's disease, lactate, and more. So, with all that said, anything you want to add before we get rolling?

   4. PAPeter Attia1:09

      Only that I was so pleasantly surprised at how people, um, took to the first episode of this quarterly summary that we did in June and said, um, "Hey, that was the, like, single most valuable piece of content you've ever put out." And, um, I-- what I thought was, was, was nice that there were people who said, "Look, these are episodes I didn't listen to, and now I just got the summary," or, "These are episodes I didn't listen to, and I got this summary, which made me go back and listen to the actual episode," or, "Hey, I did listen to it, but honestly, it's just hard to remember everything." So, um, you know, I, I think when we sat here three months ago and recorded the first one, we were sort of like, "Well, you know, we hope people like it, and if you don't like it, we, we certainly won't waste anyone's time doing it." But, uh, the, the, um, I don't-- I, I think it might be the most emails we've ever received for a single podcast with people saying, "This was fantastic. Please do it more." So, um, it's really nice to hear that, and obviously, it's our pleasure now to just make this a regular part of what we do each quarter.

   5. SPSpeaker2:10

      Yeah. And you kind of hinted at there too is, you know, it's important to note these aren't replacements for listening to episodes. Like, a lot of times they're good either refreshers, good to figure out to go back and listen to, or just to kind of put the pieces together based on what you heard. And so, with that said,

3. 2:28 – 15:27

   Julia Wattacheril episode: liver health and disease

   1. SPSpeaker2:28

      first episode we will look at is the one with Julia Wattacheril on liver health, liver disease, NAFLD, MASLD, everything as it relates to the liver. So, you want to kick us off?

   2. PAPeter Attia2:41

      Yeah. This was, um, you know, this was an at times technical episode. Um, a-again, it's a, this is a classic episode of "The Drive," right? Meaning y-you just, you don't expect to turn on a podcast and, and walk into a graduate level seminar on the liver. But if you take a step back and think about it, we kind of need to, right? It is arguably one of the most important organs in the body. It is certainly an organ, uh, as we discuss, that for which we have no extracorporeal support, meaning, you know, if your kidneys fail, God forbid, that's very bad, but at least you have the option of dialysis. Uh, if your lungs fail, again, not a good thing, but at least you have a ventilator. Even if your heart temporarily fails, we have ways to support that outside the body, and yet remarkably, we don't have this for the liver. If a person goes into liver failure, their only solution is a liver transplant. And, um, what that speaks to, obviously, is the diversity and complexity of function in this organ. So the role that it plays, and, and we really talked about it in three categories: metabolism, protein synthesis, and detoxification. Um, th-there simply is no parallel for those things. Now, we of course then talked about the role of alcohol. Everybody's aware, of course, that alcohol is metabolized by the liver, and therefore that, uh, excess alcohol is, is toxic, but we talked a little bit about the how and the why, right? And that the metabolite of ethanol known as acetaldehyde, um, basically causes all of the downstream problems by overwhelming the redox potential of cells in the liver, and that creates the attraction of free radicals and inflammatory cells. Um, we did a great job, I think, really just kind of talking about w-w-- dose makes the poison here. Um, so if a, if a standard drink contains about fourteen to fifteen grams of ethanol, that will usually be found in about twelve ounces of a regular beer. Um, interestingly, my favorite beer, which contains, like, ten percent alcohol, it would be-- you'd get that fourteen grams in far less. Uh, five ounces of wine, one and a half ounces of liquor. Um, so if you're trying to think about how much ethanol you consume, um, you have to be mindful of the drink. I notice that when I'm pouring a glass of wine for myself or somebody else, it's never five ounces. It's probably closer to eight. Um, so, you know, a-again, I, I don't think it's intuitive for people to think about how many grams of ethanol they're consuming. Um, and we wo-- we didn't go much further into it here because we've done so much other content, which we can link to in the show notes, about the toxicity of ethanol based on how many grams per day or grams per week you're consuming. Okay. Next major topic we got into was that of what is called MASLD or metabolic dysfunction-associated steatotic liver disease. That's a mouthful. Um, why did we bring that up? Well, because you'll always hear me, and for that matter, many other people talking about NAFLD or non-alcoholic fatty liver disease. So, um, this was an education for me as well, and I think for the listener, which is, um, we talk about NAFLD, and that's been something that's been talked about for the last twenty years. It's the fastest growing, uh, form of liver disease, uh, in the developed world. Um, and it's probably poised, um, in its, in its, uh, long-term sequelae to be the leading indication for liver transplant, uh, within the next decade. But the reason that the liver societies and the medical societies have taken on this name change is to basically be more encompassing. Um, so again, NAFLD has the intuitive point of saying, okay, it's, it's, it's a fatty liver disease that does not result from the consumption of alcohol, because of course, AFLD or alcoholic fatty liver disease would, would be the sort of sister disease. But the, this idea of MASLD or metabolic dysfunction associated, uh, steatotic liver disease, um, speaks to the complete overlap of insulin resistance metabolic syndrome type 2 diabetes here. Now, um, to be clear, the overlap is so strong that I honestly think for those of you as listeners, I don't know that it matters that much. According to Julia, ninety-nine point six percent of people who meet criteria for NAFLD will also have the diagnosis of MASLD. So at that level, it's not really clear. Um, the diagnosis is based on metabolic dysfunction. So that's, that's really the key thing when it comes to MASLD is you also have to have insulin resistance, but it does not require fibrosis. It requires also that at least five percent of the hepatocytes, so hepatocytes are the liver cells, it's the functional unit of the liver, they have to contain fat. One of the things that we talked about that I used to know, and this is a great example of doing this podcast, is like there were things I once knew and then I kind of forgot, and this was one of them, was about the difference between kids and adults and the different pattern of fibrosis that they have. So in kids, it's more circulated around the portal vein. Uh, the portal vein, again, this is maybe a little more in the weeds than people want, but for me it was very interesting. The portal vein is the vein that brings the majority of the nutrients to the liver. So the portal vein is formed by the confluence of two enormous veins in the abdomen, the superior mesenteric vein and the splenic vein. And so they merge together and run into the liver, and that's carrying, you know, just tons of nutrients in, into the liver. And, and in that sense, the liver has two blood flows that are coming into it, one through the portal vein and one through the hepatic artery. Um, so what's the implication of this? Well, again, uh, the anatomy of it notwithstanding, what's the implication is, um, what do you see from a diagnosis perspective? And in kids, you're going to see an earlier increase in, uh, ALT, AST, and GGT. Now again, you'll often hear these things referred to as, um, liver function tests. We talk about how, you know, that's, that's really-- We accept that as terminology, but the reality of it is they really tell us nothing about liver function. Um, they are enzymes that are associated, uh, with, with, with liver or hepatocyte health. And when those enzymes go up, we generally understand that some sort of injury has taken place. We'll talk about that more in a moment. In adults, the, uh, fibrosis and steatosis tends to occur closer to the central vein, and as a result of that, uh, you see a delay in the enzyme elevation. So what does that mean clinically? It means that if you're an adult and you're developing steatosis and fibrosis, it could actually be taking place for quite a while before you see it. And, and that's why another huge takeaway, which I'll get to in more detail in a moment, is that this reliance on elevations of the transaminases, which are the technical names for ALT and AST, and using that as your threshold for concern, uh, might be waiting a little bit too long. So, so now if you look at the top three causes of liver injury in the form of steatosis and fibrosis, you have MASLD number one, followed by alcoholic liver disease, again, something we should never forget, and then finally, uh, infections, of which hepatitis is the most common.

   3. SPSpeaker10:15

      And real quick on that, Peter, just so people understand is, you know, we had an older episode with Chris Saunende kind of on organ transplantation, and back in that episode, y'all talked about the liver. But the fact that MASLD is now number one is something that wasn't even close to true twenty, thirty, forty years ago, correct?

   4. PAPeter Attia10:36

      Yes. In fact, I even write about this a little bit in Outlive that I, I, I recount a story when I was, uh, God, either a medical student or an intern ver-- you know, so more than twenty years ago, um, operating on a patient and, you know, one of the jobs-- I think it was when I was an intern because one of the jobs of the intern is to pre-op the patient. Pre-op the patient means get them ready for surgery, and among those things is understanding how much alcohol they consume because when a patient is undergoing major abdominal surgery, as was this patient for the resection of a colon cancer, uh, alcohol withdrawal is a medical, uh, uh, uh, it's, it's a very serious medical complication. So patients who are drinking three or four drinks a day when they're in the hospital will either need to have a continuous, uh, infusion of ethanol or they'll have to have more benzodiazepines to cope with the withdrawal, which, which can actually be fatal. So point of it is, you better understand how much alcohol your patient drinks. And I'm talking to this guy the day be-- the night before surgery, and he's telling me he doesn't drink anything. Okay, great. You know, and I, you know, whatever. I ask in a de-arming way. It's not like, you know... These are questions that people typically answer without reservation. We get into the operating room to do surgery on this guy, and his liver looks like it's a piece of fat. Um, and at the time, I, I, I think everybody just assumed, A, I was a moron for not finding this out ahead of time, and B, once they realized, yes, I did in fact ask, that he was lying. Um, and in fact, what I now realize, 'cause we never really gave it another thought. Let's-- I, I wish I could tell you, like, this led to, you know, some, some lifetime journey of mine to understand it. It was just, "All right, let's get his colon out and make sure his cancer's gone." But I now look back and realize he-- this guy clearly had what we would have at the time called NAFLD. So that's a long-winded way of saying you're absolutely right. Twenty to twenty-five years ago, this was really not something that was recognized, although it was probably far more prevalent than we believed. Um, but I would say that by, I would say twenty ten to twenty twelve, most people felt like, yeah, this is, this is an epidemic, um, and, and this is going to be an enormous burden on the healthcare system as far as liver transplantation. Again, getting back to the point at the outset, which is that, um, extracorporeal support of a dysfunctional liver is not possible. So we should spend just a second talking about hep B and hep C. Um, obviously people have heard of those things. For hep B, we do have a vaccine today. Um, for hep C, we do not. Conversely, for hep C, we have a treatment, uh, whereas for hep B, we do not. Um, so the net-net is if you're, you know, someone who's coming of age today, you know, you're a teenager today, um, you're probably going to have a hep B vaccination, um, which is going to protect you from that, and should you contract hep C, you're going to have a treatment. However, there are many people for whom, uh, you know, hep B was acquired before a vaccination was prevalent. Um, and why do we care about this? Well, we care about it for two reasons primarily. Uh, the first is the risk of, um, liver failure and all of the things we talk about through this pathway of steatosis, fibrosis, and ultimately what is called cirrhosis, the irreversible fibrotic change of the liver. But the other thing we have to talk about here is hepatocellular carcinoma, which is a deadly type of cancer if not caught very, very early. Um, and so the, the cancer risk here is, is, is a, is a greater issue from the infectious side. So, um, you always want to be screening patients for hep C, um, and hep B regardless, um, if-- of, of, of the workup. So in other words, when we're working patients up for, you know, usually the first thing we're seeing is this elevation in transaminases, um, we're also including a hep C and a hep B, uh, workup. You know, the other thing to keep in mind here is that MASLD and alcoholic liver disease are also increasing the risk of hepatocellular carcinoma. So it's not just hep B and hep C. Um, and as a general rule, again, this was something I learned in the podcast, either I'd forgotten it or never knew it, that as the scarring and fibrosis of any of these diseases, MASLD, uh, alcoholic liver disease, hep C, hep B, as the degree of scarring and fibrosis increases, uh, so too does the risk of cancer. And by the way, I misspoke there a little bit. For hep B, that, that risk is regardless of disease progression. So, so let me just restate that. So hep B, you're going to see about a three to five percent per year cancer risk regardless of where you are in the disease. Uh, so fortunately, again, we have a vaccine to reduce your risk of that. Um, but for the others, it-- the risk of cancer goes up with the risk of disease. Okay, I think

4. 15:27 – 27:42

   Noninvasive methods to diagnose liver conditions, and how to manage and improve liver health

   1. PAPeter Attia15:27

      the last thing to talk about on this topic is what-- you know, how do you make the diagnosis? Because the gold standard for this is to do a biopsy. Um, and it's not that a liver biopsy is, you know, as complicated as a cardiac biopsy or even a lung biopsy, but, um, that's not a procedure you would just go and do willy-nilly to stick a, uh, to stick a needle into, uh, into the liver, um, with its risk of bleeding primarily or also infection. So w-really what we want to do is understand how to, how to make this diagnosis, um, noninvasively. So look, a-again, nobody wants to do a liver biopsy. So, so we're really talking about blood-based biomarkers and, uh, radiographic, um, or, or imaging modalities. So, so let's start with the most obvious of these and start with the blood-based biomarkers. If we're now going to look at blood-based biomarkers, the two most common of these, the transaminases, which again are erroneously a-and often referred to as liver function tests, are ALT and AST. And unfortunately, we cannot diagnose MASLD/NAFLD with those, uh, biomarkers. Um, now w-the reason that we see an elevation of these during, uh, uh, fat accumulation and/or fibrosis in the liver is that these are enzymes made by the hepatocytes that are released into plasma when the liver is stressed. So as you see more ALT and AST, that indicates more stress. But it gets a little complicated because AST is also found in muscle. And therefore, as you exercise, you will also see more AST increase into the plasma. And in fact, that's one of the things we use to try to understand this. Um, so I-- my AST is always higher than my ALT. My ALT is typically in the mid to high twenties, and my AST is typically in the low to mid thirties. That is the typical pattern for me and for many of our patients, and we know that that is a pattern that is pretty typical of people who are doing quite a bit of exercise. Now, the general rule of thumb is that you would like to see an AST and ALT both below about thirty IU per liter. Um, again, I just told you that my AST is typically a little bit above that. So I-- you know, normal results for me might be an ALT of twenty-five or twenty-six and an AST of thirty-three or thirty-four. Um, am I concerned about that? No. I've obviously, you know, b-being a curious person done a-- done, you know, some more imaging stuff to, to make sure there's nothing going on. But, you know, ul-ultimately, you just have to handle each of these situations kind of clinically. There are also pharmacologic things that will raise them. So lipid-lowering drugs are a very common offender, um, and w- and will raise AST and ALT. Um, w-what is the threshold at which you should be concerned? You know, if you typically see somewhere between a one and a half and twofold persistent increase, that would really justify investigation. Even if it's in response to a drug, it would probably justify stopping that drug. For example, if you're on a statin and this is happening, that's probably reason to stop a statin. And certainly in our practice it is, even though the guidelines might suggest you tolerate a higher level of increase.

   2. SPSpeaker18:47

      When you kind of say stop a statin, does that mean if you're treating someone with a statin for potential CVD risk and you see the liver enzymes increase, you abandon treatment, or are you just looking at potential other drugs to handle the CVD?

   3. PAPeter Attia19:04

      It would be the latter. So in other words, we, we treat the, you know, the, the CVD or ASCVD risk, uh, using the tools that are available. But I'm just saying that we include elevations of transaminases in the suite of things that we would view as a contraindication. So look, I don't think any doctor out there would say, "I'm going to give my patient a statin, but if they developing-- even if they develop, you know, debilitating muscle pain, we're just going to keep hammering them with it." Of course not, right? Like, you know, and, and four, four to five percent of patients will develop significant, uh, myopathy from, from a statin use. Um, it's reversible, but you know, obviously you're going to stop the drug and, and find an alternative. We would just consider a significant elevation in transaminases, uh, sig-- you know, a change in insulin sensitivity. Those would be the big three things we always look to, um, get people off a statin or at least off one statin onto another or just off the class altogether. Let's talk about what maybe is a better test here because I sort of just alluded to the fact that those, those tests don't work very well. They, they really lack sensitivity and specificity. So if a, if a physician really wants to understand if their patient has, uh, MASLD and make that diagnosis, they really want to understand how much fat is present and how much fibrosis, if any, is present. And, um, y- so, so my takeaway was that the, the gold standard was probably, uh, magnetic resonance elastography and proton density fat fraction or PDFF. Um, so you know, again, that's, that's sort of l- looking at MR technology, um, so meaning an MRI, uh, to make the diagnosis. Now, the problem with this is that it's, you know, obviously costly and it's not a widely available test. You, you can't just go to an MRI and get that done. That's a very specific, um, protocol. So I would say from a practical standpoint, the more common tool are, um, ultrasound and vibration methods, um, that are less expensive, that are easier to do in a, in a clinic. Um, and there are-- there's a branded version of this that we typically use called FibroScan. So it's a vibration-controlled transient elastography, um, and it uses both vibration and ultrasound to basically give a, a, a, what's called a CAP score. Again, I don't know that the details of this are entirely needed. For us, it's interesting because we do these things, but, but basically this CAP score is something of... it's called controlled attenuation parameter, and we actually want to see that number, right? So now we're actually able to quantify the degree of fat and fibrosis in the liver, and now we have a biomarker that we're treating. Because remember, although we didn't talk about it enormously in this podcast because we've talked about it so much elsewhere, the real question here is what are we doing when we have this information? So you've, you've, you've, you've now confirmed your patient or you as the individual have fat or fibrosis in your liver. Now what? Well, here's the thing. It's not a really clear indication for a drug per se. This is something that is going to respond most favorably to a reduction in excess adipose tissue and an improvement in insulin sensitivity. Uh, and it-- and of course, depending on the etiology or removment-- a removal of the, uh, insulting agent. So, um, y- you know, I guess the way I would close this summary up would be to say that what are we doing when we see this? Well, we're, we're getting our patients to lose weight, and again, that's not an easy thing to do. Uh, it is, it is simple but not easy, right? Simple in concept, um, can be challenging in practice, although at times it relies on drugs like GLP-1 agonists. Uh, but we're also being mindful of taking things away. So if a patient, let's say, is drinking five or six drinks a week, which is, you know, would not be considered excessive, but their, you know, their FibroScan score comes back showing modest, uh, steatosis and/or fibrosis, well, we're going to take all alcohol out of their diet, right? Because why would you add any additional insult? So in addition to, you know, putting them on a program that's going to help them lose weight and improve insulin sensitivity, we're going to remove alcohol. The other things we're going to do, although I think we have far less data for this, um, are going to be remove liquid fructose from their diet. So, um, y- you know, they're, the, the-- every time a study has been attempted, to my knowledge, to look at the isocaloric impact of liquid fructose, um, it has been unable to discern if that is different from isocaloric glucose because the subjects usually end up losing weight even when you make an attempt at isocaloric substitution for fructose to glucose in liquid form. So in other words, two things change and you can't tell. Uh, that said, we continue to abide by the idea that liquid fructose and alcohol should probably be minimized if not avoided in people with MASLD/NAFLD. So it's a bit of a long summary, but it is a very important topic, um, and I hope that either for folks who have listened to it or plan to go back to it, listen to-- listening to it, this can sort of prime that discussion.

   4. SPSpeaker24:12

      One follow-up question on what you said. If someone is kind of curious on the state of their liver, you mentioned, you know, ultrasound might be the easiest and most widely available thing. Do you have all your patients get ultrasounds to test their liver, or is it only if you see potentially other things that are concerning that you want to see the state of it?

   5. PAPeter Attia24:35

      Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. So if you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic, and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, The Qualies, an additional member-only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAttiaMD. You can also leave us a 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. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of all disclosures. [outro music]

Episode duration: 27:43