The Importance of Uric Acid as a Biomarker

Chris Kresser:  Dr. David Perlmutter, welcome back to the show. It’s always such a pleasure to have you.

David Perlmutter:  Dr. Chris Kresser, [it’s] good to see you again. I’m glad you’re looking so healthy.

Chris Kresser:  Thank you. So when I heard, I can’t remember, I think it was from you or one of the people on your team, about your next book called Drop Acid, I was definitely intrigued. And I thought for a second your work was taking a totally different direction, one that I think we both are interested in and support, the idea of psychedelic-assisted psychotherapy, etc. But it’s not exactly what, once I read the subtitle, I thought, oh, okay, I understand.

David Perlmutter:  Well, I hope it wasn’t too disappointing for you.

Chris Kresser:  Not at all. As I explained in the intro, uric acid [is] a marker that I have always included in my introductory blood panels for all of my patients for over a decade of clinical practice, and it can be very revealing. And I think, as you’re going to explain, it’s one that’s accessible. It’s affordable to test and it’s quite meaningful, but it’s also often ignored in the conventional medical paradigm.

David Perlmutter:  Almost always.

Chris Kresser:  Yeah, why is that? Why do you think [so]?

David Perlmutter:  Well, you and I, and everybody else learned about uric acid very specifically in the context of gout. Pretty much [the] end of [the] story, maybe kidney stones, but that was really it. This is not your grandfather’s uric acid anymore. We’ve now, over the past two decades, seen incredibly detailed research showing that uric acid is not just this extracellular thing that crystallizes and makes your great toe hurt in gout. But it’s actually playing a fundamental role, actually [a] mechanistic role, in so many of our really challenging metabolic issues that, my gosh, you talk about day in and day out. And now we have another very powerful tool, and that is reining in our uric acid if it’s elevated, and it’s elevated an awful lot these days in Western countries. [In] adults, uric acid levels are so much higher than they used to be.

In America, for example, [in] the 1920s, the average uric acid level was 3.5 milligrams per deciliter. Now, [the average level for] adults in America is 6 [milligrams per deciliter]. And, interestingly, that’s still below what the lab or the doctor will tell you is normal. And, first of all, I don’t want my patients to be in the normal range because they deserve optimal A and B; that number is derived from its relationship to gout. In other words, that’s the number, the concentration of uric acid in the blood, where crystallization begins to happen. And we know that the cardiometabolic issues, the raising of the blood pressure, [the] raising of the blood sugar, the increased body fat, for example, all happen a lot lower, like 5.5, being as much as we can really tolerate.

So this is research going on around the world. One article, interestingly out of Japan, is called “Uric Acid in Metabolic Syndrome: from [an] Innocent Bystander to [a] Central Player.” And that’s really where we are now. This doesn’t just happen to be elevated in insulin resistance and elevated blood pressure and hypertriglyceridemia, etc. It’s playing a role in causing these problems. Well, that’s worrisome on the one hand, but I look at that glass as half full because we can target it really easily. I’m sure that’s something we’ll talk about later on.

The Difference Between Normal Ranges and Optimal Levels for Important Biomarkers

Chris Kresser:  Absolutely. I just want to linger here for a moment, because I think it’s a really important concept and, of course, talked about with other markers. But this difference between, I’m doing air quotes here, “normal range” and “optimal range” for a particular marker, and you just hit on that with uric acid. There [are] so many other examples from [vitamin] B12, to vitamin D to just focusing on metabolic issues. How about fasting insulin, fasting glucose?

David Perlmutter:  You bet.

Chris Kresser:  The range for fasting insulin goes up to what, 17, 18? Sometimes even higher. And folks like Peter Attia, myself, yourself, probably want to see that more down in the seven, eight, or lower range. And all these ranges have been often designed to detect full-fledged disease.

David Perlmutter:  That’s right.

Chris Kresser:  And we’re not after that. We’re after how do we prevent that disease in the first place? So why don’t you, in the context of uric acid, [give] a very basic overview of the physiology involved, like what is uric acid? What’s it doing?

David Perlmutter:  I’ll do that. Let me just comment, though, on that topic that you just brought up. Because it’s so important that people realize that things like diabetes, hypertension, obesity, etc., or the diseases that are derived from coronary artery disease, Alzheimer’s [disease], cancer, type 2 diabetes, again, these are not binary issues. Really the only binary issues that we know of are things like being pregnant, for example.

Chris Kresser:  You either are or you’re not.

David Perlmutter:  Or you’re not. There are very few binary issues in medicine. And to think that at 124 blood sugar, well, you’re kind of up there, but [you don’t have diabetes]. And then at 125, all hell breaks loose, because now [you have diabetes], right? And [the] same thing with A1C. And so many of these metrics, certainly blood sugar [is] one that is really getting a lot more scrutiny as of late, even a serum sodium and sodium consumption. These are things that are analog that being a so-called “pre-diabetic.” Well, you’re not actually diabetic, with the word “yet” [in] air quotes hanging in the background. That’s 88 million Americans. And you add to that the 34 million who [already have diabetes], but let’s talk about those pre-diabetics. They’re happy to say, “Oh, I’m not diabetic.” They don’t say the “yet,” but “I’m not diabetic.” And we fall into this sense of security when we’re not yet in a category. And certainly, gosh, hemoglobin A1C is such a great example of that. Ideally, we want our A1C around 5.2, maybe 5.3. And at 5.6, you’re not diabetic; that’s for sure. And watch television, and everybody’s jumping up and down, because I got my A1C below seven.

Chris Kresser:  Right.

David Perlmutter:  That’s terrible. [At] an A1C of 6.8, you’re in big trouble as it relates to metabolic problems, and the downstream effects of those metabolic problems, like Alzheimer’s [disease] being increased at an A1C of 5.8. So I had to double-click on that for just a moment because that whole notion of either, of being so digital about whether you are or aren’t is so unfair to people. And it does speak to the notion of being in the optimal range, not just in the normal. What is normal? It’s average.

Chris Kresser:  That’s right. Average.

Blood Sugar and Cravings for Sweet Things

David Perlmutter:  A lot of people, you check their whatever, and whatever that standard deviation from the mean is, you say you’re in the normal range. Well, for people who are under the care of Dr. Chris Kresser, that’s not good enough. And I praise you for getting that word out to people that we can do better. And that’s how you prevent disease, by dealing with what’s best for you today so that you’re not going to be having troubles in 10 years, in five years, next week.

Now, we’ve identified that uric acid is a really powerful new player at the table and joins blood sugar, fasting insulin, body mass index, and blood pressure as a powerful metric, by which we determine metabolic health. It’s not that it happens to be elevated when people are hypertensive, or have type 2 diabetes, or I hate the term “pre-diabetic.” Because again, the sense of security, because “I’m not diabetic yet.” But it doesn’t happen to be elevated in conjunction with those things. It is playing a causal role. And that’s what’s so exciting, because now that we’ve identified that, and again, this is two decades of research. Now that we’ve identified it, we can target uric acid. There [are] so many things that we can do to help bring it down. And even before that, we can start to ask the question, “What is causing uric acid to go up in adults and children, adolescents, especially around the world? What has suddenly happened?” And this is the uric acid that directly relates to insulin resistance, therefore increasing our risk of diabetes by raising our blood sugar right away today.

It’s the uric acid that directly targets various pathways that we’ll talk about that raise blood pressure, that increase what’s called “lipogenesis” or the production of body fat. So there are many, many ways that this elevation of uric acid insinuates itself as a player. And you know the good news is now, we know that and we can look at those things in each person, and in population groups that are raising the uric acid. So I think the first place to start is where is it coming from? What causes uric acid to be made in the body? And the easy part, in terms of taking the quiz that follows our time together today, is that it only comes from three sources: a special sugar called fructose, who knew, alcohol, and a chemical that we get from certain foods called purines. And purines are in the foods that we eat, the breakdown products of the DNA and the RNA that are in the cells of the food that we eat. [The] reality is that most of the purines in our body actually don’t come from food, but come from the normal wear and tear breakdown of our tissues that we always engage in, especially if we’re vigorously exercising.

Alcohol. We know where that comes from. And fructose, well, I think a lot of people may not know where that comes from. That’s in over 60 percent of the packaged foods sold in America’s grocery stores, added to those foods to make them sweeter. Why? Because you and I, and everybody else walking the planet, likes sweet. Our desire for sweet is a powerful survival mechanism because it does several things. It identifies foods that are safe because by and large, foods that are toxic would never be sweet. It identifies foods that are at the maximum level of their nutritional advantage. And finally, it has served us to indicate that winter is coming. Basically, fruits ripen in the late summer, early fall, the wild blueberries that our ancestors may have found, and it’s a signal to make fat. This fructose metabolized into uric acid basically tells our bodies winter is coming. And you better get ready for it. And interestingly, [the story of] our metabolism of fructose into this danger signal called uric acid begins some 14 to 17 million years ago, long before Homo sapiens or any of our hominid groups were even around. Primates experienced some selection pressure because over about a million years, that’s an awful[ly] long time for us to think about, in terms of Homo sapiens, but the world began to cool. And as the world cooled, there was less and less food. Any selective advantage would lead to more likelihood of survival. And one selective advantage was making more fat.

I’m not saying that we selected or nature selected for fatter primates, but a little bit more fat would allow them to survive during times of food scarcity. And the mechanism is a mutation or series of mutations in an enzyme called uricase. [That’s] the enzyme that breaks down uric acid, and we lost it. We lost the ability to break down uric acid, and that was a powerful survival advantage for us, our primate ancestors, our Paleolithic ancestors. We have that same uricase mutation today whereby we don’t break it down, and our uric acid levels are four to five times higher than the uric acid levels of other mammals. So we have this elevated uric acid right now, globally, that’s being targeted by suddenly a change in the environment that’s signaling the body to make fat, store fat, [and] increase blood sugar production, so we can power our brains, increase our blood pressure as a hedge against dehydration, but we’re targeting that pathway 365 days a year. And what are we seeing? Dramatic increased rates of obesity. Right now, as we have this conversation, one-third of American adults is obese. That’s not just overweight, but obese, and that number in the distant future, in 2030, that’s obviously the distant future from now, that will be 50 percent. It means one in two American adults won’t just be overweight, needing to drop a few pounds, but by [body mass index] will be obese.

Weight Gain and Metabolic Issues

Chris Kresser:  I think the pandemic may have even accelerated that timeline from what I’ve read in terms of the amount of weight gain that has happened during the pandemic.

David Perlmutter:  That’s right. And, when we talk about a pandemic, I mean, this is a global issue, obviously, with the globalization of the Western diet and lifestyle. And I think clearly, when we realize that the number one death on our planet right now is not some viral entity. It is a group of diseases called the chronic degenerative conditions, which are underpinned by problems of our metabolism, and are therefore related to our lifestyle choices. So we are choosing to make these chronic metabolic degenerative conditions the number one cause of death on our planet. And it plays into COVID[-19] death, as you well know.

Chris Kresser:  Absolutely.

David Perlmutter:  Metabolic issues; you end up in the hospital with diabetes or hypertension or obesity, and your chances of a bad outcome are dramatically increased. And when you recognize the connection of elevated uric acid to those very problems, hypertension, diabetes, or at least insulin resistance, the increase in body fat, you might think, gee, I wonder if there’s an increased risk of bad outcome based on uric acid. And you’d be right. One recent Chinese study showed that when they measured uric acid in people coming into the hospital, if your uric acid level was in the highest group or quartile, your risk of ending up in the [intensive care unit], ending up on a ventilator, or ending up dead, was increased as much as three-fold. So that’s an attention grabber, isn’t it, as it relates to uric acid?

Chris Kresser:  Absolutely. And I again want to reflect on something you said, because I think it’s a really important concept for people to understand and something we both talked about a lot. This power of looking through the evolutionary lens to understand these mechanisms where you have an adaptation that occurred, in this case, millions of years ago that was adaptive to the people living at that, or in this case, animals, and then eventually, maybe early hominids that were living at that time in that place in that particular set of circumstances [where] food scarcity was a much bigger problem than food abundance. And now we have that same genetic, biological programming, but we’re living in an environment where, of course, food scarcity, for some people around the world, is still an issue. But in the developed world, food abundance is by far the bigger threat that we face. And yet we still have this biological machinery that is essentially tuned to protect us from food scarcity.

What Is an Evolutionary Mismatch?

David Perlmutter:  Yeah, I laugh because I basically used that terminology in an article I wrote about this topic, half a century ago. I published it in the Miami Herald in 1971 long before I think you were born; correct me if I’m wrong.

Chris Kresser:  Wow. Three years before I was born.

David Perlmutter:  Okay, there you go. And I asked that question. I said that evolution is not keeping up with these changes that we’re experiencing. And the final sentence was, but what about us living today with the outdated machinery? Exactly in just the words that you talked about. And it’s true that we call this an evolutionary environmental mismatch. We’re living in an environment that just isn’t suited to our heritage. We can’t change yet, necessarily, our genome, at least in terms of its hardwiring, but we sure as heck can change the environment. In other words, what influences our physiology and plays upon our genome, by perhaps emulating many of the lifestyle events of our ancestors. That’s what the so-called “Paleo movement” is all about, which is interesting because that’s the last time I actually saw you, was [at] a Paleo conference.

Chris Kresser:  Yeah, in person, right.

David Perlmutter:  But our genes allowed us to survive for 99.9 percent of our time on this planet under a given set of circumstances, which have suddenly, in the blink of an eye, changed. And now we’re seeing that even longevity is declining prior to COVID[-19]. I mean, that’s when it started. So COVID[-19] certainly sped things up. But we’ve burned the candle at both ends for too long, and we’ve gotten past the advantages offered by modern technology to the extent that we are now losing ground.

Chris Kresser:  That’s right.

David Perlmutter:  And when we look at something like all-cause mortality, there’s an interesting study that came out of Japan published in 2009. They looked at 90,000 people (42,000 men [and] 48,000) women, and they followed them for eight years. And they looked at all-cause mortality in comparison to what their uric acid levels were at the beginning of the study. And what they found was that people with the highest uric acid above seven had a 16 percent increased risk of dying from anything whatsoever. They had a remarkable 39 percent increased risk of cardiovascular mortality, dying of a heart-related event, a 35 percent increased risk of dying of a stroke, and, interestingly, an eight to 13 percent increased risk of death for every point of uric acid greater than seven.

Chris Kresser:  Which gives us a lot more confidence in the findings that monotonic relationship, it just keeps going up as the uric acid goes up.

David Perlmutter:  That’s right, and these are correlative studies; they correlate having a high uric acid to increased risk of death. But I take that information just as another interesting sidelight in terms of yes, in addition, we understand the mechanisms by which uric acid is able to do that.

Which Foods to Eat and Which to Avoid for Optimal Uric Acid Levels

Chris Kresser:  Let’s go back to what produces uric acid. You mentioned fructose, alcohol, and purines. But let’s dive a little bit deeper on fructose and alcohol in particular. So fructose is found, as many of the listeners will know, both in highly processed and refined foods like sugar-sweetened beverages, soda, [and] all kinds of packaged foods that you wouldn’t even expect it to be in necessarily that they just put it in. But it’s also found in fruit and whole fruits that people might eat. So what level of fructose and let’s say form of fructose intake do you feel is problematic when it comes to your uric acid levels? Are we only talking about the highly refined sources of fructose? Are we also talking about whole fruit? Does it depend on the person and their metabolic status? What’s your position on that?

David Perlmutter:  Well, to be fair, everything depends on the person to some degree, right? Because we’re all different. But the issue with fructose isn’t a question of whether it’s refined or not refined. It is chemically fructose. It’s a thing. The main issues are the amount of fructose you are consuming and over what period of time. So that’s why there’s an advantage of eating fruit as opposed to drinking a glass of fruit juice. If you drink a glass [of] fruit juice, generally, that happens quickly, or you drink a soda that happens really quickly, and the amount of fructose in a glass of fruit juice or soda is dramatic. When we’re looking at 36 grams of sugar, and by and large, table sugar is 50 percent of fructose. But a lot of what goes in, at least [in] sodas, is something called high-fructose corn syrup. And that has more fructose than glucose. So normally, table sugar [is] 50/50 sucrose. But this is a modification such that there’s even more fructose. Why? Because fructose is sweeter than glucose, so you don’t have to use as much; it is cheaper. So that’s obviously the bottom line [for] food manufacturers. Think about that term for a moment, “food manufacturers.”

Chris Kresser:  It should be an oxymoron, right?

David Perlmutter:  It is an oxymoron. But that’s what they are using because it’s really cheap, since the advent of the technology in 1958, [with the] University of Oklahoma making this sugar out of corn. But it really didn’t take off until the 1970s. But now it’s everywhere. And it goes by so many other names, fructose, or the various names of sugar that I can’t blame people for not understanding that these bizarre names on the label that you’ve never heard of before, but they’re just changing the name and getting away with it. But that said, that’s always an argument against eating packaged foods anyway and shopping the periphery of the grocery store.

So getting back to fruit. We talked about the quantity, and there’s not that much fructose or sugar in fruit. An apple might have five, maybe even 10 grams of sugar in it, but that isn’t something you drink right down. You eat an apple; it’s going to take you some time because A. it’s not a sudden surge of fructose, [and] B, the fiber in the apple is going to slow the fructose absorption. So again, the presentation of fructose to your physiology, specifically its absorption and then transport to the liver, is slowed. C, what does C stand for? Vitamin C. Vitamin C [has] long been known to be very helpful in treating gout, high uric acid, because it aids in the excretion of uric acid at the level of the kidney. And D would be the bioflavonoids, meaning that fruit contains a suite of bioflavonoids depending on the fruit, and some of them, particularly luteolin and quercetin, target the actual enzyme called xanthine oxidase, which is also targeted by the gout drug called allopurinol. So, nature provides ways for us to dump our uric acid and even reduce the production of uric acid in our bodies, if we avail ourselves of these really great tools.

Therefore, the answer to that very important question (I don’t think I have done a podcast [where] that question hasn’t been asked) is [that] fruit is okay. An apple a day keeps the doctor away. Five apples a day, the doctor you will pay. So in moderation. [The] same thing [is true] with vegetables. There are some vegetables that are actually high in purines, and therefore, you would think you should avoid, because they might raise uric acid. And these vegetables have been on the “don’t eat” list as it relates to gout for an awful[ly] long time because they’re high in purines. Like the cruciferous vegetables, and mushrooms and things like that. [It] turns out that they are associated with decreased uric acid. Again, many of the same mechanisms, especially quercetin, and other bioflavonoids that help reduce the formation of uric acid in the first place.

The other source of purines are the organ meats, like liver and kidney, and small concentrated very cellular types of animal products like sardines, mussels, and scallops. It doesn’t mean you can’t have them. It means you should know what your uric acid level is. And then, if I’m eating a lot of liver, that might be something that I should literally take off the plate. But you have to get a sense as to where you are in this whole discussion, and then make the modification. I think most people who are paying attention to all that you are teaching really get that they shouldn’t be eating a lot of sugar and probably understand quite clearly that fructose is something to avoid. But I think the purine part of that story might be somewhat new to many people. And finally, as it relates to alcohol, it depends on what kind of alcohol you are drinking. Hard liquor is associated with increased uric acid. Wine is pretty much neutral in men and actually is associated with decreased uric acid in women. But the worst player of all is beer. And [that’s] tough for me to say that right now during playoff season, but nonetheless. Beer gets you on two accounts. Number one, the alcohol. But number two, beer is exceedingly high in purines because of the yeast that is used to make beer, the brewer’s yeast.

And interestingly, this whole notion of uric acid and metabolic health. I’ve already quoted two studies from Japan; they’re way ahead of us on understanding A, [why] it’s important and B, what we can do about it. So they’ve already started marketing non-purine beer, because they know that beer is a huge resource for people to raise their uric acid and hence give them problems. So because of the alcohol and the purines, we now understand where the beer belly is actually coming from. That beverage is telling [the] body, get ready for winter, get ready for food scarcity, make fat, and raise your blood sugar to power your brain.

Chris Kresser:  Yeah, well, the phrase “beer belly” came from somewhere, right? It’s clear that that has, like you said, a double whammy effect when it comes to uric acid, and I think also just weight gain in general. So that’s helpful to break down for folks. Because I know a lot of people have those specific questions of, should I avoid all fructose, meaning no fruit whatsoever? Or, just avoid the larger hits of fructose from sugar-sweetened beverages, fruit juice, and the stuff that is included? And as you said, of course, it will depend on the person. But in my experience, as a clinician, most people are able to tolerate one or two servings of fruit a day, especially if they’re the lower-sugar fruits like blueberries or raspberries or something like that, in the context of a whole foods diet.

David Perlmutter:  And leave the skin on if ever you can, like for apples.

Chris Kresser:  Right, don’t peel them. As much fiber as you can get with them.

David Perlmutter:  Yeah. And also, that’s where many of the bioflavonoids. I mean, your mom used to say, “That’s where all the vitamins are.” But she was close, right? But there are other things going on in this game that are really important for us.

Chris Kresser:  Yeah.

David Perlmutter:  But let me make it a little bit more difficult because I think everybody’s got everything now.

Chris Kresser:  Yeah, but my audience likes the nuance. So let’s bring it on.

David Perlmutter:  Sure, I’ll [crosstalk 29:11] purines and fructose a little more complicated in that our bodies manufacture fructose as a survival mechanism. Because once that happens, once we trigger the body to make fructose, it goes on to make things like body fat and raise our blood pressure and increase our production of glucose, gluconeogenesis. So the question [we] should be asking [is] what would cause our body to activate this polyol pathway and convert glucose, blood sugar, into fructose? Well, what might that survival input be that would cause us to need to do that? And one very powerful thing that’ll turn that pathway on is dehydration. Meaning how does our body know when we can’t find water? What happens? When we get dehydrated, our serum sodium goes up. That’s the first marker. It turns out that elevated serum sodium triggers this polyol pathway to make fructose, because fructose turns on uric acid to make fat.

Well, why would we want to make fat if we can’t find water? What would be the advantage of that? And to answer that question, I’d like everybody who’s listening to us right now to think of [an] incredible animal that can walk across the desert. And it’s the camel. And what is its unique identifying characteristic? It has [a] big hump on its back. If you look inside the hump, you’re not going to find a couple of gallons of water; what you find is fat. The reason it has fat and can survive [in] the desert without drinking water is because when we metabolize fat, we convert it into two things: carbon dioxide that we exhale and water. We make metabolic water when we burn fat as a fuel. So when we are facing dehydration, our serum sodium goes up, we make fructose, [it] turns to uric acid, we increase our production of body fat, [and] we make a little bit more water. And that was in the day, a survival mechanism.

Now the problem with that pathway today is that we can jump our serum sodium levels in a heartbeat by eating salt. So when you’re watching the playoffs, and you’ve decided you’re not going to drink beer, but you sit down with a bag of pretzels that are salted, immediately your serum sodium goes up, your body activates the polyol pathway, you produce more fructose, and all the downstream negative things happen even though you’re not eating fructose, because you’ve made more fructose in your body. And as such, your body thinks it’s dehydrated, makes more fat, [and] raises your blood pressure so that you can make sure that you get blood supply to your organs, and it creates a survival mechanism, survival scenario that you do not need. You don’t need more fat because you’re sitting on the couch watching the playoffs or whatever you’re doing.

My point is that people are eating so much sodium. We’ve known for three decades that higher salt consumption is related to [a] dramatic[ally] increased risk for diabetes, obesity, and certainly, everybody gets the memo on this one, hypertension or increased blood pressure. But the exact mechanisms whereby this was happening have remained elusive until we’ve started to understand what’s going on with uric acid, what’s going on with the kidney, the role of inflammation in the kidney brought on by this whole experience, and then what’s the ultimate payoff for us in understanding it; we can make better recommendations. And it may be as simple as look, I know you’re going to eat that bag of chips. I can’t stop you. But do me one favor; do yourself a favor. After you do that, drink two glasses of water. Immediately, you dilute down your sodium and you stop activating this mechanism. And to be sure, this mechanism is profound. This activation of the polyol pathway that converts glucose into sorbitol and sorbitol into fructose even happens in the brain. And a recent study demonstrated that the levels of these intermediates, sorbitol and fructose, are four to five times higher in the Alzheimer’s brain in comparison to age-matched non-Alzheimer’s [disease] patients. What is it telling us? It’s telling us that this powerful pathway is activated in the Alzheimer’s brain. And why might that be? It might be because we know one other thing is dramatically elevated in the Alzheimer’s brain, and that is glucose. When glucose is elevated, it forces that pathway along to ultimately make fructose. And fructose is actually something that the brain can metabolize and then can metabolize into uric acid.

Now, that may have offered some survival advantage in the past, but certainly, today by compromising the brain’s energetics because the uric acid damages the brain’s energy factories called the mitochondria; that’s not going to play out well for people today. We know that fundamentally, in the Alzheimer’s brain, the mitochondria aren’t working well, the cells can’t make energy, and, ultimately, they perish for lack of being able to use fuel.

Chris Kresser:  Absolutely. And I just was thinking a few times as you were talking, so much goes back to eating real food. What you said, the periphery of the grocery store and starting from looking at whole fruit and all the other compounds in whole fruit that mitigate against the potential harm of fructose. And then, you can say a similar thing for organ meats. They’re very high in certain nutrients, but they’re also high in other nutrients that help offset those nutrients that could potentially be an issue. Of course, they can still be an issue. I mean, if you have excess uric acid, you don’t want to be eating a lot of liver. If you have high iron levels, you also don’t want to be eating a lot of liver because it’s so concentrated in iron. But I’m continually struck by the wisdom of nature, in that respect, where if a food is high in something else, it almost always has counterbalancing mechanisms in the form of other nutrients. Whereas when you’re eating stuff that has been manufactured, manufactured food, that’s rarely, if ever, taken into consideration. You’re only getting jacked up levels of a particular compound without any of those other balancing factors. And sometimes, people seem so [crosstalk 36:24].

David Perlmutter:  It’s even how it’s created. You’re right.

Chris Kresser:  Absolutely.

David Perlmutter:  I’m going to go to the health food store, that’s a good thing, and I’m going to have a great big glass of fresh squeezed organic, created by [crosstalk 36:39].

Chris Kresser:  Fair trade.

David Perlmutter:  [Crosstalk 36:41] whatever, carrot juice, right? And I’m watching them make my carrot juice. You hear the sound, the carrots are going through, and this gorgeous orange juice [is] trickling out.

Chris Kresser:  Right. Bright color, good smell.

David Perlmutter:  We’ll put a shot of something in it just to make it a different name. But what do they do once they make your carrot juice? Two important things happen. First, there’s a byproduct, which is all that horrible stuff, that sinewy fibery stuff that they throw in the garbage, right? The second thing that’s created is juice that gives you a very powerful slug of sugar right now. And in the context of our ancestors, they didn’t juice carrots; they didn’t juice anything. And the hunter–gatherers [weren’t] going to find cartons of Tropicana hanging from trees when they were hunting and gathering. Hunting and gathering isn’t hunting down a convenience store and gathering up the Doritos. You’re right. Nature has incredible wisdom here. And that’s why if people want to do something with a carrot, by all means, use some kind of machine that saves the fiber, for crying out loud, because it’s not sawdust; it’s really important for you. That’s where there’s so much nutrition.

We didn’t mention, but the microbiome, as well, thrives when it gets that fiber. When you just drink the juice depleted of that fiber, oh my gosh, your gut bacteria [are] sitting there going, “Yes, carrots.” They’re watching it, and they’re going, “Oh no, they’re throwing out the fiber.” And then they don’t work as aggressively in maintaining your gut lining or manufacturing B vitamins or neurotransmitters or targeting the expression of your DNA, for crying out loud. So we’ve got to nurture our gut bacteria. It turns out this is interestingly quite related to uric acid. We know that higher levels of uric acid favor the overgrowth of extremely proinflammatory strains of bacteria. And interestingly, several studies have demonstrated that in patients with gout, by and large, a situation of very high uric acid, that a crazy technique called fecal microbial transplant, whereby a stool specimen from somebody without gout who’s relatively normal is transplanted in the colon of [a] patient [with gout], and they have a dramatic reduction in the frequency and severity of their gout attacks. So [that’s] saying to us that the gut bacteria have a role to play in uric acid metabolism, as well. And we know that one of the ways uric acid is excreted is through the gut. Primarily, it’s from the kidney.

This notion that we make our own fructose, I think, is something that needs a little further unpacking moving forward, because you can be on a great program not eating fructose in any way, shape, or form. And yet you’re still making uric acid through the fructose pathway because, for example, you have sleep apnea. Think about that. When blood oxygen saturation goes down, and there are plenty of instances these days where that is happening. But if it happens because of sleep apnea, which is not unusual, then that turns on this polyol pathway in your body. It feels like it needs to make more fructose to make more fat and, ultimately, more glucose. So who has sleep apnea? Well, generally, these are people who are overweight, and as such, then they are put in a situation where they’re even gaining more weight, making their sleep apnea worse. So it becomes a very vicious cycle, feed forward, no pun intended, sure.

Chris Kresser:  Why not?

David Perlmutter:  Yeah, why not? I think what we laid out in Drop Acid is this, the science that I think is so important to understand to get your arms [around]. Yeah, you can read the studies that show lowering uric acid is good for X, Y, and Z. But when you get how these pathways are working, number one, and number two, as you had mentioned earlier, when you look at it from a historical perspective and an evolutionary perspective, you realize that these things allowed us to survive. We say, oh, insulin resistance is a terrible thing, right? It’s always what do we do to keep ourselves from becoming insulin resistant? Actually, it’s context dependent. Insulin resistance is a wonderful thing if you are facing starvation. Insulin resistance is what you need to happen if you’re a bear getting ready to hibernate, for example. You dramatically want to be insulin resistant so that you have a higher blood sugar [level] and can make more body fat. So you’re going to survive for the X number of months that you’re sleeping in the cave or hibernating.

It’s really something to think about in terms of taking a step back, because we’d love to say, elevated blood sugar is necessarily a bad thing. Well, no, it’s not. If you’re starving and you’re activating pathways to make more blood sugar, it’ll power your brain and allow you to be clever enough to avoid two things: starvation and predation. Being eaten by other animals in the hunter–gatherer days. So having increased gluconeogenesis is a good thing. That takes us to a very interesting switch, if you will, that we are either telling our bodies that we’re feasting, or it’s a time of famine. That either the hunting is good, or the hunting is bad. If the hunting is good, we’re activating something called [adenosine monophosphate] (AMP) kinase, meaning we’re telling our physiology [that] we don’t need to make fat, [and] we’ve got plenty of food. We don’t need to make blood sugar; we got plenty of sugar being made and we’re eating it. We really want to keep our AMP kinase part of this metabolism activated. And the alternative is activating another way that AMP is dealt with called AMP deaminase. Another pathway. That’s the famine pathway. That’s saying to your physiology, uh-oh, no food. Whatever we get, we better turn down the metabolism, stop burning calories, shut down the mitochondria from working, and make as much fat as we possibly can. And at the same time, we sure as heck better make more blood sugar so that we can power our brains so we can get out of this mess. That’s AMP deaminase. Or if you’re getting ready to hibernate for the next four months. I don’t know many people who actually, these days [crosstalk 43:29].

Chris Kresser:  You better rephrase that. Yeah, maybe they do.

David Perlmutter:  But hibernation is a time when you shut your metabolism basically off.

Chris Kresser:  Yeah, completely down.

David Perlmutter:  Your blood sugar goes up and you’re going to burn your body fat. But in getting ready for hibernation, you’re making as much fat as you possibly can.

Chris Kresser:  Yeah.

David Perlmutter:  So these are the two pathways. Do we want to be AMP kinase? Or do we want to be AMP deaminase? Do we want to tell our bodies the hunting is good, [and] we don’t need to store fat? Or do we tell our bodies whoa, we’re not going to have food coming up, [so] we better make as much fat as we can? And it turns out that uric acid helped make that decision. At higher levels of uric acid shut down AMP kinase. It’s about the worst thing we would want to do. We want that AMP kinase to be lit up. And one of the reasons we exercise [is] that’s a powerful activator of AMP kinase. It’s why we take berberine or quercetin. They’re AMP kinase activators. It’s why people take a drug called metformin if [they have diabetes]. It activates AMP kinase and tells the liver, hey, we don’t need to keep making glucose because we have enough.

Chris Kresser:  Yeah.

David Perlmutter:  But unfortunately, when uric acid is elevated, AMP kinase gets shut down, and we activate a totally different pathway, this AMP deaminase. And we need to override, so we need to get uric acid under control fundamentally. That’s the big fundamental right there. That pathway. Which way are you going here? Are you going to be lean and mean? Or are you getting ready to hibernate and building as much body fat as you can so that you can go and [crosstalk 45:11].

Chris Kresser:  Live off your fat stores for a long time, yeah.

David Perlmutter:  You bet. And we talk about hibernation and fat storage. But you think about the hummingbird, for example. The hummingbird can have as much as 40 percent of its body weight fat because it makes this epic 1,000- [or] 2,000-mile journey, a hummingbird. So it’s one of the fattest animals on the planet when it’s getting ready for this trip. Though you don’t look at it and say, oh, it’s fat, but it’s got a lot of body fat. And what does it drink prior to this epic trip? If you want hummingbirds in your backyard, you get a hummingbird feeder, and you fill it with sugar water, right? That’s what nectar is; it’s sugar. And they do that to gain body fat so that they’ll have a resource for calories and water. Remember, burning fat makes water. Whales have so much fat because they need the energy, of course, but they don’t stop along the way. Because if I’m an underwater water fountain, and can drink fresh water, they do not drink fresh water. They may get some fresh water if they eat plankton, for example, or krill. But by and large, they’re making what’s called metabolic water. And you remember the camel story that we talked about earlier?

Chris Kresser:  Yeah. This is so fascinating, and I think anyone who’s been listening carefully knows they need to get their uric acid under control and manage it. Earlier, we talked about the fact that [with] the lab, if you go into your primary care physician, you get a blood draw, and it says [the level is] normal, you can’t necessarily accept or trust that that is an optimal result for your uric acid. So let’s talk a little bit about testing options first. It sounds like there are some at-home testing options for people who don’t have access to testing through their doctor. But either way, what is the optimal range, in your mind, for uric acid?

Talking with Your Doctor About Uric Acid Levels and Taking Testing into Your Own Hands

David Perlmutter:  Well, let me just go back a little bit. And typically, for people who go to their doctor and then want to know, well, I had a blood test last week, can you tell me? And they’ll get a call from the nurse who would say, the doctor says it’s normal.

Chris Kresser:  It’s all normal. Yeah.

David Perlmutter:  Okay, well, what was the value? No, it was fine. Nothing to worry about.

Chris Kresser:  It’s all normal, yeah. It’s so frustrating.

David Perlmutter:  Why in the world would you need to know? I mean, who the heck are you? Actually, I’m wearing a continuous glucose monitor because I really want to know. But anyhow, that’s usually the most you get, but nowadays, people can sign on to their portal and get the actual data. And again, the lab printout is going to say “in the normal range,” which is anything below seven. Remember, that has to do with gout. We want uric acid levels at 5.5 milligrams per deciliter or lower. Now that is, knowing your uric acid level or what it may have been might be as simple as a phone call or logging on to your portal. Because it’s typically included in your annual blood work. But as you mentioned earlier, you can go online and buy a uric acid monitor. In fact, we may have sent you one, as well.

Chris Kresser:  You did, yeah.

David Perlmutter:  Good. And it’s a simple finger stick. People have been doing that kind of thing for years to check their blood sugar at home. Even strangely enough, [people without diabetes]. Who knew? But here’s my monitor right here. It’s what it looks like. You do a finger stick. Here’s my most recent level. I don’t know if you can see that, 4.7.

Chris Kresser:  Yep.

David Perlmutter:  But there’s nothing to it, and it’s nothing you have to do every day. You can do it every two weeks. You can do it every four weeks. But then, the implementation [crosstalk 48:45].

Chris Kresser:  One question, how labile is uric acid as a marker? In other words, how quickly will your diet and lifestyle choices impact the levels?

David Perlmutter:  It can respond very aggressively and very quickly to certain things. And let’s talk about that for just a moment. [A] really interesting study out of Oxford looked at 22 young men with mild elevation of the uric acid and one intervention. No dietary changes or other lifestyle changes, but it was a placebo-controlled trial, either took a placebo. I wonder if that placebo is a sugar pill; that would not be fair, right? Or they took quercetin, 500 milligrams a day. Their uric acid levels in the quercetin group dropped 8 percent in two weeks. So it can come down significantly. If you go on a long run today, longer than normal, and maybe pick up your pace a little bit, your uric acid level might well come up half a point tomorrow because of the breakdown of the proteins in your body forming purines and through that mechanism. If you fast for a day or two, your uric acid will transiently go up.

But I think that’s the value of being able to test. You don’t want to really hang your hat on what it’s doing moment to moment. You want to look at the trends. You want to have a few variables like, this week, I really concentrated on whatever it may be. On eliminating hidden sources of fructose from my diet. Oh, and by the way, two variables. I also added in some quercetin, 500 milligrams a day. I’ll check it in a week or two, and you’ll see that it will most likely come down. So, it is something that you end up following, along with all the other cool things that we get to follow, the length of time we slept, the quality of our sleep, our continuous glucose measurements, our pulse rate when we’re running, [and] how many minute miles we’re doing right now. All the things that are really important to follow. Glucose monitoring, I think, is hugely valuable, but uric acid is right up there with all these things now that we know its role in metabolic disturbances.

Now, let me give you a sneak preview, because this is news as of yesterday, and the blog that I’m writing, actually, I started this morning. Polycystic [ovary] syndrome [(PCOS)] affects between four and 13 to 18 percent of women who [crosstalk 51:13].

Chris Kresser:  Childbearing age.

David Perlmutter:  Who would be fertile in America. And it is an endocrine/metabolic disorder, extremely common, described as being the most common cause of infertility in North American women. But it’s not just as it relates to menstruation and having cysts on the ovaries, which actually isn’t necessary for the diagnosis. It’s an endocrine issue characterized by [a] significant increase in androgenic hormones like testosterone in comparison to estrogenic hormones. [It’s] also characterized by metabolic issues like elevated blood sugar, insulin resistance, especially. And it is because of that, that I’ve [begun] studying that because these metabolic issues that these women experience, they may have the full-blown metabolic syndrome. Well, in my study over the past couple of years, metabolic issues light up something called uric acid in my mind. Could there be a relationship between elevated uric acid and PCOS? And it turns out that women with PCOS have dramatically higher uric acid levels. Is it cause or is it effect? I don’t know the answer to that . I don’t know that having elevated uric acid is giving women these issues. But in the studies, it looks like when you control for diabetes and you control for elevated body weight, for example, that even when you do so, the uric acid levels are still elevated.

So this bears evaluation that, especially women with PCOS, and I know I’m talking to a lot of people right now, [who], by all means, get your uric acid level checked. And what’s the harm in engaging in some activities to lower your uric acid? Because it’s really the metabolic issues that are paramount here. The endocrine, as well, with the troubles menstruating, amenorrhea and dysmenorrhea. But the endocrine issues are the long-term life-threatening issues because they paved the way for heart disease, Alzheimer’s [disease], cancer, and diabetes. So I would say that a sneak peek here is to understand, especially in PCOS, what the uric acid level is. And there’s nothing wrong with engaging this program that we’re talking about in helping to drive [down] that uric acid level.

Chris Kresser:  I imagine that’s really important, as well, for women who are at risk for gestational diabetes, which is a growing concern.

David Perlmutter:  You bet. That’s classic. If they manage to become pregnant, [the] risk of gestational diabetes is far increased. [The] risk of not carrying, of prematurity, is increased and [the] risk of miscarriage is dramatically increased, as well. And I don’t know yet the role of uric acid in those issues that accompany risk in PCOS. But I’m going to look into it because I think it’s really fascinating. This is a large number of people.

Chris Kresser:  Absolutely. It’s a large and growing number of people and a huge threat to humanity.

David Perlmutter:  [Inaudible 54:22], you’re right.

Chris Kresser:  Yeah. Dr. Perlmutter, this is really fascinating. I think it’s a potential game changer for a lot of people. And what I love about it, too, is once you get the basic science down, it’s pretty simple and easy to understand. You have a single marker that you’re tracking, of course, potentially with other markers that you’re, hopefully, paying some attention to. But people are often pretty overwhelmed, in general, but especially since the pandemic, so having something like this that is relatively simple and straightforward, it’s affordable to track with the home testing, like you mentioned. And there are some simple strategies that they can use that are outlined in your book, some of which we talked about, and some of which we haven’t. Dietary strategies, some supplements that can be helpful. I think we need more of these kinds of simple, accessible practical strategies. So I was really excited to learn about this.

David Perlmutter:  I’m glad you didn’t say hacks. I don’t like that word. Strategies. I’m loving the word strategies.

Chris Kresser:  No, you know me; I’m not in the biohack camp. Although I have an appreciation for some of that. But yeah, just simple strategies and tools that become part of your normal routine. That’s the problem I have with hacks is we need to make this stuff second nature. Just things that we do to live a good life, nothing more than that. Just really effective steps that we take to improve our health and well-being.

David Perlmutter:  Well, my goal is to work bottom up. In other words, direct to consumer. Certainly, that is a technique that the drug companies have really [crosstalk 56:03].

Chris Kresser:  Mastered.

David Perlmutter:  [It] works exceedingly well. But informing people that they will then say to their doctors, by the way, I may have read the book, or I saw the podcast, whatever, and I’d like to [check] my uric acid. And most of the time, unfortunately, I think, what the response is going to be [is], well, why would you care? You don’t have gout. So, that’s the one approach. But I think the top-down approach, as well, that I wrote this book, after reviewing close to 500 peer-reviewed references so that our medical colleagues can understand that this has been research going on around the world for 20 years plus. The first book on this topic, looking at uric acid apart from gout, was written in 1898 by Dr. Alexander Haig. And it was uric acid in relation to cognitive decline, depression, [and] all kinds of other issues. So it’s worth looking at.

And the simplest thing anybody can do is to Google two words: metabolic and uric. You don’t want to Google metabolism because then you get uric acid metabolism, but metabolic and uric and your screen will light up with wonderful peer-reviewed research studies from around the world that have been talking about this for so very long. And, now it’s available to each and every one of us. And as you well said, getting it under control is not challenging. It’s not something exotic. These are the foods to eat; these are the foods to avoid. Here’s why sleep is important. Here’s what you should know about exercise. And here’s how you can measure it. It’s pretty much for people who’ve been following you for the past several years. Understand that it’s just empowerment. It’s just knowing more about yourself so you can be your own advocate and chart your own health destiny.

Where to Go to Learn More

Chris Kresser:  Excellent. So where can people learn about the book and pick up a copy?

Chris Kresser:  Great. And I’m excited to share this with the clinicians [who] we train and the health coaches, as well. I think it’s important information for all health professionals, like you said, to be aware of, in addition to individuals who are trying to improve their health. [I] always enjoy our conversations, Dr. Perlmutter.

David Perlmutter:  My pleasure.

Chris Kresser:  Thanks for this important contribution.

David Perlmutter:  Thank you, Dr. Kresser.

Chris Kresser:  Good luck with the book, and [I] look forward to our next conversation.

David Perlmutter:  [I do,] as well. Thanks again.

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