Transcription
Hi folks, Dr. Rob Cyvis. I am the carb addiction doc and I am and have been a clinically practicing metabolic health specialist. What does that mean? I see patients every day. I consult with them and I check blood work on everybody. So I see tens of thousands of bits of blood work, uh, repetitively. And as you look at blood work in people changing their diet and people on various diets and with various health issues, certain patterns emerge. And one of the common concerns that we have, and it's very, very poorly understood. It's misunderstood, and the, the physiology and the pathophysiology is very poorly understood, and yet it is a common, common cause of disease, and that is uric acid. Uric acid. I routinely check uric acid in all the blood work because it tells a very powerful metabolic and biologic story. So let's do a deep dive into what uric acid is, where it comes from, and some of the errors that most practitioners out there assume.
So what is uric acid? Well, fundamentally, when you look at human energy, when you look at energy in the human system, energy comes from three primary molecules, okay? Sugar molecules, monosaccharides, glucose, galactose, fructose, which have a six-sided circle or hexagon made of carbon molecules attached to which is hydrogen and oxygen. So the backbone of glucose, galactose, fructose, monosaccharides is carbon, hydrogen, and oxygen. When you look at fat, fatty acids from ketones all the way through to C24, all of the carbon molecules are basically a long chain of carbon, hydrogen, and oxygen that contain electrons that contain fat that get transferred out. So when you look at those two molecules, carbon, hydrogen, and oxygen, the third common source of energy, there are others, but the third common source of energy is protein, amino acids. And protein, when you look at the different structures of the 21 amino acids, they consist of three molecules: carbon, hydrogen, and oxygen. Notice the common theme. All of these energy-consuming molecules contain within carbon, hydrogen, and oxygen structure electrons that contain energy. So they trap energy. But the big difference with protein is it contains another molecule. By definition, amino acids all contain nitrogen. So you've got carbon, hydrogen, oxygen, and nitrogen.
Now, here's the coolest thing about the human body. You take any of these molecules and you plug them into the energy-extracting organelle inside of cells. What's that organelle called? Everybody knows this name. It's called the mitochondria. Mitochondria. And mitochondria are essentially the houses of an electron transfer chain process. So the mitochondria regulate the transfer of energy-containing electrons from carbon, hydrogen, and oxygen molecules, carbohydrates, proteins, and fats, and transfer them and build up a new molecule called ATP, adenosine triphosphate, three phosphate molecules which contain the new electron, and there's a pathway by which that happens. So you've got this carbon, hydrogen, oxygen molecule entering with a very low energy level phosphate called AMP, adenosine monophosphate, and then as you go through this electron transfer chain, you go to ADP, and then ATP, which is the most charged-up form of energy. And ATP can then be used by the cell for various energy-requiring, uh, uh, uh, functions. So ATP is the cellular form of energy. It comes from the food that we eat: protein, carbohydrates, and, um, and pro, and, and, uh, sugars.
And the beauty is this: what spits out at the back end? So you've got your ATP containing the, the energy that gets spit out on the other side of the mitochondria. But then what is the remnant of CHO? So beautiful. The human biology is so beautiful. Well, CHO gets converted to carbon dioxide, CO2. [sighs] Which we breathe out. That is a, carbon dioxide is a waste product of the energy transfer system. And I'm not going to do it in front of you. I'm not going to go pee, but I'm sweating a little bit. So H2O, we sweat it out, we pee it out, we poop it out. Beautiful. So, in goes all these energy-containing three molecules. ATP goes off. Carbon, hydrogen, oxygen, sorry, carbon dioxide and water comes out the back end. That's how the mitochondria functions, except for one thing. When you are extracting protein from, uh, protein from, sorry, energy from protein, you also have to deal with nitrogen, the N. And in humans, that N is converted to NH3 or ammonia, which then through the urea cycle, several molecules, gets converted to urea, blood urea nitrogen, and in human beings, that requires very little energy. The urea cycle is, is very low in energy requirement, and the urea bun is very soluble in the blood, and we pee it out.
So the first thing I can tell you, when I, as a doctor, look at protein utilization as a source of energy: protein either goes toward energy or it goes towards structure, muscle protein, enzymes, signaling molecules, hormones. But is protein on the structural side where it's being used as an intact amino acid-derived protein, or is the individual amino acid being broken down to energy? I can look at your BUN and tell you if you're too little, exactly the right amount, or too much in terms of protein being turned to sugar and protein being turned to energy. Now, if protein is being turned to energy, it's either because you're overeating protein, which is very important, we'll come to that, or because your bo, you're not eating a lot of carbohydrate, and your body needs and has a demand for sugar. Well, the source of the sugar is protein, protein being converted to sugar in the liver. So we'll understand these. But in human beings, urea, blood urea nitrogen is the major waste product for nitrogen. Okay?
If you're watching this channel, you're probably already on a low-carb diet, or on a ketogenic diet, or a carnivore diet. You've already made that decision, or at least you are inquisitive about making the decision. And I think one of the key things about people on a low-carb or keto diet is they've, they understand that sugar consumption is not the answer. Your body runs best on clean fuel, and that fuel is ketones. Now, the ideal ketones are made in the liver from fat. But there are times when you're dragging a little bit, when you're a little flat, and that's where exogenous ketones, Ketone IQ, strategically can make a wonderful difference because they do not involve sugar. They do not involve carbohydrates, and there is no insulin spike. In fact, they augment fat loss, fat utilization, and the ketogenic or ketosis experience. Uh, Ketone IQ gives you pure, biologically identical, bioidentical ketones. One slug tastes like crap. So have a switch, sip of coffee with it. But one slug helps you to sustain ketosis, particularly as you're adapting to a low-carb or a keto diet. It's exactly the same ketone that the liver makes. And the difference is that you're in control of how much and when you are adding it to your system. It helps you to go longer without the crash and without the need to eat. Make it part of your routine. Have it available. I have them on my desk at work. I have them, uh, on my dining room table. If the family's eating and I don't feel like eating, I'll smack one of these down.
And while we have uric acid, uric acid is not a primary form of nitrogen waste in, in, uh, humans, but it still exists. It still exists as a backup. Now let's look at animals where the ur, uh, where uric acid, which is a, a solid, a solid crystallized product, where uric acid is the primary source of nitrogen waste. So there are animals out there who are not mammals. Mammals have developed BUN, urea, as their primary source of, of nitrogen waste. But there are animals, particularly birds and reptiles, who are carnivores. All they do is they eat meat. And they primarily get rid of their nitrogen in the form of uric acid. Now, in order to form uric acid, you have to convert that nitrogen into something called a purine. Purine. Okay? Purines are used in DNA. They're used actually in AMP, ATP, and ADP. So purines are in humans and other animals essential. But in the uric acid cycle animals, they produce purines, and then the purines go through a particular pathway to form uric acid, and then they poop out. They don't pee out, they poop out the uric acid. So, uh, while it is soluble at very low levels, it crystallizes, it forms solid, very, very quickly. So if you go to an island where there are lots of birds, that guano smell, that horrible smell, that's uric acid that you're smelling. In human beings, we do have a rudimentary retained purine pathway, but purines are also essential for DNA, for RNA, which occurs in every cell except maybe red blood cells, and also ATP, ADP, AMP degradation. So when those energy blocks get used up, they can be converted across to purines and then excreted as uric acid. So it's a very, very low-level system, but it absolutely does occur in humans. And in fact, what's interesting is that in humans, a low amount of uric acid actually has an antioxidant role equivalent to vitamin C because we don't produce vitamin C from sugar. Uh, we produce uric acid. So uric acid gets produced by the purine pathway in humans. So that's the biology.
Now let's focus on what is happening. And the question then is, where is nitrogen allowed to flow in the human body? Because the question I, I asked then, this, this question that I'm asking here juxtaposes to the common convention of uric acid in humans where, oh, it's too much red wine, it's too much liver, it's too much purines and pro, and pyrimidines, and you're breaking down absolute garbage. That is not true. The source of uric acid in reptiles and birds as carnivores is from protein nitrogen waste. And that nitrogen is converted to ammonia, the ammonia to purines, and the purines to, to, uh, uric acid. So the question is, why then in human beings is that same pathway not being promoted? Yes, we use BUN first, but why don't we ramp up uric acid? And, oh, no, you don't. But nobody has explained it, and in fact, the explanation is incorrect. So let's look at where nitrogen is allowed to flow. Humans do not use, humans do not use purine synthesis as a nitrogen disposal system. They don't take the nitrogen from ammonia, turn it into purines, which is very high costly in energy, and then turn it to uric acid. At least that's the understanding. But that's the direct lineage. No, it doesn't occur that much in humans. Little bit, but not a lot. But there is absolutely an indirect formation of purines, and this is what most people don't ever, most physicians, most scientists don't think about or don't talk about.
So as we mentioned, in birds and reptiles, the uric acid is the primary nitrogen, uh, waste product. But, um, it is a mistake to think of DNA and nucleotides, the ADPs, the AMPs as being the primary source of, uh, um, um, of purine synthesis in humans. Okay? Purines are made by the liver and the intestine. So purines are synthesized in humans by the liver. And where do purines come from in the liver? They come from amino acids, glycine, glutamine, aspartate, together with folate. So here's the paradox. They no, uh, uh, um, um, humans don't use the purine pathway, the uric acid cycle pathway as a primary waste. And yet in the liver, don't look at this, don't look at this. In the liver, those amino acids, the aspartate transaminase, alanine transaminase are converting amino acids into purines. So it's happening. You can't ignore it. It is absolutely happening. And then also, when we use up ATP and GTP and we use up the signaling. So there's two forms. There's the ATP and GMP, which are energy transfer molecules, electron transfer molecules. And then we've got cAMP and cGMP, which are signaling molecules, energy-rich signaling molecules. Well, when these get broken down, they also go down the purine pathway. And we're continuously, especially when we're physically active, using up ATP and damaging it and not repairing it, but building new ATP. So there's the cycle of ATP. And then every cell, every cell in the human body is undergoing autophagy and repair at some point, either repair or destruction. And every cell in the human body has DNA except for red blood cells. And every cell in the body, the individual organs or organelles have something called ribosomes. And ribosomes have something called RNA, which are old parts of viruses and fungi and bacteria, but they're incorporated into human cell organelle function. So we are continuously producing RNA and DNA breakdown products, all of which, so we've got proteins, we've got ATP, uh, GMP cycle, and we've got DNA and RNA continuously being turned over and becoming purines, which become uric acid. That's the source in humans.
Okay, let's think that one through. It is not consumption. It is not consumption. It is production that drives uric acid. Okay? And, um, so while 90 to 95% of nitrogen goes through the urea cycle, 5 to 10% still goes through the uric acid cycle in human beings, in every human being. Okay? So what then happens when we increase purine synthesis, and how does this happen? Well, when that happens, we see uncontrolled cell signaling. We see cell signaling disruption. We see nucleotide DNA and RNA imbalance. And we see up to lethal levels of elevated uric acid routinely or commonly seen on high lean protein diets. So the observation is a lean protein diet has a substantial increase in uric acid production, hyperuricemia, poor or undermined cell signaling, and nucleotide DNA imbalance. Okay, so we see that. Where else do we get uric acid from? Fructose. Fructose. Fructose. Fructose. The commonest sugar in the modern standard American diet. Fructose leads to ATP depletion, and fructose is the commonest cause of elevated uric acid. Now, not in my patient population, but, uh, in that group of patients who are consuming a lot of fructose, that directly leads to an increase in uric acid.
So in humans, nitrogen absolutely, first important statement, nitrogen absolutely enters the purine cycle in humans, despite the fact that it wasn't intended to do so. And the purines come from glutamine, glycine, aspartate, the three common amino acids. Okay? Fructose, if you eat it, and then gluconeogenesis from lean protein, and then if you are undergoing autophagy, or if you are exercising excessively, those are also sources of purines. Our diet has a tiny fraction of excess purines if we're eating a lot of organs. But the biosynthetic nitrogen waste as purines is absolutely happening in humans, and that is so important to understand that yes, purines are important in building materials, but they also form part of the uric acid cycle. So while nitrogen waste is very carefully regulated and very tightly limited, it can act as an overflow pipe for excess nitrogen going through the old purine cycle. And in particular, um, when your BUN system is overwhelmed, and we are converting excess protein to sugar and storing it as fat, that's where uric acid metabolism increases.
And what does that do? What does uric acid do? Uric acid can crystallize out in certain organs. Can crystallize in the skin. We get to, can crystallize in the joints. Everybody knows it as gout. It can crystallize in the k, in the kidneys, and its saturation point is very low. So it can crystallize in kidneys, and it is uric acid stones are the second commonest forms of stones after oxalic acid stones. But oxalic acid stones often contain a component of uric acid. And then the big one that nobody's talking about is that uric acid crystallizes in vessels, in arteries, in particular, in arteries that already have a mild amount of plaque. So while the plaque may be essentially cholesterol or lipid plaque, that attracts the uric acid, and uric acid is an independent driver or increaser of atherosclerosis. Very important to understand. And what does it do? What does the uric acid do? A very pro-inflammatory. Ask anybody with gout. It is a major activator of the inflammatory system in the heart, in the kidneys, in the toes, and in the skin. It activates the endothelial cells, can promote high blood pressure, and promotes metabolic stress, the adrenal override stress. And at what level does this occur? It starts to occur at a uric acid level above six. Crystallization occurs typically anywhere from a uric acid level of 6.2 to 6.8 and above. So essential to measure your uric acid.
So why, why do humans on a lean carnivore diet get high uric acid? And there are three converging effects. The first mechanism is increased endogenous purine turnover. We talked about that. The high protein becoming high amino acid flux, ATP turnover, increasing AMP degradation, forming hypoxanthine, xanthine, and uric acid. This is energy metabolism driven. So what we've been told before doesn't happen, absolutely is occurring. But it is not driven by dietary purines. It's driven by dietary proteins and ATP degradation. That's why lean protein raises uric acid when you are depending on protein as your source of energy. And in fact, the more fat you eat, so a fatty carnivore often does not produce a lot of uric acid. So when you're using fat as your fuel source, I use the phrase "fat protects protein." But dietary purines does not explain elevated uric acid levels.
Second mechanism: competition at the kidneys. And this is huge. Uric acid excretion shares common transport pathways with lactate, with ketones, and with organic acids. So if you're in ketosis, or if the pH of your blood is slightly low because you're producing lactate, which is a normal part of exercise, that competes with uric acid. Uric acid concentration builds up in the bloodstream because you're not peeing it out, and you get crystallization. And in particular, on a high-protein, low-fat gluconeogenic state where you are turning protein into sugar, lactate rises and renal uric acid clearance drops. So the uric acid accumulates even when production is average. And this is very importantly why if you already have elevated uric acid or you've had a background of gout early on, when you start a carnivore diet, even a healthy high-fat carnivore diet, uric acid always spikes because you're producing ketones and lactic acid that compete. And then over time, the levels normalize. And in fact, your uric acid levels come down if you're on a high-fat carnivore diet. But expect to have a gout attack, to have kidney stones early on on a carnivore diet. Not a blame for the carnivore diet, but something your body has to get used to.
And then the third mechanism is ammonia handling, which increases uric acid indirectly. Okay? So ammonia rises with excess protein being used as sugar. The ammonia usually becomes BUN or urea. Excess nitrogen slightly gets shunted into purines, as we saw in the liver. But the big thing is that when you are converting protein to sugar, you're increasing your ATP cycling, and the breakdown of ATP increases uric acid. So it's a byproduct of protein consumption. And the ATP cost itself drives higher nucleotide turnover and secondary uric acid production. So it's an indirect contribution. Indirect, but pretty much a direct contribution. So why obligate carnivores do develop, especially if on lean protein and running at a slight energy deficit, do develop elevated uric acid is for these three primary mechanisms. And the way you solve this is by reducing your protein fraction and tracking BUN levels to see if you're getting adequate protein but not too much, as uric acid was protein waste, and to increase your fat consumption. So your primary source of energy is fat, and you're not heavily relying on protein turnover and ATP turnover through protein as a source of energy. And then the final one is, even if you're on a carnivore-based diet, radically limiting your consumption of fructose because fructose messes with that entire system by itself.
So yes, it is not the human body doesn't primarily make purines intentionally. It's a byproduct. But this is just a misfiring rather than a pathway that doesn't occur. And it is essential for people to understand this explanation when they start a carnivore diet because uric acid is such a powerfully harmful product when it crystallizes out in blood vessels, in the heart, in the toes, in the joints where it can destroy joints, as kidney stones, and in the skin. So a high-protein diet without sufficient fat raises ATP turnover, reduces renal uric acid clearance, and results in an increase in endogenous uric acid production and uric acid crystallization. So yes, your nitrogen load matters. And all these people on the internet saying, "Eat more protein, eat more protein." This is how much they don't understand nitrogen metabolism. They don't understand nitrogen metabolism. They're obsessed over concerns with muscle and don't lose muscle mass and blah, blah, blah, blah, blah. Very unlikely to happen because most muscle comes from turnover protein, and you want to minimize uric acid and protein waste. So that metabolic signaling is crucial, and really the logical step then is to reduce your protein, not by absolute amount, by relative amount, by increasing and making sure that you are on a fat-heavy or fat-dominant carnivore diet. Ideally a 70/20, a 70/20, or even lower on the protein side, which will normalize uric acid production.
Now, the final, the final question is, what does exercise do to all of this? Exercise makes it worse. I love exercise. I'm a huge promoter of exercise, but exercise promotes protein, especially early on, protein turnover. And the, the exercises that are the worst are sprinting and HIIT, H-I, uh, high-intensity interval training to begin with, as well as prolonged endurance where you run out of stored energy, you run out of sugar. Okay? And in low insulin states, they can all promote the increase in uric acid. So, should you exercise? Of course you should. Of course you should. But go for shorter, low-intensity bursts as you are changing your diet. Once you become fat-adapted, then you can go back to the high endurance. Then you can go back to the HIIT training and the sprint interval sprints. But as you're converting, it's better to go for a walk or a light jog for a while. It's better not to stress the system during that conversion part, and eventually slowly raise things as you are able to use fat better.
And then also, and I know this is bizarre, track insulin because in low insulin states, you produce more uric acid. And if you are insulin suppressed, your uric acid goes up. So you want to have a normal three-phase hormonal cycling each day. A storage phase dominated by insulin, dominated by testosterone, which promotes protein synthesis rather than protein utilization. You want to exercise perhaps just before that storage period so that you're replenishing your muscles. And then you want to have a prolonged autophagy, a prolonged fat utilization phase where you are repairing and restoring tissue and reducing uric acid levels. But I test uric acid on everybody, and we can mitigate against it either with allopurinol, colchicine, but better still with a diet. But don't underestimate the role of uric acid in heart disease. Oo, a lot of science has been covered, but uric acid is a critically important marker of protein waste, not through purine production, but indirectly. Let's have a look at your blood work and do your own individual analytics and modify your diet based on BUN, creatinine, and uric acid. I am the carb addiction doc. Very important to understand this. I know it's difficult. But let's figure out what the optimal ratios of protein, fat, and other substrates are that you eat. Not based on some gum flapper on the internet that might look like T-Rex with added muscles. Cuz that's not me. Let's look at your blood work and determine for you how much protein you should eat and what your protein-fat ratio is, rather than listening to some gum flapper on the internet that's usually either got their, their top upper part of their body exposed, their big muscular beasts, or they're in a tight little bikini and their muscles have muscles. If you are that person, sure, but most of us are not. And even for those people, let's look at the numbers and modify diet based on the numbers, not the expectation. I am the carb addiction doc. If I made you think, even if you disagree with me, I've done my job. And check your blood work to know, cuz if you don't know, you don't know.