If you want to make your thiamin feel needed, the last thing you want to do is go on a ketogenic diet. But thankfully for you keto dieters out there, thiamin doesn’t have any feelings. A ketogenic diet has neurological benefits. Why do we have to eat such an enormous amount of food? Complex Science Clear Explanations Class is starting now Hi. I’m Dr. Chris Masterjohn of chrismasterjohnphd.com. And you’re watching Masterclass with Masterjohn. Today we’re in our fourteenth in a series of lessons on the system of energy metabolism. And our topic today is the intersection between thiamin, carbohydrate metabolism, and the environment. Because, believe it or not, although diet can be a source of thiamin deficiency, there’s a lot of reasons to believe that thiamin deficiency could be a problem in the environment, such as exposures to toxic molds or other things of that nature. This is something that’s really poorly explored. But it’s something that’s really serious and that we need to pay attention to. So let’s dig right into it. As shown on the screen, burning carbohydrate for energy requires twice as much thiamin as fat. That’s because the two key roles of thiamin in energy metabolism are in the alpha-ketoglutarate dehydrogenase complex and the entirely analogous pyruvate dehydrogenase complex. Now the alpha-ketoglutarate dehydrogenase complex needs to convert alpha-ketoglutarate to succinyl CoA during the citric acid cycle, whether you’re getting your energy from protein, carbohydrate, or fat doesn’t matter. And the pyruvate dehydrogenase complex, by contrast, needs to convert pyruvate to acetyl CoA only during carbohydrate metabolism because pyruvate is derived from glucose. Now we’re leaving out protein metabolism and thiamin is not irrelevant to protein metabolism. And in fact even pyruvate can be derived from the amino acid alanine. And so even the pyruvate dehydrogenase complex can be used in protein metabolism. However, we’re going to ignore those for two reasons: number 1 is we haven’t gotten to protein metabolism yet. And we’re not in a position to talk about it at that level of detail for protein. Number 2, quantitatively those things don’t matter. If we just ignore protein metabolism, it doesn’t really alter to a meaningful degree the main crux of the issue in terms of how you would manipulate your macronutrients in order to spare thiamin. So what we can say is the big take-home message is that you need twice as much thiamin when you burn carbohydrate as when you burn fat. And overall the biggest bang for your buck in terms of sparing thiamin is going to be to go on a low-carbohydrate diet, regardless of whether you’re eating a low-carbohydrate, moderate-fat, moderate-protein diet, or a low-carbohydrate, low-protein, high-fat diet. You will get some benefit from further restricting protein. And so the diet that would maximally spare thiamin would be a ketogenic diet: one that is very low in carbohydrate, very low in protein, and also high in fat. But the difference you get from restricting protein is relatively small and operating on the margins. Because thiamin is so much more important to carbohydrate metabolism than to the metabolism of the other macros, it makes sense to posit that thiamin could have a specific role in diabetes and prediabetes, characterized by elevated fasting glucose and by postprandial glucose intolerance. Shown on the screen is a small study from a few years ago investigating that. What they did was they took 17 subjects who had impaired glucose tolerance, three of whom were recently diagnosed with type 2 diabetes, the others of whom were pre-diabetic. They gave them 100 milligrams of thiamin hydrochloride 3 times per day for 6 weeks for a total dose of 300 milligrams per day over the course of that time period. Then they gave them an oral glucose load of 75 grams and they took their two-hour glucose, which is shown on the screen. And you can see that from baseline in the black bars to the diagonally striped bars, which represent the six-week mark, nothing happened in the placebo group. But two-hour glucose was reduced in the thiamin group. Now this was a very small study. And the effect looks meaningful. But it’s not the be-all end-all of treating diabetes. When we go from a little under 10 to a little under nine we’re talking about decreasing postprandial glucose from 180 to 162 milligrams per deciliter, units that are way more familiar to me and to many of you who are in my United States audience. We really want to get those under 140 or in these units at least under 7.8 to say that we’ve resolved the impaired glucose tolerance. Nevertheless, this is a small study in what is a very limited pool of data overall. But it’s hopeful, and it really does drill home the point that there may be a specific role for thiamin in dealing with carbohydrate metabolism. Now if we really wanted to investigate this, what we would want to do is select from among the people who have impaired glucose tolerance, the people in whom thiamin deficiency is most likely to be the reason. If we can find those people and treat them, I think that’s where we’ll get the best results. What’s really interesting is that so far we’re not looking at thiamin-deficient people. We’re now going to turn to thiamin deficiency. And what we’ll see is that when you’re talking about a profound deficiency the signs and symptoms are overwhelmingly neurological. Now we’re not in a position yet to talk about all of the signs and symptoms and relate them back to thiamin and metabolism. Because thiamin has important effects on the antioxidant system, which we haven’t talked about yet. And on neurotransmitter synthesis, which we haven’t talked about yet. And in fact many of the symptoms that we’re going to gloss over include cardiac symptoms like an enlarged heart. What we’re going to focus on today is the neurological symptoms. Which are the overwhelming symptoms with or without the cardiac involvement anyway. But the reason they’re so fascinating in the context of talking about carbohydrate versus fat metabolism, is that if you look at ketogenic diets, which derive their metabolism overwhelmingly from fat, and thereby would be the most thiamin-sparing diets that there are when considering macronutrient metabolism. The cases in which ketogenic diets have proven to be most useful so far are largely neurological applications. The ketogenic diet was born in the treatment of refractory epilepsy, seizures that didn’t respond to normal treatments. Even now, people are considering it for Alzheimer’s. Anecdotally people are using it for things like infection-induced brain fog and things like that. So let’s turn our attention now to looking at the neurological consequences of severe thiamin deficiency. The early models of experimental thiamin deficiency in animals described it as polyneuritis, inflammation of many nerves. And what you see on the screen is a slide from the pictures of Robert McCarrison, in his book “Studies in Deficiency Disease” in 1921. Every animal that’s thiamin deficient has its own characteristic species- specific neurological condition that results. And in birds, you have a characteristic retraction of the head that’s called star gazing, and rigid legs. In monkeys, the characteristic sign is called wrist drop, where the wrist becomes limp and the monkey loses the ability to hold up the hand. Although I have no way of showing it on the screen, the characteristic sign in rats is that they keep walking around in circles. The well-established signs of thiamin deficiency in humans are shown on the screen. Biochemically you’re going to see elevations of pyruvate and alpha- ketoglutarate for the reasons that we’ve discussed. But you’re a lot more likely, for reasons we’ll talk about in the next lesson, to see lactate. Because lactate is what you’d expect to find outside of cells. You’d have to get enormous accumulations of pyruvate for it to be spilling over in the urine. Lactate again for reasons we’ll talk about in the next lesson, could elevate for many other reasons. Alpha-ketoglutarate out of these would be most specific to thiamin deficiency. There are other aspects of amino acid metabolism that we’re not ready to discuss yet where you could see other biochemical signs, but we’ll save that for later. Classically, thiamin deficiency has been known as beriberi. It includes peripheral neuropathy, which is weakness, numbness, pain, or tingling in the extremities. Impairment of reflexes, with or without cardiovascular symptoms that can include an enlarged heart, elevated heart rate, elevated cardiac output, and congestive heart failure. Another well-established syndrome of thiamin deficiency is Wernicke’s encephalopathy. This can involve weakness or paralysis of the muscles around the eye, ataxia, which is problems with your coordination, and confusion. Also peripheral neuropathy is very frequent. Korsakoff’s psychosis can be a progression of Wernicke’s encephalopathy, but it can also be found on its own. It involves amnesia and confabulation. Confabulation is to have fake or distorted or misinterpreted memories that become real to you. Decreased spontaneity and initiative. If someone with Wernicke’s encephalopathy is treated in the emergency room by people who understand the disease, high-dose intravenous thiamin can prevent the progression to Korsakoff’s psychosis. So it’s incredibly important to recognize Wernicke’s encephalopathy. Nevertheless, as we’ll see in the next slide it often goes unrecognized and diagnosed at death. The quote on the screen is from the thiamin chapter the latest edition of the well-respected textbook, “Modern Nutrition in Health and Disease.” “The diagnosis of Wernicke’s encephalopathy is based generally on the acute appearance of ocular palsies,” which is paralysis possibly with tremors of the muscles around the eye. “Nystagmas,” which is rapid uncontrollable eye movements. “And gait ataxia,” which is the inability to coordinate your movements during walking. “As well as disorders of mentation,” which is disorders of how you think. “In addition, more than 80% of patients with Wernicke’s encephalopathy shows signs of peripheral neuropathy. However, these diagnostic criteria are nonspecific, and the diagnosis of Wernicke’s encephalopathy is missed in many patients with alcoholism, as well as those with HIV or AIDS. The reason for the high degree of underdiagnosis rests with the overzealous use of the classic triad of symptoms (ophthalmoplegia)” which is the disorders of the muscles around the eye, “(ataxia)” the disorders of walking “(and confusion) espoused by many textbooks. In practice, many cases of Wernicke’s encephalopathy are confirmed at autopsy and do not manifest this triad of symptoms. And patients may show only psychomotor slowing or apathy.” They go on: “A rewriting of this textbook definition of Wernicke’s encephalopathy is long overdue. In the meantime, thiamin deficiency should be suspected in all patients with grossly impaired nutritional status associated with chronic diseases, with particular attention paid to patients with chronic alcoholism, gastrointestinal diseases, HIV and AIDS, and persistent vomiting. Thiamin should be administered parenterally, in a timely manner. It is essential to administer thiamin to all patients before infusions of glucose or parenteral nutrition are given.” Wait a second. They said confirmed at autopsy? [Wah wah wah.] Clearly even severe cases of thiamin deficiency are massively under-recognized and under-diagnosed. Bu I’d also like to suggest that there are many causes of moderate thiamin deficiency that go unnoticed even beyond this. Because what if suboptimal thiamin status plays a role in glucose intolerance for example? Furthermore, as we’ve seen, thiamin deficiency is so overwhelmingly neurological that we have to wonder in cases where people report improvements in their neurological outcomes or their cognitive outcomes, with low-carbohydrate diets, including ketogenic diets, could this be related to the key role of thiamin and carbohydrate metabolism and the sparing effect of a fat-based diet on thiamin status? Now let’s move on to talk about some of the reasons why people may have suboptimal thiamin status, because understanding this might help us understand how to improve the metabolic flexibility of people who have difficulty tolerating carbohydrates. The most well-established causes of thiamin deficiency are shown on the screen. They include a diet poor in thiamin-rich foods, such as whole grains, legumes and meat. Gastrointestinal and liver diseases. Persistent vomiting and chronic alcoholism. Because ethanol decreases the absorption of thiamin, impairs the storage of thiamin in the liver, and inhibits brain thiamin phosphorylation. Remember thiamin pyrophosphate or diphosphate is the active form. Now if you look at thiamin-rich foods, you’ll notice that whole grains, legumes and meat are listed. In fact, if you exclude foods that are enriched with supplemental thiamin, you’ll see that most thiamin-rich foods have about a milligram of thiamin per 100 grams, which is enough to meet your daily requirement of thiamin if you eat just over one serving of those foods. And you’ll also notice that if it’s found in whole grains and legumes, then you could easily meet your thiamin requirement on a vegan diet. On the other hand, if it’s found in meat you could easily meet your thiamin requirement on a carnivorous diet. However, there are two types of diets where you can’t easily meet your thiamin requirement. Number one is a diet overwhelmingly composed of foods that have been stripped of their natural nutrients. Historically beriberi was associated with the consumption of white rice for that reason. Nowadays, junk food is fortified with thiamin. So you’re unlikely to get a thiamin deficiency from eating refined enriched flours, like white bread products, today. However, you could still get a thiamin deficiency if you mostly eat fat. Because thiamin is found in whole grains, it’s found in legumes, and it’s found in meat. But it’s not found in large quantities in fat. And who eats diets that are mostly fat? Ketogenic dieters. This is really critical because I’ve been saying through this entire lesson that a ketogenic diet is thiamin sparing. But the diet that maximally spares thiamin is also the diet that if it doesn’t contain supplemental thiamin, doesn’t have any thiamin. Shown on the screen is an example from 1979 where people developed optic neuropathy when they were being treated with ketogenic diets for refractory epilepsy. And that happened because they were given the ketogenic diet with no B vitamin supplements. As soon as they were given thiamin supplements, everything started turning around. So we have to remember that even though fat requires half as much thiamine as carbohydrate does, it doesn’t require zero thiamin. So if you cut your thiamin requirement in half, but you don’t eat any thiamin, you can still get a thiamin deficiency. There are other potential causes of thiamin deficiency. For example, raw fish can contain thiaminases that destroy thiamin. This was initially discovered when people tried feeding wolves on exclusively raw fish diets. Now no one really knows where the thiaminases in fish come from, but it appears not to be an intrinsic property of fish but something that happens because of the fish’s environment, and we’ll come back to that in a few minutes. Heat and processing causes significant losses of thiamin. During baking you destroyed 20 to 30 %, during pasteurization you destroy 20% and pet food processing destroys 90%. In fact, what they do with pet food is they add ten times more thiamin to the pet food than they want, and then they blow it to smithereens, knowing that 10% will be left, which is just enough to satisfy your pet’s thiamin requirement. Now keep in mind, of course, that as we said before if you’re eating a natural diet of natural whole foods that includes either meat, legumes or whole grains, you’re probably going to exceed your thiamin requirement enough that destroying 20 to 30 percent in baking or pasteurization is okay. Nevertheless, if you’re borderline or you have other reasons for thiamin deficiency, then the toll that heat and processing takes could become significant. Gut bacteria have been found to cause thiamin deficiency. Unfortunately all the data that we have on this is from a long, long time ago. So we don’t really have any basis to find thiamin-destroying gut microbes in humans with current fecal stool tests, because no one’s studying it right now. In addition, in cattle in veterinary science it’s been known that thiamin destroying microbes in the rumen of cattle are the major source of thiamin deficiency in that context. In humans who consume the larvae of an African moth, anaphe venata, which they eat in the rainy season in Nigeria in the southwest, July through October, they get thiaminases from those moth larvae. And they eat the larvae traditionally with carbohydrate-rich foods. So on the background of a thiamin- deficient diet, they consume thiamin-destroying thiaminases in the moths together with carbohydrates that increase their need for thiamin, and clinical thiamin deficiency results. Out of these, the most fascinating is environmental thiamin deficiency. There are regional outbreaks of thiamin deficiency in wildlife that are attributed to antagonists in the environment, and we don’t really know what they are. This really brings to the front burner for me the question of: are we humans subject to environmental thiamin deficiency? On the left panel of the screen is a bird that was found in an area surrounding the Baltic Sea. You can see that it has the characteristic star gazing neurological defect that Robert McCarrison had identified in experimental thiamin deficiency in birds almost a hundred years before this publication. They find this with paralysis and seizures a lot in some of the areas around the Baltic Sea. On the right is data showing that when they treat these birds with thiamin, 9 out of 10 recovered. But in the birds that weren’t treated with thiamin, none of them recovered, providing pretty strong evidence that what’s happening is a regional outbreak of thiamin deficiency. They also find tremors, seizures, and death among these birds. When studied in more detail, they found low-tissue concentrations of thiamin, and high latency of alpha- ketoglutarate dehydrogenase and another enzyme, transketolase. High latency means that they took the enzymes and they tested them to see their activity. Then they added thiamin and tested their activity again. If there’s a large increase in the activity of the enzyme after adding thiamin to it, that means there’s high latency. High ability of the enzyme to be activated with extra thiamin. When that’s the case, it’s a strong sign of thiamin deficiency because it means that that bird has been making thiamin-dependent enzymes that don’t have any thiamin in them. And why would the bird do that unless the bird didn’t have enough thiamin to activate the enzymes it was trying to make? Now this enzyme, transketolase, is a thiamin-dependent enzyme that protects against oxidative stress. We haven’t talked about that in this series of lessons yet, but let’s note it now because it’ll come up later. But also because in humans you can test transketolase in red blood cells. It’s the best marker of thiamin deficiency in humans that we have and no laboratory in the United States offers it as a clinical test. If you’re out there and you run a clinical laboratory, I plead with you, begin offering erythrocyte transketolase activity as a test for human thiamin status. So far no one knows exactly what’s causing thiamin deficiency in the Baltic Sea. The researchers have speculated that it might be traceable to thiamin antagonists produced by algae in the dead zones and is thus traceable to the environmental problems that are causing those dead zones to arise. Meanwhile, lake trout in the Great Lakes have also been subject to these outbreaks of regional thiamin deficiency. In that case, investigators have partly traced it to alewifes, which are non-native fish that have been introduced in that environment. And alewifes produce thiaminases that can accumulate up the food chain and cause thiamin deficiency in the animals that are above them in the food chain. Now the alewifes do have thiaminase in their tissue, but it’s only been partly traced to specific microbes in their tissue. And no one knows where 90% of the thiaminases from the alewifes is coming from. So these outbreaks are really mysterious. Here’s what we know about potential thiamin antagonists. Very early on it was shown that sodium sulfite in vitro, meaning in a test-tube, irreversibly cleaves thiamin. Now I don’t know if this has any clinical relevance. However, sulfite is something that you normally turn into sulfate with enzymes that require molybdenum, an essential mineral, to be activated. So I think it’s theoretically possible that someone could have a molybdenum deficiency, then produce sulfite in their metabolism that doesn’t get metabolized to sulfate, and that could destroy thiamin. Again, that’s speculative, but it seems like it could happen. We know that fish and shellfish contain thiaminases. And we have the evidence that seems to correlate them with things in the environment and trace them to bacteria. But these are very poorly understood. We know that ferns produce thiaminases. And we know that in ferns they vary seasonally. As I mentioned before, the larvae of the African silkworm produces thiaminases. And in human feces, clinical thiamin deficiency, particularly in Japan studied many decades ago, has been traced to bacteria such as Bacillus thiaminolyticus, Bacillis aneurinolyticus, and Clostridium thiaminolyticum, which is now, or at least later became called Paenibacillus thiaminolyticus. Now it’s important to note that the people who were naming these were naming them after thiamin destruction or nervous system destruction. And this research has largely been abandoned to my knowledge decades ago. So I think it’s very possible that there are thiamin- destroying microbes in the human gut, with no good way to test them right now, until we start doing more research on it. There are fungi such as Trichosporum aneurinolyticum, Candida aneurinolytica, Lentinus edodes. And finally most recently an amoebaflagellate, Naegleria gruberi. I have no idea if I’m pronouncing these right, so don’t hold me to it. But most recently the first amoeba was found that can be a contaminant of water to produce thiaminases. So there’s a lot of things that we don’t know about thiamin deficiency. And yet there’s a lot of things that we know. For example, you can suspect it on the basis of glucose intolerance and toleration of fat better that carbohydrate. You can suspect it on the basis of neurological conditions. And you shouldn’t wait to diagnose it at autopsy, but you should look for it with even any plausible scenario of nutritional deficiency combined with neurological symptoms. And we know that it isn’t just caused by a diet that lacks either meat, whole grains or legumes. But it can also be caused by microbes and poorly understood things in the environment. What that means is we may be dealing with gut issues, with toxic mold exposure, maybe even chemical exposures and things that vary in our environment that are poorly studied. On that basis, we need to start thinking outside of the box and realize that there could be things that are interfering with thiamin even when dietary thiamin deficiency seems implausible. And even when someone doesn’t have things like persistent vomiting, alcoholism, and those other classical things associated with the history of Wernicke’s encephalopathy. Therefore, I plead especially with the healthcare practitioners out there, start thinking more about thiamin deficiency when you see something as simple as glucose intolerance, especially if it’s accompanied by neurological problems. And start thinking beyond just diet as a plausible explanation of thiamin deficiency. And think through things like mold exposure and other environmental causes. Finally we don’t have, at least in the United States, the ideal marker of thiamin status, erythrocyte transketolase. But we do have the ability to look for urinary organic acids. And if we see things like elevated lactate and alpha- ketoglutarate in the urine, that can be really helpful in trying to understand the possibility or look for the possibility of a thiamin deficiency. Fnally there’s no known detriment to taking thiamin supplements. And so if everything seems plausible, then whether someone gets better with thiamin supplementation could be a useful way of going about trying to figure out and solve the problem. The audio of this lesson was generously enhanced and post-processed by Bob Davodian of Taurean Mixing, giving you strong sound and dependable quality. You can find more of his work at taureanonlinemixing.com. To continue watching these lessons you can find them on my YouTube channel at youtube.com/chrismasterjohn. Or on my facebook at facebook.com/chrismasterjohn. Or you can sign up for MWM Pro, to get early access to content, enhanced keyword searching, and self-pacing tools, downloadable audio and transcripts, a rich array of hyperlinked further reading suggestions, and a community with a forum for each lesson. If you really want to own these lessons, study them, and get the most out of them, you can sign up for MWM Pro at chrismasterjohnphd.com/pro. All right, I hope you found this useful. Signing off, this is Chris Masterjohn of chrismasterjohnphd.com. You’ve been watching Masterclass with Masterjohn. And I will see you in the next lesson.