thiamine

Paradoxical Reactions With TTFD: The Glutathione Connection

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TTFD and Low Glutathione

Some individuals experience negative reactions and the worsening of symptoms when they begin thiamine repletion therapies using the more biologically available formulations like thiamine tetrahydrofurfuryl disulfide (TTFD). Dr. Lonsdale calls these paradoxical reactions. In this article, I examine the chemistry beyond these reactions and provide some hypotheses regarding why they happen and how to mitigate them.

TTFD Basics

In order to understand why some individuals react negatively to TTFD supplementation, it is essential to understand the basics behind TTFDs molecular configuration and how it is processed by cells. The primary difference between ordinary thiamine and TTFD is an extra chemical group called a mercaptan group. The mercaptan is derived from allicin, a compound found in garlic, and is connected to the thiamine molecule via a special sulfur-sulfur bond called a disulfide bond. Importantly, it is this unique chemical group that accounts for TTFD’s ability to traverse membranes in the body without the need for a transport system.

Upon ingestion, TTFD is mostly absorbed into the blood from the gastrointestinal tract in whole form as TTFD. As it travels through the blood, it can penetrate the brain and other organs without cellular transporters. One of the main sites of absorption is the red blood cells. Upon penetration of the red blood cell membrane, TTFD must first be processed or “broken apart” before it can release the thiamine contained within its chemical structure. After thiamine is released into the cell, the ancillary mercaptan group must also be processed and/or detoxified through alternative pathways. It is therefore theoretically plausible that errors involved in the processing of TTFD could contribute toward negative side effects or reactions to this nutrient.

How TTFD Is Processed Inside the Cell: The Glutathione Connection

For TTFD to “release” its thiamine, its disulfide bond must gain electrons from another donor molecule. In chemical terms, this process is referred to as reduction. Once this reduction occurs, thiamine is freed and can then go on to participate in cellular biochemical reactions.

Of the few molecules which have been shown to reduce TTFD, glutathione performs this function most effectively. As the cell’s primary antioxidant, glutathione is responsible for donating electrons to neutralize reactive oxygen species, and can either be found in its reduced form or its oxidized form. Once a reduced glutathione molecule (GSH) has donated its electron, it bridges with another to molecule to form oxidized glutathione (GSSG). GSSG is then recycled back to two GSH molecules through accepting electrons from NADPH via the enzyme glutathione reductase (vitamin B2 as FAD dependent). TTFD and Glutathione

When TTFD enters cells, GSH in red blood cells chemically reduces TTFD via a process called “disulfide exchange” (presumably using a protein called glutaredoxin). Reduced glutathione becomes oxidized glutathione and TTFD “releases” thiamine to producing free thiamine inside the cell with an extra TFD mercaptan group left over.

The initial phase of processing TTFD requires that cells have enough reduced glutathione. Furthermore, the more GSH you have – the faster the rate of this reaction. So in simple terms, to obtain thiamine from TTFD the cells “use up” their reduced glutathione.

I recently had correspondence with one individual who only gained tolerance of TTFD after supplementing with 200mcg of selenium in the form of sodium selenite. Selenium supplementation in different forms has been shown to increase red blood cell GSH levels by up to 35%. This is thought to occur due to selenium’s ability increase glutathione synthesis through upregulating the enzyme gamma-glutamylcysteine synthetase. I suspect that poor glutathione status might be one of the reasons for benefit from selenium.

Having enough glutathione is clearly very important, but recycling it is also essential to maintain a pool of glutathione in its reduced form. Unfortunately TTFD can place a burden on this system, and this was demonstrated in one old study from Japan which showed that TTFD administration rapidly lowered red blood cell GSH. Interestingly enough, that same experiment showed that GSH levels were restored within 5-10 minutes. This restoration was accomplished by the vitamin B2 (as FAD)-dependent enzyme glutathione reductase, which donates electrons to GSSG with the reducing power of NADPH to recycle it back to two GSH.

What this basically means is that cells require a robust antioxidant system to properly process TTFD and return back to their original state. First, cells need enough of the antioxidant GSH to cleave thiamine. Second, cells also need to be able to recycle the oxidized glutathione back to its reduced state.

Poor Glutathione Status and Difficulty With TTFD

Immediately, we see two potential issues that could arise from TTFD supplementation which might provide a better understanding of why some people may not tolerate this molecule.

In someone who has poor glutathione (GSH) status, they might theoretically be less able to cleave thiamine from TTFD. There are many reasons why someone may have poor glutathione status:

  • Low precursors (cysteine, glutamate, glycine)
  • Chronic oxidative burden and/or inflammation
  • Deficiencies in the nutrients required to generate, process, or utilize glutathione (B6 or selenium)
Alternatively, an individual may have enough resources to make glutathione, but if they cannot recycle it through the necessary machinery (i.e glutathione reductase), then taking a substance which depletes their GSH (like TTFD) might further contribute towards their oxidative burden.

A total and/or functional riboflavin deficiency is the probably the most common culprit responsible for poor glutathione reductase activity. The glutathione reductase enzyme also requires adequate reducing power from NADPH to drive the enzymatic reaction. NADPH is derived from niacin (vitamin B3) and is generated in the pentose phosphate pathway which, ironically, requires the thiamine-dependent enzyme transketolase.

In the context of poor enzyme activity, without the reducing powder to drive GSSG back to GSH, the oxidized form of glutathione can theoretically drift towards the path of generating a free radical called the glutathione radical. This alone could further contributes to oxidative stress and cell damage.

Below is a hypothetical scenario to demonstrate my point:

  1. An individual suffers from long-term thiamine deficiency and has suboptimal riboflavin status
  2. Thiamine deficiency leads to lower activity of transketolase
  3. Low transketolase activity produces a lack of NADPH
  4. A lack of NADPH and a lack of FAD means that glutathione reductase is unable to efficiently recycle glutathione, which produces an imbalance between reduced/oxidized glutathione.
  5. Intracellular GSH is further lowered by taking high dose TTFD, and there is not enough enzyme activity to recycle it back
  6. Oxidative stress is made worse

In the above scenario, taking a high dose of TTFD may not be appropriate. Rather, restoring NADPH levels through supplementing with ordinary thiamine and supporting the glutathione system via other measures might be advised before starting with TTFD. Optimal riboflavin status is also necessary for the above processes to run smoothly.

Older research in Japan showed that TTFD supplementation could lead to a secondary B2 deficiency through increased urinary excretion. The increased need for glutathione reductase could at least also contribute to this effect. When taking TTFD, it has downstream effects on other nutrients. Hence, these supporting nutrients should also be taken in conjunction when someone is supplementing TTFD in high doses.

Some basic laboratory measurements of glutathione status include:

  • Whole blood glutathione (low)
  • Gamma-glutamyl-transpeptidase (high)
  • Urinary pyroglutamic acid (high)

Furthermore, there are several functional markers which can be measured to assess riboflavin status, including direct measurement of red blood cell glutathione reductase activity:

  • Urinary glutaric acid (high)
  • Whole blood B2
  • Urinary adipic, suberic, ethylmalonic acids (high)
  • Urinary succinic acid (high) can also be suggestive along with a few other organic acids
  • Erythrocyte glutathione reductase activity (low)

To summarize, the initial cellular processing of TTFD requires adequate levels of reduced glutathione. Glutathione becomes oxidized, and so TTFD has can have a depleting effect on GSH and increase the requirement for recycling. If there is insufficient active B2 (as FAD) or NADPH levels, glutathione is not likely to be recycled sufficiently and may lead to GSSG radical formation.

It is therefore possible that the glutathione-depleting effect of TTFD could be responsible for some of the side effects associated with supplementation. This is probably most applicable in individuals with poor glutathione recycling and underlying oxidative stress. Therefore, nutrient therapies that may support this initial phase of TTFD metabolism include:

  • Selenium (improve GSH levels)
  • Riboflavin (improve GSSG-GSH recycling)
  • Niacin (increase NADPH)
  • Ordinary thiamine (increase NAPH via PPP)
  • NAC, glycine and/or glutathione TAKEN HOURS AWAY from TTFD (GSH precursors)

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on October 26, 2020. 

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Recurrent Fever With Swollen Glands: Febrile Lymphadenopathy and Thiamine

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fever swollen glands - Febrile Lymphadenopathy.

Every profession has its jargon and the medical profession is no exception. Perhaps it is even more addicted to jargon than other professions. The title used here refers to an extremely common disease, particularly in children. Febrile is the word used to describe fever. Lymphadenopathy simply means that lymph glands are swollen. The mechanism is as follows: the throat becomes infected, often with streptococcus and may affect the tonsils or adenoids. A message is sent from the throat to the brain that reacts to cause the body temperature to be raised. We will see why later. The lymph glands in the neck are stimulated to get bigger as part of the immune response. The child feels sick and accepts bed rest and these essentially defensive reactions are referred to as the “illness”. Often a treatment such as aspirin is given to the child to bring the temperature down under the mistaken concept that this is the dangerous part of the illness. A previous post on this website described a case of Reye’s syndrome, a deadly disease known to occur as a result of giving aspirin to bring the fever down. It is of course true that a very high temperature such as 106°F is considered to be dangerous. But this is because the brain mechanism that initiates this temperature is itself in an abnormal state and may be the actual source of the danger.

Understanding Fever as an Immune Response

If we look at this situation in the cold light of day, we can come to false conclusions. Yes, this is the expected situation with an infected throat and it is invariably treated with antibiotics. But let us see what is really happening in all cases of this common affliction. The brain has received a message from the throat that an attack by a microorganism is occurring. The brain sets up a defense mechanism and I refer to the microorganism as a “stressor” (the enemy). The brain is programmed to recognize the attack as dangerous to the organism. The physical aspects of the infection and the brain mechanisms that receive the message and activate the defense are in constant communication. The body temperature is raised by the brain as part of this defense.

Microorganisms, the stressors, are programmed by Mother Nature to operate at maximum efficiency at 37°C, the normal temperature of the human body. By raising the body temperature, the environment for the microorganisms is detrimental to its action and decreases its virulence. No rise in body temperature indicates that the brain is sick!

Inflammation Is an Immune Response: Resting Boosts Immune Function

The inflammation of the throat makes it harder for the microorganism to gain entrance and is also part of the defense. Strangely enough, we now know that inflammation is controlled and governed by the brain. A message to the lymph glands in the neck increases their size to cope with the expected passage and trapping of bacteria from the infected area and is part of the immune response.

The bed rest or fatigue that occurs with illness is yet another part of the immune mechanism. Bed rest conserves the cellular energy needed to activate the defense mechanisms.

You can readily see that all of these reactions that we call sickness are scripted and controlled completely by the brain. It may come as a surprise to many readers, but fever, inflammation and energy conservations are necessary immune reactions. Diminishing or overriding those reactions, usually by trying to reduce fever with a drug or failing to rest rather than assisting the body’s defense systems, may only prolong the illness and perhaps even create new ones.

The modern method of treatment is, of course, to kill the organism. Little thought is given to whether the supply of energy in the brain is sufficient to run the complex organization of defense. It also assumes that the genes that oversee the immune response are intact and functionally healthy.

Nutrient Interactions With Immune Response

Now I must tell you about two children, both of whom had suffered from repeated episodes of febrile lymphadenopathy (Lonsdale D. Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: report of two cases). Each child had been treated by antibiotic therapy with their recurrent episodes over a two or three-year period on the assumption that they were caused by bacterial infection. Both were medical puzzles because evidence of bacterial infection was lacking and it was assumed that the recurrent episodes were viral in nature. I had the opportunity to study one of them in detail.

The child had been admitted to a prestigious hospital and a swollen gland in the neck had been biopsied under the impression that it might explain the disease. The pathologist had reported an enlarged but otherwise perfectly normal gland structure. The mother told me that at this hospital he had also had the concentrations of vitamin B12 and folic acid measured in the blood, presumably because they were looking for evidence of deficiency. She volunteered that “the doctors told me that I was giving him too many vitamins”, apparently because the two vitamins had been found to be in an unusually high concentration. She also volunteered that this was very strange to her “because I had not been giving him any vitamins at all. The doctors didn’t believe me”. This naturally intrigued me.

Without going into the technical details, I found that he had evidence of abnormal thiamine metabolism. The folic acid and B12 concentrations were indeed extremely high. When I gave him the big daily doses of thiamine, these two vitamins each fell into its range of normal blood concentration. I discharged him from the hospital where these studies had been carried out, continuing the high dose treatment with thiamine. Two or three months later, the mother called me to say that her child had not had any episodes of fever and was extremely well. I responded to her by asking if she was interested in stopping the thiamine in the interests of science. She did stop it and three weeks later he had an episode of sleep walking, spontaneous urination as he went down the stairs and another episode of febrile lymphadenopathy.

You may well ask how the sleep disturbance could possibly be associated with the throat problem, so continue reading. I readmitted him to the hospital and clinical examination revealed the sore throat and a very large lymph gland in the neck. The folic acid and B12 concentrations were once more elevated. I restarted the thiamine and the two vitamin concentrations again fell into the normal range. The enlarged lymph gland disappeared and I discharged him from the hospital with instructions to continue the high dose thiamine. About a year later she reported that the episodes had begun again. I told her to add a multivitamin to the thiamine and again the episodes ceased. The other child also had evidence of abnormal thiamine metabolism that was resolved by the administration of large doses of thiamine, but unfortunately, I was not able to study him further. Please note that both children had been indulged with ad lib candy and soft drinks.

Nutrient Deficiency in the Face of High Sugar Intake: Altered Immune Responses

The explanation is construed from a rational approach to the genius of Mother Nature. I have already described the normal mechanism of defense to infection organized by the brain. Think of the body as being like an old-fashioned fortress. When an approaching enemy is spotted by soldiers on the Eastern battlements, a message is sent to the commander. The commander is then able to plan the defense and off duty soldiers are deployed to the scene of impending attack.  Imagine that the commander is drunk and he sends the reserve soldiers to the Western battlements. Or perhaps the commander imagines falsely that he has received a message and deploys his defensive soldiers throughout the fortress unnecessarily, a “May Day” without reason. Obviously the commander would be to blame.

This is an analogy for the brain/body response to infection. Messages throughout the body are automatically relayed through the autonomic (automatic) nervous system and by the hormones released from the endocrine glands. Hormones, carried in the blood stream, are messengers. White blood cells are “the defending soldiers”. Both the autonomic and endocrine systems are under the control of the more primitive lower part of the brain, the commander in the analogy and the part of the brain that is known to be peculiarly sensitive to thiamine deficiency. There is good scientific evidence that thiamine deficiency will make the “commander” much more sensitive to incoming signals from the “battlements”.  Like the “drunk commander”, it organizes a complete defensive reaction without there being any need.

To be a little more scientific, thiamine deficiency causes reactions in the lower brain that are exactly like a mild to moderate deprivation of oxygen. That is why thiamine deficiency is reported scientifically to cause pseudo-hypoxia (pseudo, false: hypoxia, deficiency of oxygen). These children had been indulged with ad lib. candy and soft drinks. Even if they had had the average intake of thiamine from the diet, essential to the processing of sugar, it was insufficient to metabolize the sugar. You might say that this was an increased sugar/thiamine ratio, equivalent to dietary thiamine deficiency with a normal healthy diet.

Microorganisms Attack: The Immune Response Defends

Each case of the usual form of febrile lymphadenopathy can be visualized as a hostile attack by a microorganism (a stressor) requiring a defense response. However, in the case of these two  children, when the brain ”commander” was exposed to thiamine deficiency  (pseudo-hypoxia), itself imposing  brain stress, it  became hypersensitive to virtually any form  of incoming signal from the environment. It is therefore possible that a change such as ambient temperature was being perceived falsely as a dangerous threat to the organism (the patient). Hence, it is hypothesized that any proposed minor form of stress initiated the defensive response, mediated and organized by the lower brain that is programmed to perceive danger. It is possible that a virus in each case may or may not have been responsible for being the “stressor” but it is more likely that the “commander” was initiating an unnecessary defense based on a false perception of a non-existent attack such as ambient temperature change.

I have to turn to analogy once more.  A car has an engine. Its essential function is to produce energy. The energy has to be transmitted to the wheels through individual mechanical parts that are connected together to form an energy consuming transmission. In the human body each cell has its own engines and they are called mitochondria. Their function is also to produce energy that has to be converted into mental and physical action. Thiamine is essential to energy production from the mitochondria and a series of enzymes are the equivalent of the mechanical parts of the transmission in a car and therefore can be thought of as an energy consuming biochemical device. Therefore, mitochondria produce energy; the transmission consumes it in mental and physical action. Folate (folic acid) and vitamin B12 are essential to this biochemical transmission. Because thiamine deficiency depletes cellular energy, the enzyme dependent (energy hungry) transmission developed problems. Folate and B12 accumulated in the blood simply because they were not being used. When thiamine was given to this boy, cellular energy improved and the two vitamins were consumed in their actions and their concentrations decreased in the blood.

Sleepwalking: An Example of Brain Dysfunction?

Sleepwalking has always been a puzzle. A sleepwalker is not consciously aware of what he or she is doing. I remember the case of a man who drove his car for 70 miles and had no recollection of doing it. I had found from my clinical experience that sleepwalking children would stop doing this with the administration of nutrients, particularly thiamine and magnesium. The fact that the subject of this discussion urinated as he descended the stairs indicated abnormal automatic autonomic nervous system activity. This was pretty good evidence that it was oxidative deficiency in the brain that was responsible for both physical and mental abnormal activity after therapeutic thiamine had been withdrawn.

The Use of a Multivitamin: Completing the Nutrient Team

As the story above indicated, the episodes of febrile lymphadenopathy began to return about one year after he had been discharged with instructions to take only thiamine. There is a particular relationship between thiamine and magnesium because both of them are cofactors together for the same enzymes. However, vitamins and minerals are non caloric nutrients that work as a complex team. There might still be nutrients in naturally occurring food that await discovery. Mother Nature knows how they all should be balanced. The further we move from our biologic origins by the introduction of artificial foods in our hedonistic pursuit of pleasure, the more illness can be expected. Our present medical model is concerned only with killing the attacking agent. Rather simple clinical research revealed an anomaly of this nature in the organization of defense, without knowing how common it is. It should surely focus our attention on the role of nutrition in providing the raw materials for this organization. An infection gives rise to a battle. There are only three possible outcomes: the enemy wins: the defense wins: there is stalemate. The stalemate possibility suggests that chronic long term infection can be tackled by the use of energy producing nutrients that improve the efficiency of a defensive program.

Unfortunately, there are problems with what appears to be a simple solution. Even natural food does not have the nutrient density that it used to have because of changes in farming practices. Also, whether we like it or not, evolution is going on all the time and in the modern world, the smartest brains have the greatest evolutional advantage. Those interested in following the numerous posts on this website will note that post Gardasil thiamine deficiency appears to affect the brightest and the best. I have suggested that relatively poor nutrition, coupled with a smart brain, creates a greater risk of succumbing to a risk from vaccination, mild infection or trauma.

I have seen several articles that state the uselessness of dietary supplements, claiming that the numerous vendors are cheating the public. My own library research reveals numerous papers on the subject of supplementary nutrients coming from many parts of the world other than America. Although they are not cheap, the expense is very much less than the drugs issued by pharmaceutical companies and their curative or preventive properties are huge. Humanitarian research in this area of relative ignorance is a modern necessity.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

Photo by Kelly Sikkema on Unsplash.

This article was published originally on April 19, 2016.

Rest in peace Derrick Lonsdale, May 2024.

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Coordinating the Body’s Defense

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attack and defend

Human beings live in a world where they are under continuous attack. In this post, I will outline the nature of the attack and how we defend ourselves.

Homeostasis

The prefix “homeo” means “the same, steady”, and the definition of homeostasis is “the tendency towards a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes”. Although we are surrounded by bacteria and viruses that are ready to attack us, generally speaking we remain healthy. We can assume that the body’s capacity for maintaining health has adequate energy to maintain homeostasis. That must mean that we are defending ourselves continuously, but any form of imposed stress, such as an infection, demands a surge of energy to meet it. The miracle of being alive means that our defensive machinery is always operating automatically. The body consists of between 70 and 100 trillion cells, each having a responsibility in its own right. We exist because we have inherited a code from our parents called DNA. If this is in a perfect state, all that is required is food to supply energy. The defense is referred to as “an illness”.

How We Defend Ourselves From Infection

As an illustration, I am going to use the form of a typical attack referred to as a streptococcal sore throat, whose technical name is “acute febrile lymphadenopathy”.

Why does the throat become sore?

As we all know, because of inflammation. This is a defensive process because the inflammation is an attempt to block the passage of the bacteria into the body.

Why do we get swollen glands in the neck?

The swollen glands are known as lymph nodes. They become enlarged because it is an attempt to capture and destroy the bacteria as they pass from the throat into the body.

Why do we develop a raised body temperature?

As we all know, the normal body temperature is 37° C.  This is the temperature at which bacteria are at their most efficient state. By raising the body temperature, the efficiency of the bacteria is reduced.

The Brain and the Inflammatory Reflex

We now know that inflammation is under the control of the brain. It sends signals through the nervous system that is known technically as “the inflammatory reflex”. In fact, the entire defensive system is under the control of the brain, as is illustrated by a case that I have already described on this forum, but bears repeating.

Years ago, I was confronted by the case of two boys, both of whom experienced recurrent acute febrile lymphadenopathy. Of course, they had been treated by repeated antibiotic therapy, even though any form of infection had not been proved. Cutting out the technicalities involved, I was able to show that both of these boys were deficient in thiamine, leading to a reduction in brain energy. Each of these two boys had been indulged throughout life with an ad lib ingestion of sweets. It was probably responsible for the thiamine deficiency. Again, without going into the necessary technical factors, the lower part of the brain that controls the defensive machinery becomes unduly sensitive from the energy-deficiency caused by the insufficiency of thiamine. What was really happening was that the part of the brain that controls the defensive machinery had become hypersensitive. It was reacting to a variety of otherwise harmless environmental stimuli under the false Impression that an Infective microorganism was the stressor. There were other factors that supported this explanation, but they are highly technical and inappropriate for this post. The case was published in the medical literature.

It is not easy to understand that the acute febrile lymphadenopathy in each of these 2 boys was really a perfectly appropriate defensive reaction to non-existent bacterial attack, if such an attack had been the reality. If we acknowledge that bacterial invasion of the body is a form of stress, we are supporting the conclusion that “stress” requires a surge of brain energy to operate the defense. This is true for any form of stress, including trauma and mental action.

Because lack of oxidation had made the brains of these boys hypersensitive to any form of stimulus, they must have been overreacting to the perception of some form of environmental stress under the false Impression that it represented a bacterial invasion. Of course, we cannot know if this is the truth, but all the biochemical studies supported this explanation of the observed facts.

Genetics

The perfect structure of the human body is undoubtedly the ideal. It would mean that we had inherited a perfect genetic code in DNA. It is unlikely that perfection in structure is ever achieved in any of us and that we each have a share of genetic mistakes known as polymorphisms. These are not sufficient to cause disease on their own, but perhaps they introduce genetic risk. Another factor may have to play a part. For example, type 1 diabetes has a gene or genes in its background. But the disease does not emerge until later in life, often after a minor stress such as a cold or injury. If the gene(s) were the sole cause, the symptoms of diabetes could be expected to appear at birth. What I am hypothesizing is that a breakdown in health requires more than a single factor. We have indicated that Imperfect genetics is one factor and some form of stress is another.

Nutrition and Malnutrition

We have indicated that a surge of energy is inevitably required for the automatic machinery to go into defensive action. That comes from our food whose efficiency in synthesizing that energy comes from two distinct parts. The first part is called calories and the second part is known as non-caloric micronutrients. Mother Nature “knows” the exact proportion of each part of the food. We do not! Is it not obvious that our food has to  be that supplied only by MN?

Because the brain is the organ that needs the largest amount of oxygen, it quickly reacts to a mild insufficiency by producing a variety of sensations called symptoms. It is almost as though the brain is trying to warn its owner that it is lacking energy. Of course, the trouble with that is that the cause has to be interpreted in practical terms. The lower brain that controls the autonomic nervous system (ANS) is highly sensitive to oxidative deficiency, so the many symptoms experienced by the patient come from dysregulation of that system. For example, a common symptom is heart palpitations. The explanation for them often given by the physician, is that it is from “heart disease”. Dysfunction of the ANS is not considered. A series of laboratory studies found to be abnormal in heart disease are applied. Abnormal laboratory results are essential to the present concept of “real disease” and when they are found to be normal, the interpretation of the palpitations is that it is “psychosomatic”. Unfortunately, there are millions of patients who go through a series of specialists seeking an answer to their multiple symptoms. Each specialist gives an answer that is governed by current diagnostic concepts or their particular specialist status. Some of these unfortunate patients have recorded their experiences by posting on Hormones Matter and anyone seeking help may find the solution in one or more posts that address this problem.

Chronic Illness and Covid Longhaulers

Consider this. An attack by ANY microorganism is a “declaration of war”. There are only 3 outcomes: the microorganism wins (death), you win (cure), or there is stalemate (chronic disease). The brain is responsible for organizing and controlling the defense. If its inherited construction is perfect, all it requires is energy. Probably a perfect DNA never occurs and many, if not all of us, have gene defects known as polymorphisms that are insufficient to cause disease on their own. Epigenetics tells us that genes (say, polymorphisms) are influenced by nutrients. Any form of “stress” (a nasty divorce, a deadline, surgery, even an inoculation) demands a surge of energy to meet it. I suggest that “Longhaulers” after Covid-19 are suffering stalemate. Thiamine and magnesium together stimulate energy production, making the job of the brain more efficient to “win the war”. That is why thiamine deficiency has been reported in critical illness (stalemate) and after surgery. It strongly suggests that people who die from Covid-19 were experiencing high calorie malnutrition when they were assaulted by the virus. It also suggests that nutrition in America is inadequate to meet the stresses of modern life!

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

Image credit: fxxu via pixabay.com, cc0 license.

This article was published originally on August 9, 2021. 

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Mitochondrial Metabolism Drives Genetics and Epigenetics

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mitochondrial metabolism cell fate

For the last forty years or more, the fate of cells was believed to be predominantly, if not solely, determined by genetic blueprints. Everything from the earliest stages of gestational development to the expression of diseases like cancer was, and largely still is, considered genetically determined. Environmental considerations, while acknowledged, are believed to play a much lesser role.

As the genome was mapped, the medical industry, especially those in the field of cancer research, held out great hope for identifying the genetic origins of disease, only to be let down repeatedly. Researchers failed to link up to 95% cancers to any genetic defect and the frequency of genetic defects associated with the vast majority of non-cancer related disease processes was found to be less than a measly one percent. To accommodate the discrepancy between expectation and data, random chance entered the conversation. Researchers argued that what could not be accounted for by genetics or the few environmental causes considered, must be the result of randomly generated mutations; stochastic events for which we have no explanation. A study published in 2015, supported that claim.

These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells.

It is important to understand what randomness means in this context. Here, when genetic variations arising from computer simulations cannot be attributed to either known genetic and/or recognized environmental associations with cancer, they are classified as random. In other words, what is unknown or unrecognized within the confines of the experiment is considered random. As one might imagine, this creates a few problems. Most notably, we don’t know what we don’t know. To say with any certainty that something is random suggests all variables are known and accounted for within the given model. This is just not so, especially with regard to the environmental contributions to illness. Here, not only are the recognized carcinogens limited, but the manner in which we consider these and other non-genetic variables relative to cancer or any disease process is flawed, and ultimately, biased. What is considered environmental in this context, for example, is poorly defined.

In cancer epidemiology, the term “environmental” is generally used to denote anything not hereditary, and the stochastic processes involved in the development and homeostasis of tissues are grouped with external environmental influences in an uninformative way.

That said, in the aforementioned study specifically, the apparent randomness was shown to be associated with the number of stem cell divisions in particular tissues. Tissues with highly replicative stems cells were more likely to generate ‘random’ genetic variants and thus cancer. Mathematically, and indeed, intuitively, this makes sense. More activity equals more chance for error. We see this all of the time in machine learning and computer simulation experiments where random errors occur based upon the number of calculations. We also see this in basic mechanics where increased activity means more wear and tear.

I would venture that in biological systems, however, where life interacts with itself and its ‘environment’ continuously, dynamically, and non-linearly, the randomness posited by the linear probabilities observed in computer simulations may not accurately represent real world response. Perhaps the association between increased stem cell activity and cancer is moderated by other variables that we have yet to fully appreciate. In this particular study and likely others as well, the increased randomness was identified in precisely the regions that interact more closely with the environment. In other words, to use computer parlance what we are calling randomness may be a design feature rather than a bug. Would it not make sense that these regions would require increased turnover compared to other tissues more removed from direct environmental interactions? Might these tissues also be exposed to significantly more toxic insults and thus demand more energetic support e.g. nutrients, to mitigate both the potentially damaging effects of these exposures and the increased turnover? I suspect that the unmet demands of metabolism are more directly responsible for these seemingly random events. That said, perhaps instead of relegating these non-heritable mutations to the trash heap of randomness, we ought to look more closely and how ‘environment’ interacts with genetics.

Enter the field of epigenetics.

Epigenetics and Disease

As genetics fell short, an adjacent field, called epigenetics, gained steam, in some circles at least. Epigenetics technically means ‘over’ genetics. In this field, researchers look at the chemical variables that influence genetic expression without altering DNA itself. Specifically, they look at the addition of histones or methyl groups to DNA molecules, chromatin remodeling (how genetic information is organized), and changes to non-coding RNA (RNA proteins that don’t alter genes but affect their expression) to DNA molecules. Someone called these proteins ‘DNA decorations’ – a good descriptor, I think.

While these ‘decorations’ do not affect the core structure/arrangements of DNA like traditional mutations do, they are not without consequence. They activate or deactivate gene expression disrupting normal regulation. This means that whatever function the code from that gene performs, the epigenetic marker will either turn it on or off, constitutively, and generally, outside of the bounds of its normally regulated activity. As one can imagine, this can be problematic, particularly when a necessary function is re-regulated in a manner that negatively impacts cell fate during development or across the lifespan, as with cancer.

Fortunately, these changes are not necessarily permanent. They are malleable and dynamic. To that end, once the stressor is removed, so too is the epigenetic marker, at least in theory and in research situations. There are indications of lasting epigenetic memories, however. Epigenetic memories act like a DNA conditioning factor of sorts to prolonged stress such that new stressors more readily activate these patterns. Importantly, these epigenetic patterns and memories are heritable, suggesting that the stressors of our parents and grandparents decorate our DNA and permanently alter how our bodies respond to stress. Consider the research on Irish and Dutch famines where developmental malnutrition is linked to epigenetic markers associated with certain disease states generationally.

Notably, unlike in the field of genetics, were the incidence of mutations accounts for only small percentage of disease, epigenetic alterations in gene activity may account for 90% of variability of human disease. In this regard, epigenetics explains, at least broadly, why, in people with the same genetic defects, only a small percentage go on to develop cancer or any other disease processes linked to that gene defect.

As one might expect, there is an enormous and varied compendium of possible triggering factors with everything from toxicant exposures to poor nutrition and aging included. It appears that any environmental stressor or repeated behavior initiates changes to the epigenome, including more positive variables like good nutrition and exercise. This makes epigenetics an important interface between genetics and the environment. It does not appear to be the only or primary interface, however. For that, we have to dig a little deeper and ask ourselves, what is capable of driving both genetic and epigenetic activity? You guessed it. That power and responsibility resides with mitochondria.

Mitochondria speak the language of the epigenome. All substrates and cofactors required for epigenetic modifications of the DNA and histones are made by or metabolized by mitochondria. “ – Martin Picard

Everything Comes Back to the Mitochondria and Nutrition

Research over the last few decades shows that both genetics and epigenetics are the handmaidens of mitochondrial metabolism and not the other way around. And this make sense, because mitochondria are responsible for using nutrients to synthesize ATP – energy – and other important molecules that form the backbone of survival. No energy, no life. Everything from the proper unwinding of genetic code through the aberrant growth of cancer cells is determined by metabolic capacity, or more bluntly, nutritional availability. Across species, the patterns are conserved. From the earliest stages of cell development and across the lifespan, cell fate is determined by mitochondrial metabolism.

Developmentally, a growing body of research, shows just how clearly metabolism affects cell fate. An experiment using the single celled organisms called dictyostelium, the lowly slime mold, illustrates what happens when nutrients are absent. Here, when the organism has sufficient nutrients, it grows and reproduces into other single celled organisms – as expected – but when nutrient starved, it releases mitochondrial damaging reactive oxygen species (ROS), and eventually, develops into a multi-celled clump that travels to find nutrients. Nutrient availability thus, changes the fate of the cell, profoundly. Essentially, the genetic blueprint of the organism tells it to look and behave a certain way, but when genetics interacts with the environment, environment makes the final decision. In this case, in order to survive the lack of nutrients and the abundance of ROS produced by the lack of nutrients, the organism divides into multiple cells. This patterned is reproduced, more or less, in all organisms, even mammals.

Under nutrient rich situations, ROS molecules are leaked by the mitochondria whenever ATP/ energy is made. ROS are signaling molecules. As a signaling molecule, it is both necessary and regulated. Both too much and too little are problematic and thus there are other molecules and feedback mechanisms to manage its synthesis. The anti-oxidant glutathione is one the molecules charged with managing ROS.

In nutrient rich situations, mitochondria will produce energy and a supply of other important molecules that all work together to maintain the life and functioning of the cell. Regular mitochondrial replication and controlled apoptosis cycles are also involved and ensure a ready supply of healthy mitochondria capable of producing these molecules.

In a nutrient starved environment, however, there are not enough resources to maintain replication cycles and defense mechanisms simultaneously, so the cell has to make some decisions. In the case of the slime mold, and in fact, in every eukaryotic cell in any given organism, resources are shunted to maintaining defenses, into producing anti-oxidants like glutathione. Energy that is normally produced in the mitochondria, is now produced mostly in the cell itself (glycolysis), which is far less efficient, and replication and apoptosis cycles are upended. In other words, in resource poor environments, defense systems are favored over everything else. In this case, and with cancer, unbridled cell division is the defense mechanism.

Cell Fate Decisions In More Complex Organisms

While fascinating, it is difficult to appreciate the importance metabolism in cell fate decisions when the evidence comes from slime mold, but the patterns are conserved in more complex systems as well. Consider the mouse for example, where the effects of nutrient starved mitochondria are no less compelling. When nutrient dependent components of the mitochondria are blocked during early development, the cells initiate a stress response and stem cell specialization fails. Skin, lungs, and other tissues are poorly formed and the animal dies.

Research involving the earliest stages of life, the pre-implantation period from 1-2 cells for mice (up to 4 days) and 4-8 cells in humans (~6 days) clearly demonstrates the role metabolism in determining cell fate. Embryonic stem cells require mitochondrial metabolites, which depend upon key nutrients, to develop. When absent, development is arrested, sometimes irrevocably.

Importantly, when sperm and oocyte mix and life begins, it is not genetics, per se, or even epigenetics that guide cell division, cell fate, and subsequent embryogenesis, but energetic capacity – metabolism. Backing up even further, mitochondrial capacity and the local environments of both sperm and oocyte determine whether and how the two will meet. In essence, mitochondria serve as a bridge between energy metabolism and the epigenome, providing signals that can modify DNA and histone modifications, ultimately affecting gene expression and cellular function.

And then there is thiamine

When we unpack the patterns a little bit more, we see that the metabolite pyruvate is critical to this process. Recall from our discussions on mitochondrial function and nutrition, that pyruvate drives mitochondrial energy production. It is the end product of glycolysis (cytosolic carbohydrate metabolism) that, when in the presence of sufficient oxygen and thiamine, enters the mitochondria and is converted into acetyl-CoA, which after more reactions eventually becomes ATP – energy. Pyruvate, it appears, is required to activate the zygote genome. How it does this, is fascinating.

During early development (from 2-8 cells), mitochondrial enzymes from the first half of tricarboxylic acid (TCA) cycle (pyruvate dehydrogenase – PDH, pyruvate carboxylase, citrate synthase, aconitase 2, isocitrate dehydrogenase 3A, and a-ketoglutarate dehydrogenase – see graphic below) travel from the mitochondria, across the cell and into the nucleus of that cell, presumably to synthesize requisite molecules for growth. (Some years ago, I wrote about the traveling PDH enzyme research, here but had not considered its impact on cell fate more generally).

Mitochondrial nutrients
Mitochondrial nutrients from Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.

Nutrient Status Drives Metabolism

From this sampling of the research, it is clear that metabolism, which boils down to the nutrient status and energetic capacity of the mitochondria, determines cell fate, and although genetic instructions and epigenetic molecules are important, those instructions cannot be executed without the appropriate metabolic capacity. When a cell is faced with a decision about whether to live or die, reproduce or set up defense protocols, it tests the environment before taking action. Those tests determine outcome.

The cell tests whether it has the materials in its environment. If it cannot execute the metabolism, then it won’t become that cell type, in spite of signals to differentiate.

So, even though genetics and epigenetics are telling the cell to execute a particular plan of action that plan is overridden by the mitochondria within that cell if the environment is unfavorable. When this is the case, cell fate decisions focus on defensive measures. Here, we can see how cancer and other disease processes not only represent the result poor metabolic capacity relative to environmental demands, but at their foundation are simply mitochondrially-induced defense mechanisms. Indeed, with cancer in particular, researchers found that when tumor cells are placed in an environment with unhealthy mitochondria they thrive and grow, but when healthy mitochondria are present, they don’t. Taking this a step further, defects in mitochondrial metabolism have been shown to expedite the aging and senescence of cells by accelerating telomere erosion and epigenetic damage and promote genome instability and oncogenesis. In other words, poor mitochondrial function initiates the very epigenetic and genetic defects expressed in cancer and other disease processes.

In this regard, the metabolic environment becomes the most important element in development and in health or illness. Environment, in its totality, is not an ancillary tuning fork for genetic or epigenetic programming and not something to be cursorily addressed or allocated to the dustbin of randomness. It is everything.

“Instead of thinking about the gene expression networks just happening to interact with metabolism, it’s really metabolism driving [developmental decision-making],” he said, “and gene expression networks are the tools by which that occurs.

If this research tells us anything, it is that we are not hardwired, immutable, and largely, impenetrable machines that just happen to suffer developmental anomalies or fall ill to random genetic aberrations of the cancerous type. Rather, we are energetic beings interacting with the environment. The seat of that energetic capacity rests with the mitochondria. Mitochondria are key to everything, and so, if we tend to our mitochondria, and more broadly, to our environment, something many of us are loathe to address honestly, the chances of random acts of cancer and other chronic illnesses are reduced. It also means, the reproductive capacity and outcomes are improved.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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Thiamine Deficiency Causes Intracellular Potassium Wasting

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The role of thiamine in potassium deficiency

Whilst I always suspected a direct link between potassium and thiamine deficiency (outside of the context of refeeding syndrome), I had not come across any direct research elucidating the mechanisms – until NOW. In short, thiamine deficiency causes intracellular potassium wasting.

Animal research in rats showed that chronic thiamine deficiency increases sodium tissue content in heart, liver and skeletal muscle by 18-35%, while also decreasing potassium content by 18-25%. Interestingly, although tissue levels were altered, plasma levels of these electrolytes remained unaffected and stayed within the normal-high range (sodium at 141.6 and potassium at 4.8). This means that blood measurements did not reflect tissue content.

The thiamine deficient group also displayed remarkably lower levels of stored liver glycogen (0.3gm/100 vs 2.7gm/100 in controls). This inability to store glycogen is one factor which helps to explain the strong tendency towards hypoglycemia seen in many people with a thiamine deficiency.

Interestingly, the researchers showed a shift towards an increased level of extracellular water and reduced intracellular water. This finding, along with the shift in intracellular electrolyte concentrations, is 100% consistent with Ling’s Association-Induction hypothesis.

In short, the bioenergetic state of the cell governs its ability to retain potassium ions and structure water into a gel-like phase. A cell with plentiful ATP can maintain this ability, independent of the “sodium potassium pump”. On the other hand, cells lacking energy lose their capacity to retain potassium, intracellular water becomes “unstructured” and intracellular concentration of sodium ions increases and the electronic state of the cell is changed. This causes water to “leak” out of the cells into the extracellular space to produce a localised edema of sorts. Thiamine, playing a central role in energy metabolism, is partially responsible for maintaining healthy redox balance and a continuous supply of ATP. Hence, it is no wonder why a deficiency of this essential nutrient produces such drastic changes in the cellular electrolyte balance.

Thiamine, TTFD, Potassium, and Heart Function

The cells of the heart are particularly susceptible to a disturbance in electrolytes. One Japanese study on coronary insufficiency in dogs showed elevated sodium and reduced potassium content in the insufficient left ventricle. Intravenous administration 50mg thiamine, in the form of thiamine tetrahydrofurfuryl disulfide (TTFD), a derivative of thiamine with higher bioavailability and solubility than other formulations, restored electrolyte balance, likely through improving tissue energy metabolism.

Likewise, the same effect was also demonstrated in isolated Guinea pig atria kept in potassium-free medium. TTFD added to cells or administered as a pre-treatment prevented the loss of potassium and increase in sodium, which was shown to occur in controls. Importantly, this effect was not achieved by thiamine HCL or another derivative studied. TTFD also entered the atrial cells much more readily than other forms, demonstrating its superior absorbability and perhaps suggesting that this form would be useful for addressing cardiac thiamine insufficiency.

Low potassium is a known driver of cardiac arrhythmias, and TTFD possesses anti-arrhythmic properties and has historically been used to treat various types of arrhythmia in Japan.

Furthermore, thiamine TTFD was also been shown to be protective against the cardiac toxin Strophanthin-G, preventing the loss of potassium once again to preserve cardiac function. Likewise, atrial cell damage through exposure to the mitochondrial toxin N-ethylmaleimide was also prevented by high concentrations of TTFD in-vitro. This protective action was attributed to the prosthetic group specific to TTFD, and NOT the thiamine molecule itself.

So it would seem that thiamine, probably through its effects on energy metabolism inside cells, and perhaps due to an unknown “kosmotropic” property of TTFD, is extremely important for regulating cell ion concentrations. In thiamine deficiency, an underlying intracellular potassium deficiency may be going unnoticed due to unremarkable blood levels. In cases where potassium deficiency is suggested, thiamine deficiency may be indicated, and TTFD might used to more safely correct the electrolyte balance.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on May 13, 2020. 

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Energy Medicine

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Energy medicine

I have written many posts on Hormones Matter and have tried to answer the questions arising from each post. These questions and my answers have been so repetitive that I decided to try to make it clear what “energy medicine” is all about and why it differs from conventional medicine. It is only natural that the posted questions are all built on our present ideas about health and disease. What I am about to say is that the present medical model has outgrown its use. Therefore it is obvious that I must discuss what this means. First of all, why do we need a “medical model”? In fact, what is the difference between complete health and its lack? The Oxford English dictionary gives the definition of disease as “a serious derangement of health, disordered state of an organism or organ”

The American Model of Medicine

As I have said before, the present American medical model was aimed at making a diagnosis of one of many thousand described diseases. It was devised from the Flexner report of 1910 that was initiated by Rockefeller. Rockefeller wanted to make medical education adhere to a common standard, thus creating the present “medical model”. The Flexner report used the methodology of diagnosis that was current in Germany. This stated that the patient’s report to a physician is called “history”, involving the patient’s description of symptoms and their onset. From this, the physician may or may not have an idea what is wrong. The next part is the physical exam where a hands-on search of the patient’s body is made for evidence of disease. This is extremely complex when put fully into clinical operation and also may or may not provide clues to a diagnosis. The third operation is laboratory testing and it is this constellation of abnormal tests that provide scientific evidence for the nature of the disease. Each test has been researched and aside from one that is either positive or negative, others have a normal range reported in numerical terms. Perhaps, as an example, the test for cholesterol level is the best known. Each test has to be interpreted as to how it contributes to arriving at a diagnosis. Finally, the physician has to try to decide whether medical or surgical treatment must be offered. Please note that the surgical removal of a sick organ may be the signature of medical failure, for example, removing part of the intestine in Crohn’s disease, for it represents a missed opportunity to treat earlier in the disease process.

Laboratory Tests and A Drug For Every Disease

It is the constellation of symptoms described by the patient and the abnormalities found by the physical examination that constitute a potential diagnosis to formulate what laboratory tests should be initiated. It is the constellation of laboratory tests that may or may not provide the proof. There are problems with this. For instance, there may be test items in the constellation that create confusion, such as “it might be disease A or disease B. We are not sure”. Tests that are “borderline” positive are particularly confusing. The diagnosis finally depends often on who was the first observer of these constellations. For example a person by the name of Parkinson and another person by the name of Alzheimer, each described clinically observed constellations that gave rise to Parkinson’s disease and Alzheimer’s disease. Since they were first described, the pathological effects of each disease have been researched in painstaking detail, without coming to the conclusion of the ultimate cause. Finally, the pharmaceutical industry has indulged in complex research to find the drug that will reverse the pathological findings and produce a cure. Because this concept rides right through the objective, each disease is thought to have a separate underlying cause and a separate underlying cure in the shape of a new “miracle drug”. Witness the recent revival of a drug that was initially found to be useless in the treatment of Alzheimer’s disease. This revival depends on the finding of other pathological effects discovered in the disease, suggesting new clinical trials. When you take all these facts into consideration, it is a surprisingly hit and miss structure. For example, we now have good reason to state that a low cholesterol in the blood is more dangerous than a high one. Why? Because cholesterol is made in the body and is the foundation material for building the vitally important stress hormones. Cholesterol synthesis requires energy and is a reflection on energy metabolism when it is in short supply.

The Physicians Desk Reference, available in many public libraries, contains details concerning available drugs. Each drug is named and what it is used for, but often there is a note saying that its action is poorly understood. Just as often, there may be one or two pages describing side effects. In fact, the only drugs whose action is identified with cause are the antibiotics. The rest of them treat symptoms but do not address cause. Antibiotics affect pathogenic bacteria but we all know that the bacteria are able to become resistant and this is creating a problem for the near future. It is interesting that Louis Pasteur spent his career researching pathogenic microorganisms. However, on his deathbed it is purported that he stated “I was wrong, it is the defenses of the body that count”.

It must be stated that the first paradigm in medicine was the discovery of pathogenic microorganisms and their ability to cause infections. Many years were spent in trying to find ways and means of killing these organisms without killing the patient. It was the dramatic discovery of penicillin that led to the antibiotic era. I like to think that Louis Pasteur may have suggested the next paradigm, “assist the body defenses”.

Energy Medicine: A New Paradigm for Understanding Health and Disease

When a person is seen performing on a trampoline, an observer might say “hasn’t he got a lot of energy!” without thinking that this represents energy consumption. Energy has to be captured in the body and is consumed in the physical action on the trampoline. Many people will drink a cup of coffee on the way to work believing that it “creates” energy. The chemical function of caffeine stimulates action that consumes energy, giving rise to a false impression. Every physical movement, every passing thought, however fleeting in time, requires energy consumption. The person who has to drink coffee to “get to work”, is already energy insufficient. He/she can ill afford this artificial consumption of the available energy.

I am going to suggest that the evidence shows “energy medicine” may indeed be the new paradigm, so we have to make sure that anyone reading this is conversant with the concept of energy. In physics, “energy is the quantitative property that must be transferred to an object in order to perform work on, or heat, the object. Energy is a conserved quantity, meaning that the available energy at the beginning of time is the same quantity today. The law of conservation of energy states that “energy can be converted in form but not created or destroyed”. Furthermore, Einstein showed us that matter and energy are interconvertible. That is why the word “energy” is such a mystery to many people. What kind of energy does the human body require?

We are all aware that the electroencephalogram and the electrocardiogram are tools used by physicians to detect disease in the brain and the heart. If that means that our organs function electrically, then where does that energy come from? We do not carry a battery. We are not plugged into a wall socket and the functional capacity of the human body is endlessly available throughout life. The only components that keep us alive are food and water. Everyone knows that foods need to contain a calorie-delivering and a non-caloric mixture of vitamins and essential minerals. The life sustaining actions of these non-caloric nutrients is because they govern the process of energy capture by enabling oxygen consumption (oxidation). They also govern the use of the energy to provide physical and mental function.

The calorie bearing food, consisting of protein, fat and carbohydrate is used to build body cell structure. This is called anabolic metabolism. If body structure is broken down and destroyed, weight is lost and the patient is sick. This is called catabolic metabolism. In healthy conditions, food is metabolized to form glucose, the primary fuel.

Thiamine (vitamin B1), together with the rest of the B complex, governs oxidation, the products of which go into a cellular “engine” called the citric acid cycle. This energy is used to form adenosine triphosphate (ATP) that might be referred to as a form of “energy currency”. Without thiamine and its vitamin colleagues in the diet, ATP cannot be formed. Research for the next stage of energy production has yielded insufficient information as yet concerning production of electrical energy as the final step. The evidence shows that thiamine may have an integral part in this electrification process, although much mystery remains. Suffice it to say that we are electrochemical “machines” and every physical and mental action requires energy consumption.

Maybe the Chinese Were Right

In the ancient Chinese culture, an energy form called Chi was regarded as the energy of life itself. Whether this really exists or not and whether it is in some way connected to the auras purported to surround each person’s body is still conjectural. It would not be too absurd to suggest that it might be as yet an undiscovered form of energy and that it is truly a reflection of good health. My personal conclusion is that some form of electromagnetic energy is the energy that drives our physical and mental functions and that it is transduced in the body from ATP, the storage form of chemical energy. There is no doubt that acupuncture does work and certainly encourages the conclusion that the meridians described by the ancient Chinese thinkers are an important evidence of electrical circulation. There is burgeoning evidence that energy is the core issue in driving the complex process of the body’s ability to heal itself. The idea that the physician or anyone else that purports to be a “healer” is a myth, because we have the magic of nutrients that are capable of stimulating energy production as already described. The “bedside manner” is valuable because a sense of confidence and trust results in energy conservation. Remember the proverb “worry killed the cat”.

Illness and the Lack of Energy

As essentially fragile organisms, we live in a situation of personal stress. We are surrounded by micro-organisms ready to attack us. We have built a culture that is enormously stressful in many different ways, I turn once again to the writings of Hans Selye, who advanced the idea that we are suffering from “the diseases of adaptation”. He recognized that some form of energy was absolutely essential to meet any form of physical or mental stress. One of his students was able to produce the general adaptation syndrome in an animal by making the animal thiamine deficient. Energy metabolism in Selye’s time was poorly understood. Today the role of thiamine is well known. As I have described in other posts and in our book, the lower part of the brain that controls adaptive mechanisms throughout the body is highly sensitive to thiamine deficiency. Alcohol, and sugar in all its forms, both overload the process of oxidation. Although energy metabolism depends on many nutrients, thiamine is vital to the function of mitochondria and its deficiency appears to be critical. Because the brain and heart are the dominant energy consumers it is no surprise to find that beriberi has its major effects in those two organs. Symptoms are just expressions of oxidative inefficiency of varying severity. This is the reason why 696 medical publications have reported varying degrees of success in the treatment of 240 diseases with thiamine. Its ubiquitous use as a drug depends on its overall ability to restore an adequate energy supply by stimulating mitochondrial function. It is also why I propose that energy deficiency is the true root of modern disease.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

Image by Gerd Altmann from Pixabay.

This article was published originally on November 19, 2019.

Rest in peace Derrick Lonsdale, May 2024.

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Threats to Thiamine Sufficiency in the 21st Century

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challenges to thiamine sufficiency

In the first paper, Thiamine Deficiency in Modern Medical Practice , I provided an overview of why health practitioners should consider thiamine in general practice. In this paper, I would like to delve more deeply into how one becomes deficient in the 21st century.

Thiamine and Its RDA

Thiamine, or vitamin B1, is an essential and rate limiting nutrient required for metabolic health. Like the other B vitamins, it is water-soluble. Unlike some other B vitamins, it has a very short half-life (1-12 hours), and a limited reserve of about 30 milligrams. Absent regular consumption, deficiency arises quickly, manifesting symptoms that range from general fatigue, mood lability, anorexia, and nausea to cardiac irregularities, neuromuscular and neurocognitive deficits. In developed countries, where food enrichment and fortification programs have added thiamine to grain and other products, thiamine deficiency syndromes are considered to be rare and largely confined to specific populations and circumstances where thiamine ingestion, absorption, metabolism, or excretion are impaired such as poverty-based malnutrition, alcoholism, severe gut dysbiosis and/or hyperemesis.

The recommended daily allowance (RDA) put forth by health institutions considers 1.1-1.2mg of thiamine sufficient for most adults to stave off deficiency. This requirement is met easily with any modern diet, even a poor one, suggesting that the suspected low incidence of deficiency is accurate. And yet, across multiple studies that have measured thiamine status in different patient populations, none of whom can be considered malnourished by RDA standards, or alcoholic, the rate of deficiency is found to be between 20-98%; a discordance that suggests both institutional designations of thiamine sufficiency and deficiency are underestimated.

Insofar as thiamine is absolutely requisite for the conversion of food into cellular energy, e.g. ATP, and sufficient ATP is fundamental to metabolic health, something that has become an increasingly rare phenomenon in the Western world, it is possible that our understanding of thiamine sufficiency and deficiency is mismatched to the demands of modern living. If this is the case, then insufficient thiamine may be a key factor in many of the disease processes that plague modern medicine. Indeed, thiamine insufficiency and frank deficiency has been observed with obesity, diabetes, heart disease, gastrointestinal dysbiosis and dysmotility syndromes, post gastric bypass surgery, in cancer, Alzheimer’s, Parkinson’s, and psychiatric patients. Combined, these patient populations represent a far larger percentage of the population than recognized within the current paradigm. From this perspective, it is conceivable that the older designations of sufficiency and deficiency no longer apply and that for the 21st century patient, thiamine stability is a much more fragile endeavor than recognized.

Micronutrients and Cellular Energy

The most fundamental process to health and survival involves the conversion of consumed nutrients into ATP. Absent adequate ATP, health is impossible. Energy metabolism requires a ready supply of macronutrients (carbohydrate, protein, and fats) and at least 22 micronutrients or vitamins and minerals (see Figure 1.).

In developed countries, macronutrients are readily available, often in excess. Micronutrient intake, however, is inconsistent. A review article from the University of Oregon report found that a large percentage of the population had inadequate micronutrient status (4-65% depending upon the nutrient) despite excessive caloric intake. Moreover, much of the supposed nutrient sufficiency came from enriched or fortified foods. In other words, absent food enrichment or fortification, most children, adolescents, and adults had insufficient micronutrient intake. Inasmuch as most fortified foods come with a high caloric content, which effectively demands a higher micronutrient content to metabolize it; this presents a problem.

mitochondrial nutrients
Figure 1. Mitochondrial Nutrients, from: Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition

Thiamine Dependent Enzymes

From the graphic above, note how many times thiamine (vitamin B1 or TPP) appears. Thiamine is required for the transketolase (TKT), pyruvate dehydrogenase complex of enzymes (PDC), branched chain keto acid dehydrogenase (BCKAD), 2-Hydroxyacyl-CoA lyase (HACL), alpha-ketoglutarate dehydrogenase ([a-KDGH] – also called 2-oxoglutarate dehydrogenase complex [OGDC]) and for lactate recycling as a cofactor for the lactate dehydrogenase complex (LDH). Beyond its coenzyme role, thiamine allosterically regulates the expression and activity other mitochondrial proteins including:

  • Succinate thiokinase/succinyl-CoA synthetase: together with a-KDGH catalyzes succinyl-CoA to succinate.
  • Succinate dehydrogenase: oxidizes succinate to fumarate, uses the electrons generated to catalyze reduction of ubiquinone to ubiquinol for complex II (TCA>ETC linkage)
  • Malate dehydrogenase (MDH): interconversion of malate and oxaloacetate with cofactor NAD+ or NADP+.
  • Pyridoxal kinase: converts dietary vitamin B6 into the active cofactor form pyridoxal 5′-phosphate (PLP) creating a functional deficiency.

With low or absent thiamine, each of these enzymes downregulates from 10% to almost 30% resulting in a reduction of ATP from 38 to ~13 units (in culture).

Thiamine Is Fundamental

Among the 22 micronutrients needed to convert macronutrient ATP, thiamine, along with its cofactor, magnesium, sit at the entry points to this process. That means that thiamine availability controls the rates of carbohydrate, protein, and fat metabolism and their subsequent conversion into ATP. Insufficient thiamine, even marginally so, impedes this process resulting in not only reduced ATP, but also, impaired cellular respiration, and increased oxidative stress and advanced glycation end products (AGEs); the very cascades linked to the preponderance of modern diseases dominating the healthcare landscape.

  • Cellular respiration, the ability to use molecular oxygen, requires ATP, which requires thiamine. Insufficient thiamine causes cell level hypoxia and upregulates the expression of hypoxia inducible factors (HIFs). HIFs are responsible for oxygen homeostasis, regulating at least 100 other proteins including those involved in angiogenesis, erythropoiesis and iron metabolism, glucose metabolism, growth factors, and apoptosis. HIF stabilization is implicated in a range of illnesses from autoimmune disease, to heart disease and cancer.
  • Reactive oxygen species (ROS) are a natural byproduct of ATP production and serve as useful mitochondrial signaling agents. Elevated ROS, relative to antioxidant capacity, however, creates oxidative stress, damaging cellular lipids, proteins and DNA. Antioxidant capacity is reduced with thiamine deficiency while ROS are increased.
  • AGEs, the toxic byproducts of hyperglycemia and oxidative stress, are modulated by thiamine. With sufficient thiamine, AGE precursors are shunted towards energy metabolism via the transketolase and the pentose phosphate pathway rather than accumulating in tissue as reactive carbonyl intermediates common with metabolic disease.

Each of these play a role in the pathophysiology of diabetes, cardiovascular and neurodegenerative diseases. This makes thiamine status, by way of its role in ATP production, cell respiration, ROS management, and AGE metabolism, a critical variable determining health or disease.

Given its position and role in these processes, it is not difficult to imagine how insufficient thiamine intake might derange and diminish energy metabolism and how that, in turn, might impact metabolic health both locally at the cell, tissue and organ level, and systemically. What is difficult to imagine, however, given the miniscule RDA requirement for a little over a single milligram of thiamine, is how anyone in the developed world where food scarcity is rare, where thiamine is readily available in both whole foods and in fortified foods, becomes thiamine deficient. And yet, a growing body of research suggests that is exactly what is happening. Recall from above, that depending upon the population studied, insufficient thiamine to frank deficiency has been found in 20-98% of the patients tested.

Modern Challenges to Thiamine Sufficiency From Consumption to Utilization

As an essential nutrient, thiamine must be consumed from foods, absorbed, activated and transported to where it is needed, and then utilized by its cognate enzymes. At each of these steps there are challenges that diminish thiamine availability, effectively increasing thiamine need well beyond the current RDA values. In fact, many of the products and amenities that make modern living what it is, imperil thiamine status and do so at multiple junctions. The additive effects of these challenges leaves many vulnerable to deficiency.

Dietary Sources of Thiamine

The highest concentrations of thiamine in natural and non-manufactured foods come from pork, fish (salmon, trout, tuna, catfish), many nuts and seeds (macadamia, pistachios, sunflower seeds, flax seed), beans (navy, black, black-eyed peas, lentils), peas, tofu, brown rice, whole wheat, acorn squash, asparagus, and many other foods. A diet rich in organic, whole foods is generally sufficient to meet the daily requirements for the thiamine and other vitamins and minerals. Likewise, though less ideal, a diet of processed foods that has been enriched or fortified with thiamine, will meet the RDA for thiamine quite easily, perhaps even exceed it. Indeed, one serving of breakfast cereal is sufficient to reach the RDA for thiamine.

Despite the ready availability of thiamine in both whole and processed foods, the data suggest that many people find it difficult to maintain thiamine status. This is due to the interactions between the endogenous chemistry of thiamine metabolism and the chemistry of exogenous variables affecting thiamine stability. The most common factors affecting thiamine status, include high calorie, high toxicant load diets, alcohol and/or tobacco use, caffeine products, and pharmaceutical and chemical exposures.

Dietary Impediments to Thiamine Sufficiency

While fortification provides access to thiamine, highly processed foods carry a high calorie and toxicant count making them metabolically deleterious despite any potential gains from vitamin enrichment or fortification. High carbohydrate, highly processed foods diminish thiamine status by multiple mechanisms.

Other common dietary contributors to insufficient thiamine.

Although food scarcity is not as prevalent in developed countries compared to undeveloped regions, poverty still impacts nutrient status. This owes largely to the fact that highly processed foods, high calorie foods are less expensive than whole foods and thus, there is an over-reliance on carbohydrate consumption to meet caloric requirements. Here, obesity and metabolic dysfunction co-occur with micro-nutrient and sometimes macronutrient, e.g. protein, deficiency.

Pharmaceutical and Environmental Threats to Thiamine Status

After high calorie malnutrition and other dietary habits that limit thiamine availability, the next most common threat to thiamine sufficiency is the use of pharmaceuticals. This variable cannot be stressed enough. Pharmaceutical chemicals deplete thiamine and other nutrients, directly or indirectly by a number of mechanisms.  Some of this is by design, such as with antibiotics that target folate and thiamine, some of it represents off-target effects, such as the blockade of thiamine transporters by metformin and the other 146 drugs tested for this action, an increase in demand in order to withstand other mitochondrial damage. Regardless of the intended purpose, however, pharmaceuticals represent chemical stressors to thiamine and nutrient stability. As such, their regular use necessitates a concerted approach to maintain nutrient status. Some of the most commonly used medications are the biggest offenders:

In addition to the ingestion of pharmaceutical chemicals, environmental chemical exposures damage mitochondrial functioning, even at low, and what are considered, non-toxic exposures. These exposures are pervasive, often unavoidable, and tend to accrue over time, with additive and synergistic effects to other stressors. Consider the totality of a patient’s toxic load when addressing the risk of nutrient insufficiency.

Absorption and Metabolism

Assuming sufficient thiamine is ingested from diet and is not blocked or otherwise degraded by food, pharmaceutical or environmental chemicals, it then has to be absorbed in the intestines before it can be activated and transported to organs and tissues for use. Epithelial injury, microbial dysbiosis, and genetic variation, all of which are common, limit the effectiveness of this phase. Epithelial injury and microbial dysbiosis slow passive absorption, while genetic, epigenetic, and environmental variables, slow or block active transport.

At low concentrations, thiamine is absorbed in the small intestine by active transport, while higher concentrations are absorbed by passive diffusion. Active transport is mediated by two primary thiamine transporters, ThTR1 and ThTR2, and a number of additional transporters that fall under the solute carrier family of genes:

  • SLC19A1: folate transporter, but also, transports thiamine mono- and di- phospho derivatives.
  • SLC19A2 (ThTr1): systemic thiamine transport, main transporter in pancreatic islet tissue and hematopoietic cells; most abundant, from highest to lowest in the intestine, skeletal muscle, nervous system, eye, placenta, liver, and kidney.
  • SLC19A3 (ThTr2): primary intestinal thiamine transporter, also located in adipose tissue, breast tissue, liver, lymphocytes, spleen, gallbladder, placenta, pancreas, and brain.
  • SLC22A1 (OCT1): organic cation transporter 1, primary hepatic thiamine transporter; competitively inhibited with transport of metformin, xenobiotics, and other drugs.
  • SLC25A19 (MTPP-1): mitochondrial thiamine pyrophosphate carrier.
  • SLC35F3: endoplasmic reticulum and Golgi thiamine transporter, implicated in hypertension.
  • SLC44A4 (hTPPT/TPPT-1): absorption of microbiota-generated thiamine pyrophosphate in the large intestine.

Although conventional wisdom suggests that only homozygous mutations affect the performance of these proteins, in reality, there is a gradation of abnormalities that challenge thiamine uptake, particularly when environmental or pharmaceutical variables block or otherwise limit the functioning of the same protein. In some cases, genetic difficulties can be compensated for providing nutrient support at supraphyisiological doses, among the better known examples:

  • Thiamine responsive megaloblastic anemia (mutations in SLC19A2/ThTr1); megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus.
  • Biotin-thiamine responsive basal ganglia disease (mutations in SLC19A3/ThTr 2) presents in infancy or childhood with recurrent subacute encephalopathy, confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia or Leigh-like syndrome with infantile spasms. When presenting in adulthood, acute onset seizures, ataxia, nystagmus, diplopia, and ophthalmoplegia.
  • Thiamine responsive Leigh Syndrome (mutations in in the SLC19A3/ThTr2).
  • Thiamine metabolism dysfunction syndrome-4 (mutations SLC25A19/MTPP-1); episodic encephalopathy and febrile illness, transient neurologic dysfunction, and a slowly progressive axonal polyneuropathy.
  • Thiamine Pyrophosphokinase 1 (TPL1) defects cause problems in the activation of free thiamine to thiamine pyrophosphate, rendering much of the thiamine consumed unusable. TPK1 defects have been identified as condition called thiamine metabolism dysfunction syndrome 5 or Leigh-like syndrome because of the similarity in symptoms. More recently, TPK1 defects have been found associated with Huntington’s disease. High dose thiamine appears to overcome the defect in some cases.

Thiamine Activation/Deactivation

Before it can be used, free thiamine has to be phosphorylated into its active form thiamine pyrophosphate (TPP), also called thiamine diphosphate (ThDP/TDP). This is done by the enzyme thiamine pyrophosphokinase (thiamine diphosphokinase), which is magnesium dependent and requires ATP. Magnesium deficiency is common in developed countries. TPP accounts for almost 90% of circulating thiamine.

Additional thiamine metabolites include thiamine monophosphate (TMP) and thiamine triphosphate (TTP) along with the recently discovered adenosine thiamine triphosphate (AThTP) and adenosine thiamine diphosphate (AThDP). AThTP and AThDP are produced by E.coli during periods of nutrient starvation and have been found in most mammalian tissue. This likely represents a salvage pathway common in many pathogenic microbes.

Microbial Thiamine Synthesis

It is important to note, that although the consumption of dietary thiamine provides the main sources of this nutrient systemically, a smaller, but notable (2.3%), percentage of thiamine and other B vitamins is produced endogenously by various commensal bacterial populations in both the small and large intestines. At least 10 species of bacteria synthesize thiamine that is absorbed and utilized by the colonocytes. Endogenous thiamine synthesis is reduced by diets high in simple carbohydrates but increased with complex carbohydrates. Antibiotics and other medications inhibit endogenous synthesis of B vitamins directly by design as in the case trimethoprim and sulfamethoxazole and indirectly via additional that disrupt thiamine availability. Additionally, a number of pathogenic microbes produce enzymes that degrade bacterially produced thiamine suggesting the balance of gut biota is influenced by and influences nutrient availability.

In the large intestine, bacterially synthesized TPP is absorbed directly into the colon via a population of TTP transporters (TPPT-1) in the apical membrane and then transported directly into the mitochondria via the MTPP-1 for ATP production. The reduction of colonocyte thiamine and thus ATP, would force a shift towards the more pathogenic microbial populations that thrive in nutrient deficient environments and dysregulate bowel motility. This local thiamine deficiency may be a contributing factor in large bowel microbial virulence and the dysmotility syndromes so common in modern medical practice.

Enzyme Activation

The final step in attaining thiamine sufficiency is utilization. Returning to Figure 1., the key enzymes involved in this process include: TKT, PDC, HACL, BCKAD, a-KGDH and LDH.  This is an addition to the enzymes involved in the phosphorylation of free thiamine and the remaining enzymes in the Krebs cycle whose gene expression depends upon thiamine status. As with the variances and mutations in the transporters, supraphyisiological doses of thiamine may compensate for decrements in enzyme function. This has been observed in thiamine responsive PDC deficiency, characterized by excessive lactic acid; and in maple syrup urine disease, where mutations in the thiamine dependent BCKAD enzyme responsible for amino acid metabolism is impaired; also in Leigh-like syndrome, where mutations in TPK1 enzyme, which converts free thiamine to active TPP, is affected.

Is the Thiamine RDA Sufficient?

Both the chemistry and the data suggest that the current RDA of just a single milligram of thiamine is insufficient to meet the challenges presented by modern diets and chemical exposures. Owing to its role in energy metabolism, thiamine insufficiency may underlie many of the disease processes associated with metabolic dysfunction, where cellular hypoxia, increased ROS and AGEs are present. These disease processes develop long before, and sometimes absent, frank deficiency suggesting there may be gradations of insufficiency relative to the individual’s metabolic needs. Whether thiamine is a causative variable in these disease processes or simply a consequence of a complicated history of negative interactions between genetics, diet, and exposures is unclear. What is clear, however, is that thiamine insufficiency is likely far more prevalent than recognized and given its role in energy metabolism, ought to be addressed more consistently in clinical care.

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The Perils of Diagnostic Overshadowing

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diagnostic overshadowing thiamine

Diagnostic overshadowing is a phrase used to describe a cognitive bias employed by many practitioners. It assumes that all of a patient’s symptoms can be ascribed to a particular pre-existing or chronic condition. This is common in pediatrics, where health issues in children with complex needs, such as Down syndrome, are misattributed to the Down syndrome and not investigated or addressed independently. This leads to delayed diagnoses and treatment, and in many cases, poorer outcomes. It is also common when the root of the ill-health emerges from vitamin deficiencies. By way of example and with the parent’s permission, below is the case of a two-year old boy who developed both wet and dry beriberi due to thiamine deficiency. His condition was worsened by medical treatments and missed because of diagnostic overshadowing.

When Real Treatable Conditions Are Missed

Lev is a bright-eyed, curious two-year-old with Down syndrome. His eyes light up when he hears familiar voices, and he delights in interacting with his parents and siblings. Behind his bright smile, however, lies a complicated medical journey. Like many children with complex medical needs, his early years have been filled with specialist visits, medications, and hospitalizations. For much of his short life, he has been profoundly weak, struggling to gain weight, battling constant vomiting and diarrhea, and falling far behind in gross motor development. What Lev’s story illustrates most powerfully is the danger of diagnostic overshadowing: when real, treatable conditions are missed simply because a child has a known genetic diagnosis.

Lev’s story is complex. Born at 39 weeks with congenital heart defects (a large VSD and ASD), intrauterine growth restriction, and early respiratory distress, he spent his first 13 months in the hospital. By three months old he developed seizures, and by six months he was diagnosed with pulmonary hypertension. He required a GJ-feeding tube, a tracheostomy tube, and was given multiple cardiovascular medications, including high-dose Lasix (furosemide), a loop diuretic known to deplete thiamine (vitamin B1).[1],[2],[3],[4] Despite the intensity of his medical care and frequent hospitalizations, his worsening weakness and developmental regression were never investigated beyond his genetic diagnosis. His inability to lift his head or bear weight was simply attributed to “Down syndrome,” and his declining function was accepted as inevitable. No one on his conventional medical team ever evaluated him for B1 deficiency.

At two years old, Lev has not yet undergone the life-saving surgery to repair his VSD and ASD, an intervention that many children with Down syndrome receive in infancy, because his profound weakness, frequent infections, and uncontrolled pulmonary hypertension have made him too medically fragile to tolerate the procedure.

His mother, worried about his persistent vomiting, diarrhea, poor tone, and developmental delays, began researching on her own. When she came across the symptoms of pediatric beriberi, the severe form of thiamine deficiency, she brought it to the attention of his doctors. They dismissed her concerns.

Fortunately, she persisted.

Profound Mitochondrial Dysfunction

She brought Lev to me after watching my online lecture “Thiamine Deficiency in Children with Special Needs”. At our first visit, it was clear that Lev was experiencing profound mitochondrial dysfunction. He was being fed via GJ-tube with a formula that didn’t provide adequate thiamine to meet his needs. He had been exposed to more than 10 rounds of antibiotics for pneumonia, which likely disrupted his gut flora and impaired his nutrient absorption. He was still taking Lasix, a medication known to deplete thiamine, yet no one had evaluated his thiamine status.

My initial recommendations without any testing included:

  • TTFD (thiamine tetrahydrofurfuryl disulfide) – 50 mg daily in the morning
  • Riboflavin 5-phosphate – 25 mg daily in the morning
  • Magnesium glycinate – 60 mg daily throughout the day
  • Polyenylphosphatidylcholine – 900 mg daily in the morning
  • Vitamin D – 800 IU daily anytime of day
  • Iron bisglycinate – 12 mg daily, preferably on an empty stomach

Lev’s story is not unique in my practice. I’ve identified thiamine deficiency in many children with Down syndrome, often after months or even years of unexplained symptoms that were overlooked or misattributed. Children with Down syndrome are especially vulnerable to thiamine deficiency due to slower gastrointestinal motility, which increases the risk of small intestinal bacterial overgrowth (SIBO) and subsequent nutrient malabsorption.[5] Unfortunately, these underlying contributors are rarely acknowledged in conventional care. Nearly all of my patients have experienced some form of diagnostic overshadowing, where serious but treatable issues are dismissed as “just part of Down syndrome.” This pattern is far too common and far too harmful.

We proceeded with further testing, including an organic acid test and microbial stool analysis, to better understand the underlying contributors to his complex symptoms.

A Two Year Old With Wet and Dry Beriberi

When Lev’s lab results returned, they were staggering. His organic acid test showed:

  • Severely elevated pyruvic acid, lactic acid, and alpha-keto acids – textbook markers of pyruvate dehydrogenase dysfunction, a hallmark of B1 deficiency
  • Broad mitochondrial failure, with elevated markers across the entire Krebs cycle
  • Elevated tartaric acid and D-arabinitol, suggesting significant Candida overgrowth
  • Functional markers of B12, folate, B6, CoQ10, and magnesium deficiencies
  • Elevated quinolinic acid, indicating neuroinflammation
  • Oxidative stress with high lipid peroxides and 8-OHdG

His stool test revealed a severely imbalanced microbiome:

  • Overgrowth of Enterobacter cloacae and Candida albicans
  • Absence of Lactobacillus and E. coli, both important for nutrient absorption and gut health
  • Overgrowth of Clostridium species, which may contribute to inflammation and further disrupt digestion

The conclusion was clear: Lev was suffering from wet and dry beriberi, driven by severe thiamine deficiency, worsened by chronic diuretic use and malabsorption. His seizures, vomiting, poor tone, delayed gross motor skills, and even pulmonary hypertension could all be traced back to a lack of essential B vitamins, especially thiamine. [6],[7], [8]

By the time he came to my clinic, Lev could not even lift his head when placed on his belly, a basic milestone typically achieved in the first months of life. His early seizures (including infantile spasms) had resolved with medication, but their cause had never been identified. In hindsight, these seizures were likely driven by energy failure in the brain, a known consequence of B1 and other B vitamin deficiencies that impair mitochondrial function and neurotransmitter balance.[9]

Within days of starting thiamine and other supports, his mother noticed small but encouraging changes: Lev became more alert, more interactive, and began reaching for toys for the first time, as well as holding his head up when prone (on his belly). His vomiting and reflux diminished. His digestion improved. His body, for the first time in a long time, was beginning to catch up.

My recommendations after reviewing his lab results and discussing them thoroughly with his parents included:

  • Nystatin 500,000 unit tablets – ½ tablet 4 times per day
  • Biocidin – 2 drops twice a day, increasing dose slowly over one week
  • Lactobacillus rhamnosus GG – 15 billion per day, given away from Biocidin
  • TTFD – 200 mg per day in the morning
  • Liposomal CoQ10 – 125 mg per day
  • L-carnitine – 635 mg per day
  • Active B Complex – 1 capsule per day
    • Thiamin (hydrochloride, benfotiamine): 30 mg
    • Riboflavin (riboflavin-5-phosphate): 10 mg
    • Niacin (inositol hexaniacinate): 100 mg
    • Vitamin B6 (pyridoxal-5-phosphate): 25 mg
    • Folate (from (6S)-5-methyltetrahydrofolic acid [MTHF], glucosamine salt, Quatrefolic®): 680 mcg DFE
    • Vitamin B12 (methylcobalamin): 500 mcg
    • Biotin: 250 mcg
    • Pantothenic Acid (calcium D-pantothenate): 100 mg
    • Choline (dihydrogen citrate): 50 mg
    • Inositol: 25 mg
  • R-alpha lipoic acid – 50 mg per day
  • Potassium citrate – 224 mg per day
  • Continue:
    • Riboflavin 25 mg per day
    • Magnesium glycinate 60 mg per day
    • Polyenylphosphatidylcholine 900 mg daily in the morning
    • Vitamin D 800 IU daily anytime of day
    • Iron bisglycinate 12 mg daily, preferably on an empty stomach

The Bigger Picture: Diagnostic Overshadowing in Down Syndrome

Lev’s story is a powerful and heartbreaking example of diagnostic overshadowing, a common but often unspoken problem in the care of children with Down syndrome. This occurs when medical professionals attribute new, worsening, or unexplained symptoms to the child’s known diagnosis rather than investigating further. In Lev’s case, his profound weakness, inability to lift his head, chronic vomiting, diarrhea, and history of seizures were all seen as “typical for Down syndrome.” But they weren’t. They were red flags for severe nutrient deficiencies, particularly thiamine (vitamin B1).

It is imperative for physicians, especially specialists working in critical care units, to recognize the profound impact that vitamins and vitamin deficiencies can have on the physiology of their pediatric patients. In children with complex medical conditions, underlying micronutrient imbalances often go undetected, yet they can significantly impair mitochondrial function, immune regulation, neurological development, and cardiovascular stability. Medications commonly used in hospital settings, such as diuretics, antiepileptics, and proton pump inhibitors, can further deplete essential nutrients like thiamine, magnesium, and B12, compounding the medical vulnerability of these children. A deeper understanding of nutritional biochemistry is essential for preventing avoidable deterioration, improving outcomes, and delivering truly comprehensive pediatric care.

In children with Down syndrome, symptoms like poor muscle tone, delayed milestones, constipation or diarrhea, fatigue, and even seizures are frequently dismissed as part of the condition. This mindset can be deeply harmful. When clinicians stop asking why a symptom is happening, especially when that symptom is new or worsening, they miss opportunities to identify treatable, reversible causes that can dramatically change the trajectory of a child’s health and development.

Lev’s case is sadly not unique. Thiamine deficiency is well-documented in children who are on diuretics like Lasix, who have gut dysfunction, high metabolic demands, or malabsorption – all common features in children with Down syndrome. Yet this critical nutrient is rarely tested, and even less frequently treated. In functional medicine, we are trained to look beneath the surface, to question assumptions, and to search for root causes. For Lev, the cause was clear: his thiamine was being depleted faster than it could be replenished, and no one had been monitoring this vital nutrient, until it was nearly too late.

When diagnostic overshadowing leads to inaction, children suffer unnecessarily. Lev’s story is a call to parents, caregivers, and clinicians to keep asking questions and to never assume that something is “just part of the diagnosis” without first considering what else might be going on.

Lev’s journey is not over, but he is now on a path of healing. His mother continues to advocate fiercely for his care. His treatment plan includes thiamine, mitochondrial support, targeted antimicrobial therapy, and continued nutritional repletion. His case may be complex, but it is not hopeless. He will be monitored closely under my care using functional testing to guide next steps and track progress. I hope his conventional medical team takes the time to carefully review the detailed letter I sent, which outlines the root causes we are addressing and the importance of collaborative support.

Parents – Trust Your Instincts

If you’re a parent of a child with Down syndrome, or any child with complex medical needs, trust your instincts. If something feels off, don’t stop asking questions. If you’ve ever been told, “It’s just part of the condition,” I urge you to ask again. Ask why. Ask what else could be going on. Don’t be afraid to bring up what you’ve read or researched. You know your child best, and your intuition is often the first and most reliable clue that something important is being missed.

diagnostic overshadowing thiamine
July 2025. After two months of thiamine, Lev lifts his head.

Lev’s story is proof of that. His mother recognized something deeper was going on when his professional medical team didn’t. Her persistence is what led her to me and our discovery of a severe, life-altering thiamine deficiency, a diagnosis that had been overlooked despite months of symptoms, hospitalizations, and medications. Her advocacy quite literally changed the course of his life.

If you’re a medical provider, please remember this: Down syndrome is not a catch-all explanation. It is not a reason to stop investigating. Children with Down syndrome deserve the same level of curiosity, biochemical inquiry, and individualized care as every other child. In fact, they often need it more. Micronutrient deficiencies like thiamine (B1) are easy to miss, but they are crucial to mitochondrial function, GI motility, neurodevelopment, and vascular tone. These are not minor contributors; they are foundational to a child’s health and development.

Lev’s weakness, seizures, vomiting, and severe delays were not “just part of Down syndrome.” They were symptoms of a preventable, diagnosable, and treatable condition, and tragically, they were ignored for far too long.

Let’s do better. Let’s listen closer. Let’s not miss it again.

References

[1] Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999 Sep;134(3):238-43. doi: 10.1016/s0022-2143(99)90203-2.

[2] Sica DA. Loop diuretic therapy, thiamine balance, and heart failure. Congest Heart Fail. 2007 Jul-Aug;13(4):244-7. doi: 10.1111/j.1527-5299.2007.06260.x.

[3] Ritorto G, Ussia S, Mollace R, Serra M, Tavernese A, Palma E, Muscoli C, Mollace V, Macrì R. The Pivotal Role of Thiamine Supplementation in Counteracting Cardiometabolic Dysfunctions Associated with Thiamine Deficiency. Int J Mol Sci. 2025 Mar 27;26(7):3090. doi: 10.3390/ijms26073090.

[4] Ryan MP. Diuretics and potassium/magnesium depletion. Directions for treatment. Am J Med. 1987 Mar 20;82(3A):38-47. doi: 10.1016/0002-9343(87)90131-8.

[5] DiBaise JK. Nutritional consequences of small intestinal bacterial overgrowth. Pract Gastroenterol. 2008;32(12):15–28 (https://www.peirsoncenter.com/uploads/6/0/5/5/6055321/sibo_artikel.pdf)

[6] Pache-Wannaz L, Voicu C, Boillat L, Sekarski N. Case Report: severe pulmonary hypertension in a child with micronutrient deficiency. Front Pediatr. 2025 Jan 31;13:1478889. doi: 10.3389/fped.2025.1478889.

[7] C S, Kundana PK, Reddy N, Reddy B S, Poddutoor P, Rizwan A, Konanki R. Thiamine-responsive, life-threatening, pulmonary hypertensive crisis with encephalopathy in young infants: A case series. Eur J Paediatr Neurol. 2022 Jan;36:93-98. doi: 10.1016/j.ejpn.2021.12.010.

[8] Rabinowitz SS. Pediatric beriberi clinical presentation: history, physical, causes. Medscape. Updated March 17, 2014. (https://www.peirsoncenter.com/uploads/6/0/5/5/6055321/pediatric_beriberi_clinical_presentation__history_physical_causes.pdf)

[9] Lanska DJ, Fatal-Valevski A. Epilepsy in children with infantile thiamine deficiency. Neurology. 2010 Feb 23;74(8):702-3; author reply 703. doi: 10.1212/WNL.0b013e3181d2b857.

 

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

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