thiamine protein folding Archives

It All Comes Down to Energy

Published on August 10, 2023

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The Threat Around Us

Animals, including Homo Sapiens, survive in an essentially toxic environment, surrounded by microorganisms, potential poisons, the risk of trauma, and adverse weather conditions. Evolutionary development has equipped us with complex machinery that provides defensive mechanisms when any one of these factors has to be faced. Before the discovery of microorganisms, medical treatment had no rhyme or reason, but killing the microorganisms became the methodology. The research concentrated on ways and means of “killing the enemy”, the bacteria, the virus, the cancer cell. The discovery of penicillin reinforced this approach. We are now facing a period of potential impotence because of bacterial resistance, failure of attempts to kill viruses, and the resistance to chemotherapeutic agents in cancer. Louis Pasteur is purported to have said on his deathbed, “I was wrong, it is the terrain that matters”, meaning body defenses.

Hans Selye, whose research into how animals defend themselves when attacked by any form of stress, led to his description of the General Adaptation Syndrome (GAS). He recognized the necessity of energy in initiating the GAS and its failure in an animal that succumbed to stress. He labeled human disease as “the diseases of adaptation”. In Selye’s time, there was little information about energy metabolism but today, its details are fairly well-known. The suggestion of a new approach depends on the fact that our defenses are metabolic in character and require an increase in energy production over and above that required for homeostasis. If the GAS applies to human physiology and that we are facing the “diseases of adaptation”, it is hypothesized that research should be applied to methods by which energy metabolism can be stimulated and mobilized to meet the stress.

Energy Deficiency, Defective Immunity, and COVID-19

There is evidence that energy deficiency applies to each of the diseases described here. It may be the unrecognized cause of defective immunity in Covid-19 disease. Although in coronavirus disease the clinical manifestations are mainly respiratory, major cardiac complications are being reported involving hypoxia, hypotension, enhanced inflammatory status, and arrhythmic events that are not uncommon. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes may accompany acute viral infections or may follow infection by weeks, months, or longer in viral recovered patients. Electrocardiographic changes have been reported in Covid-19 patients. The authors suggest that it may be attributed to hypoxia as one possibility. Because the total body stores of thiamine are low, acute metabolic stress can initiate deficiency. Thiamine deficiency has a clinical expression similar to that observed in hypoxic stress and the authors referred to it as pseudo-hypoxia. It is therefore not surprising that defective energy metabolism can express itself clinically in many different ways.

The present medical model regards each disease as having a separate cause, but the large variety of symptoms induced by thiamine deficiency suggest the ubiquitous nature of energy deficiency as a cause in common. Obesity, a reflection of high calorie malnutrition, has been published as a risk factor for patients admitted to intensive care with Covid-19. Thiamine deficiency was reported in 15.5-29% of obese patients seeking bariatric surgery. Hannah Ferenchick M.D. an emergency room physician commented online that many of her patients with Covid-19 had what she called “silent hypoxemia”. These patients had an arterial oxygen saturation of only 85% but “looked comfortable” and their chest x-rays “looked more like edema” It has long been known that patients with beriberi had low arterial oxygen and a high venous oxygen saturation. All that would be needed to support the hypothesis of thiamine deficiency in some Covid victims would be finding a high venous oxygen saturation at the same time as a low arterial saturation. Also, edema is a very important sign of beriberi, and thiamine deficiency has been noted in critical illness.

Disrupted Autonomic Function

There have been many articles in medical journals describing dysautonomia, mysteriously in association with a named disease, but with no suggestion that the dysautonomia is part of that disease. More recently, there is increasing evidence that dysautonomia is a feature of chronic fatigue syndrome (CFS), manifested primarily as disordered regulation of cardiovascular responses to stress. Manipulating the autonomic nervous system (ANS) may be effective in the treatment of CFS. Dysautonomia is also a characteristic of thiamine deficiency. Patients with Parkinson’s disease begin to lose weight several years before diagnosis and a study was undertaken to investigate this association with the ANS. Costantini and associates have shown that high dose thiamine treatment improves the symptoms of Parkinson’s disease, although the plasma thiamine concentration was normal. They have also shown that high dose thiamine treatment decreases fatigue in inflammatory bowel disease, Hashimoto’s disease, after stroke, and multiple sclerosis. As already noted, it is also an important consideration in critically ill patients.

Multiple System Atrophy is a devastating and fatal neurodegenerative disorder. The clinical presentation is highly variable and autonomic failure is one of its most common problems. Dysautonomia was found to be a clinical entity in Ehlers-Danlos syndrome, a musculoskeletal disease, and this syndrome frequently coexists with Postural Orthostatic Tachycardia Syndrome (POTS), a disease that is included in the group of diseases under the heading of dysautonomia. Some cases of POTS have been reported to be thiamine deficient. This common condition often involves chronic unexplained symptoms such as inappropriate fast heart rate, chronic fatigue, dizziness, or unexplained “spells” in otherwise healthy young individuals. Many of these patients have gastrointestinal or bladder disorders, chronic headaches, fibromyalgia, and sleep disturbances. Anxiety and depression are relatively common. Not surprisingly the many symptoms are often unrecognized for what they represent and the patient may have a diagnosis of psychosomatic disease.

Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for a group of conditions that share common inflammatory pathways and for which there is no definite etiology. These diseases affect the elderly most severely with many of the patients having two or more IMIDs. They include type I diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus, psoriasis, psoriatic arthritis, and multiple sclerosis. The recent recognition of small fiber neuropathy in a large subgroup of fibromyalgia patients reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. These new findings support the disease as a primary neurological entity.

Energy Deficiency During Pregnancy: The Cause of Many Complications

Irwin emphasized the energy requirements of pregnancy in which the maternal diet and genetics have to be capable of producing energy for both mother and fetus. He found that preventive megadose thiamine, started in the third trimester, completely prevented all the common complications of pregnancy. Hyperemesis gravidarum is the most common cause of hospitalization during the first half of pregnancy and is second only to preterm labor for hospitalization in pregnancy overall. This disease has been associated with Wernicke’s encephalopathy, well known to be due to brain thiamine deficiency. The traditional explanation is that vomiting is the cause, but since vomiting is a symptom of thiamine deficiency, it could just as easily be the cause rather than the effect. In spite of the fact that migraines are one of the major problems seen by primary care physicians, many patients do not obtain appropriate diagnoses or treatment. Migraine occurs in about 18% of women and is often aggravated by hormonal shifts. A complex neurological disorder involving multiple brain areas that regulate autonomic, affective, cognitive, and sensory functions, it occurs also in pregnancy. Features of the migraine attack that are indicative of altered autonomic function include nausea, vomiting, diarrhea, polyuria, eyelid edema, conjunctival injection, lacrimation, nasal congestion, and ptosis.

The Proteopathies: Disorders Involving Critical Enzymes

The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine. Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease (AD), in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients. Senile plaques and neurofibrillary tangles are the principal histopathological marks of AD and other proteopathies. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins (enzymes). The crucial event in the development of transmissible spongiform encephalopathies is the conformational change of a host-encoded membrane protein into a disease associated, fibril forming isoform. A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. When this folding process is inhibited, the respective protein is referred to as being mis-folded, nonfunctional, and causatively related to a disease process. These diseases are termed proteopathies and there are at least 50 different conditions in which the mechanism is importantly related to a mis-folded protein. Energy is required for this folding process. Because of their reported relationship with thiamine, it has been hypothesized that mis-folding might be related to its deficiency on an energy deficiency basis.

It All Comes Down to Energy

A hypothesis has been presented that the overlap of symptoms in different disease conditions represents cellular energy failure, particularly in the brain. If this should prove to be true, the present medical model would become outdated. An attack by bacteria, viruses or an oncogene might be referred to as “the enemy”. The defensive action, organized and controlled by the brain, may be thought of as “a declaration of war” and the illness that follows the evidence that “a war is being fought”. This concept is completely compatible with the research reported by Selye. It underlines his concept that human diseases are “the diseases of adaptation”, dependent on energy for a successful outcome in a “war” between an attacking agent and the complex defensive actions of the body. Killing the enemy is a valid approach to treatment if it can be done safely. Unfortunately, the side effects of most medications sometimes makes things worse and that is offensive to the Hippocratic Oath. We badly need to create an approach to research that explores ways and means of supporting and stimulating the normal mechanisms of defense.

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This article was published originally on May 11, 2020.

Protein, Protein Folding, and Enzyme Activity

by Derrick Lonsdale MD, FACN, CNS

Published on March 15, 2023

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As everybody knows, organic food consists of proteins, fats and carbohydrates. In this post I am going to indicate how protein is used to create enzymes. There are animal and vegetable proteins in food. The first thing that happens when one of these proteins is ingested is that digestion breaks it down into a range of chemical substances known as amino acids. They are absorbed and circulate in the blood stream. If they are not used, they are excreted in the urine. The ones chosen to construct enzymes are then reconstituted into these biologically active proteins. As most people know, the body uses enzymes in much the same way as a complex man made machine uses cogwheels. They connect the power to the action and are essentially the “workhorses” of the body.

How Enzymes Work

In order to understand some of the principles, I am going to take an enzyme known as pyruvic dehydrogenase as an example. This enzyme initiates energy production by stimulating the metabolism of glucose, the sugar that is used in the body as fuel for its cells, particularly those in the brain. The combustion of glucose is achieved by its combination with oxygen, the principle of all forms of combustion. We have many different names for this process, depending on the speed of the reaction. Singeing, fire and explosion represent the different speeds of combustion and it must be emphasized that it is never complete. There is always ash.

However, in the body this is a very unique process. The combination of glucose with oxygen begins the complex process of energy production. The “ash” is carbon dioxide and water. The enzyme functions by bringing the oxygen and glucose together but the combustion, known as “oxidation” can only be achieved in the presence of vitamin B1 (thiamine) and magnesium. These are known as cofactors to the enzyme and are supplied in the organic food which we are designed to consume. It is important to understand that this is the gateway to the production of energy which enables us to function and explains why thiamine and magnesium are essential ingredients of health through diet. Without their sufficiency, energy production suffers and an incomplete supply of energy interferes with normal activity of the entire body and brain. This oxidation initiates action in the citric acid cycle, essentially the “engine” in each of our cells. It is a complicated process that I do not need to discuss here, but it leads to the production of a chemical substance known as adenosine triphosphate (ATP). This substance stores energy and the nearest comparison is a battery. For this reason, it is sometimes referred to as “energy currency”.

An Enzyme Is a Protein

I pointed out above that the protein in food is broken down to amino acids that are absorbed into the body and reconstituted to form the biologically useful proteins known as enzymes. An enzyme is created by collecting a group of amino acids together in a bunch to form a chain. The electrical properties of the atoms and molecules in these amino acids enable the chain to be created by what is essentially a magnetic action between its ingredients.

The next thing that happens is absolutely vital to the biochemical action of the protein/enzyme. The protein has to be folded for storage and unfolded for action. The action of folding is repetitively unique to the enzyme. Research that is going on concerning this process is essential to a better understanding of an associated disease process. Mother Nature dictates the folding process which is exquisitely complex. In order to understand how this automatic process takes place, we need to know the exact design and electrical properties of the chain, facts that are still hidden in mystery. What we do know is that there is a whole series of diseases where the enzymes are misfolded or even completely unfolded. Unlocking the exact method by which folding and unfolding takes place leads to an understanding of the basic cause of the respective disease in which this mechanism has failed. There are about 50 different diseases in which this mechanism is responsible. As a group, the respective diseases are known as proteopathies. Alzheimer’s and Parkinson’s diseases are both known as examples of proteopathies and their solution depends on our understanding of this folding and unfolding process. A review of this field of science refers to the advances that have been made over the last decade in our understanding of the fundamental nature and consequences involved.

The Role of Thiamine in Protein Folding

It has long been known that thiamine is involved in the metabolism of Alzheimer’s disease and some attempts have been made to use megadoses of thiamine in its treatment. In fact, the earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine. Throughout the last century, research showed that thiamine deficiency is associated with neurological problems including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease. Benfotiamine, a derivative of thiamine ameliorated the clinical and biological pathologies that define Alzheimer’s disease. A 12-month treatment with this agent tested whether clinical decline would be delayed in the treated group compared to a placebo group. There was a “nearly statistically significant improvement” in the treated group, a fact that the authors have concluded that they need to repeat the study. A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. Because of the known involvement of thiamine, it has been hypothesized that it plays an important part in the folding and unfolding mechanism of the respective proteins.

Prevention Is Better Than Cure

We have hypothesized that thiamine deficiency disease is common in America because of what we have called high calorie malnutrition. It has suggested that this common form of diet acts as a forerunner to one of these proteopathies because of the prolongation of the deficiency. We have suggested that the symptoms caused by high calorie malnutrition are those that collectively give rise to “the walking sick”, the individuals that are haunting the offices of physicians and who are being so frequently diagnosed as psychosomatic disease. Many of these patients have done their own research work and have concluded that the symptoms are arising from vitamin deficiency disease. Many have learned this from the posts on this website. When they go back to their physicians, claiming the true cause of their symptoms, they are almost invariably ignored and often considered to be psychiatric cases. Without a proper discussion concerning diet, many of these individuals continue with the symptoms indefinitely, concluding that they have untreatable disease. Perhaps they are not particularly surprised and may even be a little relieved when new symptoms have appeared and are diagnosed as a recognizable neuropathy such as Parkinson’s or Alzheimer’s disease. That is why it has been hypothesized that thiamine and magnesium are “keys to disease“.