In part II of this series I shift focus from thyroid to thiamine, looking at the effect of vitamin B1 on pyruvate dehydrogenase and the connection to chronic fatigue syndrome or CFS. Part 1 is here Thyroid And Chronic Fatigue
Many associations have been made with chronic fatigue syndrome and the related condition fibromyalgia, both symptomatic and biochemical. In 2016 paper attempting a metabolic profile of sufferers from CFS/fibromyalgia showed excessive lactate production pointing toward a problem with an enzyme called pyruvate dehydrogenase.
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Initially, chronic fatigue syndrome was called myalgic encephalopathy. This translates to muscle pain (myalgia) and brain disorder (encephalopathy). Both myalgia and encephalopathy can be caused by an increase in lactate. A deficiency of the enzyme pyruvate dehydrogenase leads to an increase in lactate which may be a cause of chronic fatigue syndrome in some cases. Fibro-myalgia is a similar syndrome with potentially similar biochemical patterns.
“Pyruvate dehydrogenase complex deficiency is one of the most common neurodegenerative disorders associated with abnormal mitochondrial metabolism. The citric acid cycle is a major biochemical process that derives energy from carbohydrates. Malfunction of this cycle deprives the body of energy. An abnormal lactate buildup results in nonspecific symptoms (eg, severe lethargy, poor feeding, tachypnea), especially during times of illness, stress, or high carbohydrate intake.”
It is these abnormalities in this citric acid cycle (TCA) that the previously mentioned study points towards.
“Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients.”
They identify a deficiency in pyruvate dehydrogenase and an increase in pyruvate dehydrogenase kinase. Pyruvate dehydrogenase kinase is an enzyme that regulates/inhibits/ pyruvate dehydrogenase. An increase in pyruvate dehydrogenase kinase will generally lower pyruvate dehydrogenase. This is an attack on two fronts, crippling the ability to produce energy and increasing the buildup of lactate in the system.
“These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.”
There is interaction between pyruvate dehydrogenase and thyroid hormone. It seems that a deficiency of thyroid hormone can down regulate the action of pyruvate dehydrogenase.
“Pyruvate dehydrogenase complex activity was unchanged in the hyperthyroid state but was significantly reduced (by a third) in hypothyroid rats.”
Effect of thyroid hormone on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase.
Thyroid hormone can also increase the expression of pyruvate dehydrogenase kinase – probably a protective mechanism against hyperthyroidism – much like reverse T3 in some contexts.
The pyruvate dehydrogenase enzyme is critical for turning carbohydrates into fuel. Anything limiting these reactions can lead to lower production of energy and increased lactate – which reinforces the cycle.
“Instead, the cells of people with CFS stop making as much energy from sugar as usual, and start relying more on lower-yielding fuels, such as amino acids and fats. This kind of metabolic switch produces lactate, which can cause pain when it accumulates in muscles.”
ThDP (thiamine diphosphate) is required for some of the actions of pyruvate dehydrogenase. ThDP is made from of thiamine – vitamin B1. Vitamin B1 can normalise excessive lactate production seen in chronic fatigue. The accumulation of lactate is also one of the metabolic signatures of cancer and many other chronic health problems. An experiment on rats with induced cancer showed that vitamin B1/thiamine can lower excessive lactate and normalise pyruvate dehydrogenase. (Very rough translation of the article heref)
“Correlation between pyruvate and lactate contents as well as between enzymes participating in turnover of the substrates (pyruvate and lactate dehydrogenases, alanine aminotransferase, pyruvate kinase) were studied in rat liver tissue simultaneously with tumor growth and intensive thiamin -therapy. Thiamine, administered into rats carrying carcinosarcoma Woker-256 at a daily dose 12.5 mg/kg body weight, exhibited the normalizing effect on activity of enzymes studied, on quantitative content of lactate dehydrogenase isoenzymes and on content of lactate in blood and of pyruvate in liver tissue.”
“These data served as one of the justifications for conducting a course of vitamin therapy. The introduced vitamin (B1 thiamin) has a normalizing effect on pyruvate dehydrogenase in the liver tissue of rats-tumor carriers.”
Pyruvate dehydrogenase (PDH) is active inside the cell, within the mitochondria. When there is a functional impairment of pyruvate dehydrogenase this can lead to a buildup of pyruvate. An enzyme called lactate dehydrogenase can then convert the pyruvate into lactate.
“Pyruvate dehydrogenase (PDH) is a multienzyme complex in the inner mitochondrial membrane that, under aerobic conditions, catalyzes the oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA). … In thiamine deficiency, pyruvate cannot undergo this conversion, and its concentration increases… This excess pyruvate is then converted to lactate by the action of lactate dehydrogenase… This … leads to the acidosis associated with thiamine deficiency.”
This paper details a number of instances whereby people placed on feeding tubes become very ill very quickly if they are not supplemented with thiamine/B1.
Intravenous thiamine can very quickly reverse symptoms of encephalopathy related to excessive lactate.
“Thiamine is a water-soluble vitamin that plays a pivotal role in carbohydrate metabolism. In acute deficiency, pyruvate accumulates and is metabolized to lactate, and chronic deficiency may cause polyneuropathy and Wernicke encephalopathy. Classic symptoms include mental status change, ophthalmoplegia, and ataxia.
We report the case of a 56-year-old man with profound lactic acidosis that resolved rapidly after thiamine infusion. He was admitted because of a decreased level of consciousness .
Clinically, thiamine deficiency was suspected after other causes of hyperlactatemia, such as hypoxia and hepatic failure, were excluded. After administration of 300 mg of intravenous thiamine, hyper-lactatemia normalized rapidly.”
So, theoretically, a deficiency of thiamin/B1 or dysregulation of thyroid hormone could cause alterations in pyruvate dehydrogenase leading to symptoms associated with chronic fatigue or fibromyalgia. The amount of thiamine/B1 required to prevent deficiency in most people is extremely low. It’s unlikely that people eating anything resembling a normal diet, or even many fad diets, would develop a classical B1 deficiency that would show up on blood tests.
There are, however, some studies showing that vitamin B1 can reverse chronic fatigue. It is the amount of thiamin that gets into the cell that is relevant. Absorption and circulation in the blood mean nothing if thiamine does not enter the cell, at least in the context of this article.
There are two (known) mechanisms by which thiamine can enter the cell and affect pyruvate dehydrogenase and lactate. There is an active transport mechanism and there is a passive diffusion mechanism. The Transport of Nutrients Across the Cell Membranes
A 2013 case report into fibromyalgia noted that many of the symptoms of fibromyalgia are similar to thiamin deficiency. This study gave very large doses of thiamine in order to test the theory that fibromyalgia is sometimes a problem with active transport of thiamine into the cell/mitochondria. When active transport fails this will create a cellular/mitochondrial thiamine deficiency – even when blood levels of thiamine are within the normal range.
The recommended daily allowance for thiamine is 1 to 2 mg per day. This study used up to 1,800mg, and that amount was sometimes required for improvement. Supersaturation of the blood with enormous amounts of thiamine may allow for a correction of cellular deficiency by the flooding the passive mechanism. This can lead to resolution of fibromyalgia/chronic fatigue syndromes.
“Some observations indicate that the large majority of symptoms of fibromyalgia could be the clinical manifestation of a mild thiamine deficiency due to a dysfunction of the active transport of thiamine from the blood to the mitochondria or to enzymatic abnormalities.
Patient numbers 2 and 3 never reported any improvement until the dose was increased up to 1500 mg/day, orally. An abrupt improvement instead occurred at doses of 1800 mg/day.
Finally, the interviews after 20 days of therapy showed an appreciable reduction of all the other symptoms. All patients are currently continuing the same therapy. A recent check-up of the patients did not show any decrease in the efficacy of the therapy.”
The above study mentions research conducted in 2010 into inflammatory bowel diseases (IBD, Crohn’s disease, ulcerative colitis). There is a significant overlapping of symptoms in inflammatory bowel disease, irritable bowel syndrome and disorders with chronic fatigue. In disorders of the digestive system there can be a thiamine deficiency due to malabsorption. (I’ll probably look at the gut aspect of CFS type syndromes in future, as it’s clearly significant.)
The participants of this study had blood tests for thiamine deficiency. According to blood tests none had a thiamine deficiency. The 12 participants of the study were all put on high doses of oral thiamine, all suffered from fatigue. 10 of the 12 participants had complete recovery from chronic fatigue. The remaining two had near complete recovery from chronic fatigue. This indicates a possible cellular deficiency of thiamine due to failure of the active transport mechanism which can be corrected by supersaturation with high doses of thiamine.
“To demonstrate that fatigue and other disorders related to ulcerative colitis and Crohn’s disease are the manifestation of an intracellular mild thiamine deficiency and not due to malabsorption….”
All patients were assigned to receive high doses of thiamine orally. Depending upon the body weight of each patient, dosage ranged from 600 mg/day (60 kg) to 1,500 mg/day (90 kg). The chronic fatigue syndrome scale as well as thiamine and thiamine pyrophosphate levels in the blood were measured 20 days after the beginning of the therapy. Ten patients out of twelve showed complete regression of fatigue, while the remaining two patients showed nearly complete regression of fatigue compared to the chronic fatigue syndrome scale scores before therapy. The absence of blood thiamine deficiency and the efficacy of high-dose thiamine in our patients suggest that fatigue is the manifestation of a thiamine deficiency, likely due to a dysfunction of the active transport of thiamine inside the cells, or due to structural enzymatic abnormalities. The administration of large quantities of thiamine increases the concentration in the blood to levels in which the passive transport restores the normal glucose metabolism in all cells and leads to a complete regression of fatigue.”
A significant number of sufferers of chronic fatigue syndrome and fibromyalgia report having a high stress incident at initial onset of the syndromes. Many types of stress increase the usage of thiamine and can trigger a functional deficiency (cellular or otherwise) in people who are already low on thiamin. Many overlapping digestive problems will also deplete thiamine. Stress itself will also decrease absorption.
“The stated time range for the development of severe lactic acidosis in those three cases and in several cases reported by other investigators was 7 to 34 days. In a study of eight healthy male subjects receiving thiamine-deficient diets, urinary excretion of thiamine metabolites was absent after 18 days. The rate of depletion depends on the clinical setting. Thiamine requirements increase when a person has a fever, experiences physical stress, or is pregnant. A high glucose load, such as that provided with parenteral nutrition, also increases the metabolic demand for thiamine. Thiamine loss may be increased by hemodialysis and peritoneal dialysis, diuretic therapy, and diarrhea.”
Unlike thyroid hormone, experimentation with thiamine is relatively safe, about as safe as any supplement could be. Thiamine was the first water-soluble vitamin discovered. Being water-soluble this means that an excess is generally excreted rapidly, rather than stored. The article above, by the Mayo Clinic on metabolic acidosis and thiamine deficiency states that:
“Administration of thiamine has an extremely low risk of adverse effects.”
I’m about to start experimenting with higher doses of thiamine myself. I’ll be testing low doses first. There’s always a chance of a strange reaction. It seems pretty clear that a functional thyroid deficiency or cellular thiamine deficiency can cause chronic fatigue, it also seems clear that they are not the only causes of the protean metabolic disorders…
Toxinless has looked into the quality of many thiamine supplements.