Thiamin may be the missing link to treating autoimmune disease and autonomic dysfunction. Although deficiencies in this vitamin have long been considered eradicated, case studies show supplementation with this nutrient improves fatigue in autoimmune patients in a matter of hours to days
Ali Le Vere, B.S., B.S. – One of the common threads uniting disparate autoimmune disease labels, irrespective of diagnosis, is the debilitating fatigue that plagues patients. Although methylated B vitamins have been given ample fanfare, vitamin B1, or thiamin, has garnered far less attention in communities that emphasize the holistic management of autoimmune disease.
Functions of Thiamin
One of eight essential B vitamins, thiamin is a water-soluble vitamin that functions in the conversion of food into energy (1). The active form of thiamin, known as thiamin pyrophosphate or thiamin diphosphate, is an essential cofactor in both the citric acid cycle and pentose phosphate pathway, two enzyme-mediated pathways of carbohydrate metabolism (1). The citric acid cycle, for example, also known as the Kreb’s cycle, is a central metabolic pathway in the mitochondria that participates in the oxidative degradation of monosaccharides and other nutrients, which generates cellular energy currency in the form of adenosine triphosphate (ATP) to be used in a myriad of energy-demanding cellular reactions (1).
Inhibition of the two main enzymes of the Kreb’s cycle for which thiamin is a cofactor, pyruvate dehydrogenase complex (PDH) and alpha-ketoglutarate dehydrogenase (alpha-KGDH), leads to decreased brain levels of ATP (1). Suppression of brain ATP levels impairs degradation of dopamine in the prefrontal cortex, disrupts synthesis of the nerve-insulating myelin sheath, prevents production of the neurotransmitter acetylcholine, and reduces levels of the major inhibitory neurotransmitter gamma aminobutyric acid (GABA), which collectively leads to delirium, delusions, hallucinations, and cognitive impairment (1).
The transketolase enzyme of the cytosol-based pentose phosphate pathway (PPP), on the other hand, also requires thiamin as a cofactor (1). Transketolase converts glucose-6-phosphate into both ribose-5-phosphate and reduced nicotinamide adenine dinucleotide phosphate (NADPH), the latter of which is required to donate hydrogen atoms in chemical reactions that produce particular neurotransmitters, steroids, amino acids, fatty acids, and the master antioxidant of the body, glutathione (1). Given its centrality to these biochemical pathways which generate energy for the entire organism, the effects of thiamin deficiency are all-encompassing.
The Re-Emergence of Thiamin Deficiency Disorders
The relationship between food and berberi, the classical syndrome of thiamin deficiency, was first discovered by Japanese naval surgeon Takaki in the late nineteenth century, who found that nearly two-thirds of his crew were stricken with berberi after a long voyage. Two years later, when he loaded another warship with dry milk and meat, he noticed that a much smaller percentage of the crew succumbed to berberi, such that “Takaki concluded that the disease was caused by a lack of nitrogenous food in association with excessive intake of non-nitrogenous food” (2).
In addition to impaired reflexes, peripheral neuropathy, edema, cardiovascular abnormalities and hypesthesia, or a diminished capacity for physical sensation, signs of autonomic dysfunction such as sinus tachycardia, vasovagal syncope, mitral valve prolapse, hypotension, sweating, dermographia, and attention deficit are a prominent part of the clinical expression of berberi (2, 3). Other extreme manifestations of thiamin deficiency include Wernicke’s encephalopathy, which includes signs such as ataxia, weakness, paralysis, cognitive impairment, apathy, significant spatial and temporal disorientation, and problems with movement in the muscles around the eyes such as ocular palsies, nystagmus, and opthalmoplegia (1). These symptoms are caused by lesions in brain areas including the hypothalamic nuclei, tectal plate, periventricular nuclei, thalamus, pontine tegmentum, and abducens and oculomotor nuclei, and untreated, lead to coma and death (1).
Korsakoff’s psychosis is often a progression of Wernicke’s encephalopathy (4), and includes symptoms such as amnesia, decreased initiative, and confabulation, which means distorted, fabricated, or misinterpreted memories. Although thiamin deficiency, and its extreme incarnations in particular such as Wernicke’s encephalopathy and Korsakoff’s psychosis, is considered a medical emergency, 80% of the time these diagnoses are made during autopsy (5), mainly due to low index of suspicion, and the nonspecific clinical signs of these syndromes (1).
Although the benefit of thiamin in these classical syndromes of thiamin deficiency, which were recorded as far back as the ninth century, is uncontested, milder forms of thiamin deficiency often elude diagnosis. Marginal thiamin deficiency presents with vague symptomatology, including fatigue, irritability, abdominal pain, frequent headaches, and a decline in growth rate in children (6). The World Health Organization states, in fact, that, thiamin deficiency is a clinical diagnosis confirmed upon improvement with thiamin administration:
The symptoms of mild thiamin deficiency are vague and can be attributed to other problems, so that diagnosis is often difficult…The symptoms of mild thiamin deficiency clinically improve by the administration of thiamin.(7)
In the minds of conventional providers, deficiency diseases have been eradicated in the industrialized world; however, unbeknownst to the medical establishment, it is our Western diets that are facilitating the re-emergence of these diseases considered long-abolished:
Perhaps, in the light of more modern knowledge, it is possible to state that high simple carbohydrate malnutrition can cause symptoms of early beriberi. Since beriberi conjures up an unacceptable concept in the mind of many modern physicians it is probable that it would not be considered in differential diagnosis. It is very likely that many of the poorly understood symptomatology seen today that responds to nutrient therapy is caused by a mixture of marginal classic nutritional diseases, including beriberi, pellagra and scurvy.(2)
Efficacy of Thiamin in Inflammatory Bowel Disease
Especially encouraging are the results of a small open-label pilot study of thiamin use in patients with inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, who presented with fatigue and lingering extra-intestinal symptoms despite their diseases being characterized as quiescent or in remission (8). Patients, all of whom had normal thiamin levels at the commencement of the study, were treated orally with 600 milligrams per day of thiamin, with additional doses in increments of 300 mg per day for those cases in which regression of fatigue was not considered satisfactory, up to a total of 1,500 mg per day (8). In other words, the dose was defined empirically, with calibration based upon subject weight and according to symptomatic remission.
All but two of the twelve patients exhibited a complete regression of fatigue, and in the remaining two, near complete regression was observed (8). Moreover, one hundred percent of patients reported complete regression of symptoms associated with fatigue (8). Impressively, the majority of patients also displayed improvements in intestinal function, with marked reductions in the number of diarrhetic episodes (8).
Notably, in one of the series of case studies presented, fatigue disappeared completely after intramural thiamin injection, and authors mention that “within 20 days, the patient regained complete wellness” (8). This study confirmed findings by Magee and colleagues, who found that consumption of thiamin-rich foods decreases disease activity in patients with ulcerative colitis (9).
Effect of Thiamin in Hashimoto’s Thyroiditis
Another series of case reports published in The Journal of Alternative and Complementary Medicine chronicles the use of thiamin in patients with Hashimoto’s thyroiditis who had persistent symptoms such as fatigue, depression, anxiety, sleep disruption, impaired memory and concentration, dry skin, and cold intolerance despite normal thyroid parameters (10). Patients, all of whom exhibited normal blood levels of thiamin and TPP prior to treatment, were administered either 600 mg per day of oral thiamin or 100 mg per mL of thiamin administered parenterally every four days, depending on weight (10).
In the two patients given oral thiamin, complete regression of fatigue occurred within 3 to 5 days, whereas fatigue regressed within 6 hours in the patient given intramuscular thiamin therapy (10). Although case studies rank low on the hierarchy of evidence-based data, and underscore the need for higher quality research, the mechanism linking functional thiamin deficiency to autoimmune-based fatigue is so plausible that the study authors assert:
While further studies are necessary to confirm our findings, we strongly believe that our observations represent an important contribution to the relief of many patients.(10)
Reasons Underlying Thiamin Deficiency in Autoimmunity
As indicated by the IBD pilot study in which all patients exhibited normal levels prior to treatment, yet still responded favorably to thiamin supplementation, tests of thiamin and thiamin pyrophosphate (TPP), the active form of thiamin, may be of no value in identifying functional thiamin deficiency (8).
Normal serum levels of thiamin and TPP, in fact, indicate normal thiamin absorption by the small intestine (8). Researchers instead attribute the symptoms of thiamin deficiency that appeared in these autoimmune patients in both studies to either structural enzymatic defects or to dysfunction of the vitamin B1 active intracellular transport mechanism from the blood to the mitochondria (8). Administration of large quantities of vitamin B1, on the other hand, is able to circumvent this abnormality:
The administration of large quantities of vitamin B1 orally increases the concentration in the blood to levels in which the passive transport restores the normal glucose metabolism. The glucose metabolism of all organs goes back to normal values and fatigue disappears.(8)
As an alternative explanation, one author in the New England Journal of Medicine proposes that a deficiency in activity of one thiamin transporter can cause another to pick up the slack when high doses of thiamin are administered. This occurs because one member of the solute carrier (SLC) gene family of transporter proteins, which possess structural similarity, can substitute for the function of another.
In other words, at large doses, thiamin can induce expression of the solute carrier gene family member SLC19A2, which encodes the human thiamin-only transporter 1 (hTHTR1), in order to compensate for defects in SLC19A3, which encodes the human thiamin and biotin transporter 2 (hTHTR2) (11). Increasing the concentration of blood thiamin also augments the chances that it crosses the blood brain barrier (BBB) to correct neurological deficits, since thiamin penetration of the BBB occurs via passive diffusion, an energy-independent process, when there is a surplus of thiamin available (12).
Food-Based Sources of Thiamin
Only plants, bacteria, and fungi can synthesize thiamin, so humans must acquire thiamin from external food sources. Because they are nutrient-poor, breads and cereals are oftentimes fortified with thiamin, but ingestion of these foodstuffs for thiamin sufficiency is counter-intuitive, since simple carbohydrates increase the need for thiamin. Although data on thiamin content of foods is limited (13), whole-food sources of thiamin include liver and other sources of offal, meat, pork, poultry, fish, eggs, dried legumes, nuts, and whole grains such as brown rice and bran (2).
Additionally, other plants which have relatively high thiamin content include Nicaraguan cacao, black cohosh, spirulina, string beans, kidney beans, black beans, navy beans, green beans, peas, black-eyed peas, bael fruit, asparagus, macambo, sunflower seed, shepherd’s purse, okra, high mallow, sow thistle, mountain buchu, watercress, and garlic (14). However, cooking and heat-processing of food results in considerable thiamin losses, so preparation methods matter from a thiamin sufficiency perspective (2).
Thiamin Repletion: Correcting the Deficiency
Of note, is that the dose administered in the IBD study is much higher than that which can be obtained from food, and approximately 600-fold higher than the daily recommended intake for men and women older than ten years of age (1). Due to the supra-physiological nature of the dosing regimen, patients should consult with a naturopathic or integrative doctor prior to consuming a dose of this magnitude.
However, the safety profile of thiamin, as observed in the literature, demonstrates that this intervention is benign. Unlike other immunosuppressant drugs often administered for autoimmune diseases, which can be accompanied by catastrophic side effects such as infection and cancer, there are no collateral effects of thiamin administration, even when used at high doses long-term (10).
In fact, thiamin is nontoxic to the body even at excess amounts (15), and doses as high as 3 to 8 grams per day have been used to treat Alzheimer’s disease without adverse effects (8). Only mild tachycardia appeared in one patient in the IBD study, which abated upon reduction of the dose (8).
This safety profile stands in stark contrast to a drug like hydroxychloroquine (Plaquenil), which is often prescribed to improve fatigue in autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, sarcoidosis, rheumatoid arthritis, and Sjögren’s syndrome, which poses the risk of potentially irreversible retinopathy (16) that may progress to blindness even 7 years after the drug has been discontinued (17). Similarly, newer generation biologic drugs such as antitumor necrosis factor (anti-TNF) therapy and anti-T cell strategies carry risk of autoimmune disease itself, causing the very diseases they are designed to treat in a cruel poetic irony (18).
Other considerations for using thiamin include integrating supplementation with a broad-spectrum low-dose B vitamin formulation to prevent any imbalances in B vitamins. Likewise, another factor often at play is magnesium deficiency, since the conversion process of thiamin to its metabolically active form requires magnesium as a cofactor (19). Therefore, magnesium deficiency should be corrected, since hypomagnesaemia can mimic thiamin deficiency (1).
Although scientists state, “We deem necessary a lifelong use of high doses of thiamin in affected subjects,” researchers are unable to clarify whether the aberration in thiamin transport is secondary to genetic mutations or to an autoimmune-inflammatory process (8), which raises the possibility that resolution of the underlying immune dysregulation, namely, through approaches that restore an evolutionarily appropriate diet and lifestyle template, may negate the need for high-dose thiamin long-term.
Forms of Thiamin
One potential limiting factor of thiamin use is its poor bioavailability and slower absorption as a supplement, which is why high doses of thiamin are prescribed for certain medical conditions (3). To circumvent this issue, researchers have developed fat-soluble derivatives of thiamin called allithiamines. Benfotiamine, one lipophilic derivative of thiamin which readily diffuses through biological membranes, has been shown to have clinical benefit in diabetic vascular complications (3).
Its mechanisms of action includes reduction of advanced-glycation end products (AGEs), highly oxidant compounds with pathogenic significance in aging and chronic disease states (20), and modulation of pathways that play roles in cell survival, death, and repair (3). Impressively, benfotiamine also reduces activation of the nuclear factor kappa beta (NFkB) signaling pathway, the gateway to inflammatory eicosanoid mediators, and mitigates signaling down the arachidonic acid pathway, inhibiting the same cyclooxygenase (COX) enzymes (3) exploited by non-steroidal anti-inflammatory drugs (NSAIDs) without the deleterious side effects.
In addition, benfotiamine has been found to have free radical-scavenging properties via its ability to modulate levels of enzymes involved in endogenous antioxidant defense, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (3). Not only that, but benfotiamine reduces activity of glycogen synthase kinase 3 (GSK-3), which is involved in deposition of β-amyloid plaques in the brain in Alzheimer’s disease (3). Proof-of-concept of its neuroprotective abilities have been demonstrated in recent studies showing that benfotiamine reduces plaque accumulation, improves symptomatology (3), and inhibits progression of cognitive impairment in Alzheimer’s disease (21). Therefore, due to its pleiotropic effects, thiamin in this form has the potential to improve a host of chronic, inflammatory, and neurodegenerative conditions.
Removing Anti-Thiamin Agents
Predisposing factors for thiamin deficiency include malnutrition, acquired immunodeficiency syndrome (AIDS), gastrointestinal surgical procedures such as vertical banded gastroplasty, gastric bypass surgery, colectomy, and intragastric balloon, and psychiatric disorders including anorexia nervosa, bulimia, and binge-eating disorders (1). Certain medical conditions, such as pancreatitis, renal disease, thyrotoxicosis, celiac disease, cancer, peptic ulcers, and other gastrointestinal disorders are likewise associated with increased risk of thiamin deficiency (1).
However, chronic alcoholism poses special risk, since it interferes with the rate-limiting step of carrier-mediated thiamin absorption in the duodenum (22), alongside impairing the storage and phosphorylation of thiamin that is essential to its function (1). In addition, thiamin deficiency is under-recognized in obesity and is implicated in the progression of obesity-related chronic disease states (Maguire et al., 2018). Furthermore, people with type 1 and type 2 diabetes have plasma thiamin levels that are 76% and 50% to 75% lower, respectively, than healthy volunteers (24, 25).
Certain dietary factors, such as simple carbohydrates, also have anti-thiaminergic properties (9), which is referred to as high-calorie malnutrition when excessive intake produces thiamin deficiency. Carbohydrates increase the need for the vitamin since thiamin is a major factor in the metabolism of glucose (2). What’s more, polyphenolic compounds present in tea and coffee can inactivate thiamin (2).
Also problematic are sulfiting agents, including sulfites, sulfur dioxide, hydrogen sulfites, and metabisulfites, which are used as food preservatives to prevent microbial growth, food spoilage, and discoloration, and to extend the shelf life of the product (9). Sulfites, which are contained in foods such as wines, lager, non-organic processed meats such as sausage and burgers, sulfited seafoods, and soft drinks from concentrate, are problematic because of their anti-thiamin effects, since thiamin is readily cleaved by the sulfite ion, particularly at a colonic pH (9). The role of sulfites reinforces the thiamin-autoimmune connection, as studies of ulcerative colitis have elucidated a role of sulfited foods in the pathogenesis of the disease, with high sulfite foods producing worse sigmoidoscopy scores (9)—presumably due in part to thiamin depletion.
Therapeutic Potential for Thiamin in Autoimmune Disease
Researchers state that the role of thiamin as a medicinal agent is under-appreciated in Western civilization (26). Although deficiency disorders are considered afflictions of developing societies, the prevalence of subclinical thiamin deficiency has been demonstrated to be on the rise (3). In addition, because a response to thiamin therapy is considered diagnostic of thiamin deficiency, in concert with its excellent safety profile, a trial of thiamin poses little risk. As asserted by researchers in The Journal of Alternative and Complementary Medicine,
Our team is convinced that the fatigue correlated with all autoimmune inflammatory diseases is a manifestation of an intracellular mild thiamin deficiency likely due to thiamin transporter deficiency or to enzymatic dysfunctions.(8)
Not only does thiamin deficiency cause mitochondrial dysfunction, but it also results in oxidative stress, which is central to the pathophysiology and perpetuation of autoimmune disorders. Not only that, but some of the cardinal symptoms of thiamin deficiency are features of autonomic dysfunction, or dysautonomia, which 24% to 100% of autoimmune patients have been shown to experience (27). Therefore, restoration of thiamin status in autoimmune patients has the potential to ameliorate a vast array of symptoms, since the autonomic nervous system is responsible for a diversity of largely unconscious physiological activities including digestion, urination, defecation, heart rate, blood pressure, pupillary response, and sexual arousal.
Lastly, another line of reasoning connecting autoimmunity to thiamin deficiency is postural orthostatic tachycardia syndrome (POTS), a form of dysautonomia with suspected autoimmune etiology that is often comorbid with other autoimmune diseases (28). The symptoms of POTS, which has been shown to respond to thiamin supplementation in some cases (29), resemble berberi.
Given the ubiquity of anti-thiamin agents in the Western diet alongside problems with thiamin transport in autoimmune patients, these preliminary studies raise the possibility of thiamin as a potent therapeutic option for autoimmune disorders alongside a holistic regimen that addresses mindfulness, toxicity, diet, and lifestyle.
- Osiezagha, K. et al. (2013). Thiamin deficiency and delirium. Innovations in Clinical Neuroscience, 10(4), 26-32.
- Lonsdale, D. (2006). A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives. Evidence Based Complementary and Alternative Medicine, 3(1), 49-59.
- Raj, V. et al. (2018). Therapeutic potential of benfotiamine and its molecular targets. European Review for Medical and Pharmacological Sciences, 22, 3261-3273.
- Zubaran, C., Fernandes, J.G., & Rodnight, R. (1997). Wernicke-Korsakoff syndrome. Postgraduate Medical Journal, 73(85%), 27-31.
- Thomson, A.D., Guerrini, I., & Marshall, E.J. (2009). Wernicke’s encephalopathy: role of thiamine. Practices in Gastroenterology, 33(6), 21-30.
- Shikata, E. et al. (2000). “Iatrogenic” Wernicke’s encephalopathy in Japan. European Neurology, 44(3), 156–161.
- World Health Organization, United Nations High Commissioner for Refugees. (1999). Thiamin Deficiency and Its Prevention and Control in Major Emergencies. Retrieved from http://www.who.int/nutrition/publications/emergencies/WHO_NHD_99.13/en/
- Costantini, A., & Pala, M.I. (2013). Thiamin and Fatigue in Inflammatory Bowel Diseases: An Open-label Pilot Study. The Journal of Alternative and Complementary Medicine, 19(8), 704-708.
- Magee, E. et al. (2005). Association between diet and disease activity in ulcerative colitis patients using a novel method of data analysis. Nutrition Journal, 4(7).
- Costantini, A., & Pala, M.I. (2014). Thiamin and Hashimoto’s Thyroiditis: A Report of Three Cases. The Journal of Alternative and Complementary Medicine, 20(3), 208-2011.
- Kono, S. et al. (2009). Mutation in a thiamin-transporter gene and Wernicke’s like encephalopathy. New England Journal of Medicine, 360, 17921.
- Thomson, A.D. (2000). Mechanisms of vitamin deficiency in chronic alcohol misusers and the development of the Wernicke-Korsakoff syndrome. Alcohol & Alcoholism, 35(Suppl 1), 2–7.
- National Institutes of Health: Office of Dietary Supplements. (2018). Thiamin: Fact Sheet for Professionals. Retrieved from https://ods.od.nih.gov/factsheets/Thiamin-HealthProfessional/#en7
- United States Department of Agriculture, Agricultural Research Service. (1992-2016). Dr. Duke’s Phytochemical and Ethnobotanical Databases. Home Page, http://phytochem.nal.usda.gov/ http://dx.doi.org/10.15482/USDA.ADC/1239279
- Hope, L.C., Cook, C.C., & Thomson, A.D. (1999). A survey of the current clinical practice of psychiatrists and accident and emergency specialists in the United Kingdom concerning vitamin supplementation for chronic alcohol misusers. Alcohol and Alcoholism, 4(6), 862–867.
- Lehne, R.A. (2007). Pharmacology for Nursing Care. St. Louis, Missouri: Saunders-Elsevier Inc.
- Abdulaziz, N. et al. (2018). Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update. Current Opinion in Rheumatology, 20(3), 249-255. doi: 10.1097/BOR.0000000000000500.
- Chandrashekara, S. (2012). The treatment strategies of autoimmune disease may need a different approach from conventional protocol: A review. Indian Journal of Pharmacology, 44(6), 665-671.
- Zieve, L. (1969). Influence of magnesium deficiency on the utilization of thiamin. Annals of the New York Academy of Science, 162(2), 732–743.
- Uribarri, J. (2010). Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet. Journal of the American Dietetic Association, 110(6), 911-916.e12.
- Pan, X. et al. (2016). Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer’s disease. Neuroscience Bulletin, 32, 591-596.
- Todd, K.G., Hazell, A.S., & Butterworth, R.F. (1999). Alcohol-thiamin interactions: an update on the pathogenesis of Wernicke encephalopathy. Addiction Biology, 4(3), 261–272.
- Maguire, D. et al. (2018). The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: A systematic review. Clinical Nutrition ESPEN, 25, 8-17.
- Thornalley, P.J. et al. (2007). High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia, 50, 2164-2170.
- Al-Attas, O.S. et al. (2012). Blood thiamine and its phosphate esters as measured by high-performance liquid chromatography: levels and associations in diabetes mellitus patients with varying degrees of microalbuminuria. Journal of Endocrinology Investigations, 35, 951-956.
- Lonsdale, D. (2011). Thiamin(e): The Spark of Life. Water Soluble Vitamins, 199-227.
- Stojanovich, L. (2009). Autonomic dysfunction in autoimmune rheumatic disease. Autoimmune Reviews, 8(7), 569-572.
- Blitshteyn, S. (2015). Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). Lupus, 24(13), 1364-1369.
- Blishteyn, S. (2017). Vitamin B1 deficiency in patients with postural tachycardia syndrome (POTS). Neurology Research, 39(8), 685-688.
SF Source Green Med Info Aug 2018