Thiamine and the energy to heal.pptx

Thiamine and the energy to heal.pptx
Thiamine and the energy to heal CHANDLER MARRS, PHD
Introduction  Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition  Synopsis: Hiding in Plain Sight: Modern Thiamine Deficiency  Research analysis and case stories  HormonesMatter.com  Discussion – patient driven  Understanding Mitochondrial Nutrients – FB  Fun - powerlifting  Oldladieslift.com/Oldladieslift - FB
Objectives  To provide a framework for understanding and recognizing modern thiamine deficiency  Well fed but malnourished adults – walking sick  Basic thiamine chemistry  Role in food metabolism  Role in mitochondrial function and OXPHOS  Metabolic patterns associated with insufficient thiamine  Overview of symptoms across time  Treatment options  Resources for more information
Premise THIAMINE IS THE MISSING PIECE TO MANY MODERN ILLNESSES
WHY THIAMINE?  Thiamine is required for ATP/energy synthesis  Rate-limiting for effective macronutrient metabolism and mitochondrial energetics - OXPHOS  Thiamine is required for mitochondrial oxidation and cellular oxygenation  Insufficient thiamine -> hypoxia  No energy, no oxygenation, no life  And lots of ill-health along the way  One of the main drivers of chronic illness  An important component of acute illness Life requires energy. Energy requires thiamine.
What is thiamine?  Vitamin B1 (thiamin, thiamine) found in  Lean pork, poultry and other meats, wheat germ, liver and other organ meats, eggs, fish, beans, peas, nuts, whole grains, garlic  Processed foods (enrichment/fortification)  Antagonized by  High carbohydrate/sugar diets, coffee, tea, alcohol, tobacco, polyphenol supplements  Many (all) pharmaceutical, environmental, and industrial chemicals  Critical for  Metabolism, mitochondrial energy production, protein expression, and general function, and array of CNS/PNS functions – life itself
Basic kinetics  Humans and animals must consume  Plants and microbes synthesize  Gut microbes synthesize ~2% of total thiamine – used mainly by colonocytes  Substrate/micronutrient availability determine microbial balance  Deficiency ↑ pathogenic species (better with salvage pathways) ↓ more helpful species  Short half life: 1-12 hours  Limited storage: 2-3 weeks after complete cessation  Complete cessation is rare in west. Intake and need wax and wane.  Absorbed mainly in intestine  Passive diffusion at higher concentrations  Via transporters at low concentrations  At least 7 transporters (see ‘Hiding’ paper) discovered so far.  Transporter activity is susceptible to  Genetic defects that are quite common  Environmental regulation – meds and other substances block transporters
Once absorbed  Free thiamine is phosphorylated into thiamine pyrophosphate (TPP) also called thiamine diphosphate (ThDP)  Mg2+ and ATP dependent  TPP = ~90% of circulating thiamine  Phosphates removed or added to form thiamine monophosphate (TMP), thiamine triphosphate (TTP)  Microbial thiamine: adenosine thiamine diphosphate (AThDP) Defects in TPK linked to Huntington’s disease, possibly other neurodegenerative disease processes.
From food to ATP MITOCHONDRIA ARE KEY AND THIAMINE IS RATE- LIMITING
We believe It doesn’t matter what we eat, so long as there is sufficient intake, we get ATP.
BARRING ‘RARE’ GENETIC DEFECTS OR FRANK STARVATION All of this happens automatically
“The presumption is that all calories are created equally e.g. that calories are calories and no matter the origins of those calories, the end result will be ATP. Indeed, from the mitochondrial perspective, each fuel, no matter its origins, will be broken down to its carbon skeleton and through a series of reactions, the final output will be ATP. In that sense, the fuel source makes little difference: the net result will be ATP.” Graphic: Lonsdale & Marrs, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.
“However, and this is a big however, what this perspective fails to recognize, is to get from fats, proteins and carbohydrates to ATP, there is an entire factory of enzymatic reactions that absolutely require non- caloric nutrients - vitamins and minerals – to function properly.” Graphic: Lonsdale & Marrs, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.
In reality  Enzymes require nutrient cofactors to perform metabolic tasks.  When appropriate nutrient co-factors are present in sufficient concentrations for the enzymes to operate fully, the food we eat is successfully metabolized into end- products that are useful for all manner of processes and cellular energy is produced.  Even in the case of genetic aberrations that limit enzyme function endogenously, there is evidence that nutrient manipulation can overcome inadequate enzyme activity.  Pyruvate dehydrogenase deficiencies, Parkinson’s, and Huntington’s, for example. Graphic: Elliot Overton, https://www.hormonesmatter.com/beyond- deficiency-thiamine-metabolic-stimulant/
With Co-factor deficiency  When nutrient co-factors are in short-supply, resources are reallocated.  Metabolism shifts directions, it takes a right turn when it should move left or vice versa.  Different enzymes are activated and metabolism eventually reaches a dead-end but not before potentially toxic, unused, waste products build up. Dirtier burn.  As toxins build up, other systems become disrupted, inflammatory and immune responses are activated, demanding ever more energy to resolve.  This is the energy spiral that induces and maintains many of the illnesses we see today.
What the body needs to make energy Macronutrients with adequate micronutrients to power enzyme machinery. Graphic: Lonsdale & Marrs, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition. Absent micronutrients, it doesn’t matter how many calories one ingests, the wheel will not spin (or it will spin backwards).
When it comes to energy  Per glucose molecule  Glycolysis: 2-4 units  TCA/Krebs/Citric acid cycle: 1-2 units  OXPHOS: 30-38 units  Per fat molecule  OXPHOS: >100 units  Protein  Substrates for the synthesis of other proteins  Glucose via liver gluconeogenesis (- 4)  Glutamine > a-KGDH > 24 units of ATP  Used primarily in quickly replicating immune cells and cancer > reverse spin of TCA  Pyruvate to citric acid cycle or converted to lactate 90-95% of ATP produced via mitochondrial OXPHOS El Bacha, T., M. R. M. P. Luz, and A. Da Poian. "Dynamic adaptation of nutrient utilization in humans." Nat Educ 3, no. 8 (2010).
When it comes OXPHOS  Can’t get into the mitochondria without thiamine.  All roads are blocked  We don’t metabolize foods well  Even glycolysis is challenged Combs Jr, G.F. and McClung, J.P., 2016. The vitamins: fundamental aspects in nutrition and health. Academic press. Thiamine is king
When we lose thiamine, we lose ATP Imagine this happening in vivo in different tissues/organs. What havoc would this initiate? What disease processes might evolve?
When OXPHOS is blocked “OxPhos defects trigger mtDNA instability and cell-autonomous stress responses associated with the hypersecretory phenotype, recapitulating findings in plasma of patients with elevated metabokine and cell-free mitochondrial DNA (cf-mtDNA) levels. These responses are linked to the upregulation of multiple energy- dependent transcriptional programs, including the integrated stress response (ISR).” –Jan 2023 Fig. 9: Conceptual model including potential sources of hypermetabolism in cells and patients with mitochondrial diseases. From: OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases It costs the cell more to do less Leads to chronic illness
Understanding thiamine – dependent enzymes JUST A BIT OF CHEMISTRY
Transketolase  Transketolase (TKT)  Located in the cytosol  Connects pentose phosphate pathway (PPP) to glycolytic and oxidative pathways  Determines energy spent on ribose for DNA/RNA and NADPH for steroid, myelin and antioxidants (glutathione, thioredoxin) versus what is shunted towards glycolysis  TKT↓ TD and long list of other disease processes  TKT activity among the more accurate tests of TD  ↑ in tumor cells – an energy siphon  But ↓ in the human http://thiamine.dnr.cornell.edu/Thiamine_biochemistry.html Mitochondrion
Thiamine dictates fatty metabolism  a-oxidation of fatty acids begins in the peroxisome  Larger FAs are broken into smaller ones  2-hydroxyacyl-CoA lyase (HACL1) – the enzyme responsible, is thiamine dependent  Impaired a-oxidation leads to  ↓ Acetyl-CoA for mitochondria> ↓OXPHOS >↓ATP  Particularly problematic for the heart  High phytanic acid/sphingolipid foods (beef, lamb, dairy, eggs) cannot be metabolized fully  May account for some food intolerances; later stage symptoms - visual field restriction, peripheral neuropathies, ataxia Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207.
In the mitochondria  Pyruvate dehydrogenase complex (PDC)  Governs entry into the TCA/Krebs/Citric acid cycle  Pyruvate to Acetyl-CoA  a-ketoglutarate dehydrogenase (a-KGDH)  Metabolic flux through the TCA, direction and speed of spin  Generates NADH>electrons for ETC  Produces and is susceptible to ROS  Branched chain keto acid dehydrogenase (BCKAD/BCKADH)  Dictates BCAA catabolism  Influences fatty acid metabolism - > increase in inflammatory diacylglycerol and ceramides (hallmarks of metabolic syndrome) Dhir, S., Tarasenko, M., Napoli, E. and Giulivi, C., 2019. Neurological, psychiatric, and biochemical aspects of thiamine deficiency in children and adults. Frontiers in psychiatry, p.207. ↓ ALZ & Parkinson’s Lactate
Insufficient thiamine > metabolic dysfunction  Blocked TKT and PDC > impaired glucose metabolism  Shifts to polyol/sorbitol, hexosamine, diacylglycerol/PKC, AGEs  Micro-vascular damage associated with hyperglycemia  Aging  Increased lactate/poor lactate recycling capacity  Pyruvate cannot enter the TCA  Fatigue, exercise intolerance and a laundry list of other symptoms  When severe lactic acidosis Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus, September 2017 Journal of Atherosclerosis and Thrombosis 25(1); DOI: 10.5551/jat.RV17014; LicenseCC BY-NC-SA 4.0
Even marginally insufficient thiamine wreaks havoc Oxalosis and thiamine  Low TKT = low NADPH  ↓NADPH > ↓ glutathione  ↓ glutathione > poor detox of glyoxal and methylglyoxal ↑ carcinogenic protein adducts  ↓pyridoxal kinase (PK) activity  PK converts inactive B6 (pyridoxine 5-phosphate) into active (pyridoxal 5-phosphate - P5P)  ↓ P5P prevents glyoxylate from being converted back into glycine, leading to high oxalates Shangari, N., Depeint, F., Furrer, R., Bruce, W.R. and O’Brien, P.J., 2005. The effects of partial thiamin deficiency and oxidative stress (ie, glyoxal and methylglyoxal) on the levels of α-oxoaldehyde plasma protein adducts in Fischer 344 rats. FEBS letters, 579(25), pp.5596-5602.
But wait, there’s more INSUFFICIENT THIAMINE INDUCES HYPOXIA NO OBSTRUCTION NEEDED
Thiamine Deficiency Induces Hypoxia  TD downregulates PDC and impairs oxidation and oxygenation  Oxidation: ability to utilize O2 in the mitochondria and efficiently produce ATP  Oxygenation: ability to traffic oxygen (↓arterial O2 saturation/↑venous) – ATP dependent function  Think ‘air hunger’ or the ‘happy hypoxic/hypoxemic’ – at least initially.
↓ PDC stabilizes HIF1a proteins  HIF1a > signals 100s of genes to  Increase angiogenesis, erythropoiesis, and glycolysis - Warburg  HIFs feedback and degrade PDC further  Upregulates pyruvate dehydrogenase kinases – energy spiral  HIFs are stabilized with any hypoxic condition – universal response  Unlike obstructive or exertional, there is plenty of O2, but it cannot be used or trafficked effectively – pseudo-hypoxia  Partly local – cell/mitochondria  Partly neural – brainstem hypoxia > dysautonomic function Watts, M.E., Pocock, R. and Claudianos, C., 2018. Brain energy and oxygen metabolism: emerging role in normal function and disease. Frontiers in molecular neuroscience, 11, p.216.
Another reason SAD is bad  Heavy in seed oils  Upregulates pyruvate dehydrogenase kinases (PDKs) – inactivate PDC  PDKs upregulated in tumor environment  Stabilize HIF1a  Heavy in HFCS  Uses more ATP than it produces  Low in nutrition  Relative to the caloric, toxicant load
And yet more hits to the PDC  Magnesium is required to activate/ phosphorylate thiamine  ~50% of population is deficient  Riboflavin and alpha-lipoic acid required for subunits of PDC  Heavy Metals  Arsenic, mercury block ALA, impairs the PDC, induces HIFs and impairs mitochondrial respiration  Symptoms similar to TD and respond to increased thiamine  Thiamine chelates heavy metals Graphic: Elliot Overton, from: https://www.hormonesmatter.com/why- thiamine-supplementation-requires-magnesium/
Just how important is the PDC? In response to severe stress, the PDC translocates to the cell nucleus.
If thiamine is that important WHY DON’T WE MONITOR IT?
When we think of thiamine deficiency  We only think of late stage, frank deficiency in specific populations with purely neuro symptoms  Beriberi or Wernicke’s encephalopathy in chronic alcoholics  Ataxia, nystagmus, confusion/memory loss  We miss the earlier symptoms in this and other populations  And we mostly miss Wernicke’s too  80% of alcohol related Wernicke’s missed 1  58% of pediatric Wernicke’s missed2  Unknown % of hyperemesis gravidarum Wernicke’s missed  Only 16% cases exhibit classic triad1 1. J Neurol Neurosurg Psychiatry. 1986 Apr;49(4):341-5.; 2. Pediatr Neurol. 1999 Apr;20(4):289-94.
Lonsdale & Marrs, 2017. Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition
We fail to recognize  More subtle, metabolic disturbances  Hyperglycemia and dyslipidemia cascades  Vague, non-specific symptoms that correspond to a long list of disease processes – but at root reflect poor energy capacity  That develops slowly across time and is non-linear  Food is abundant, obesity reigns  Symptoms wax and wane before reaching critical point – just like thiamine intake and the stressors that demand increased thiamine  Brain lesions don’t happen overnight  Or that there is even a problem  We solved nutrient deficiency, didn’t we?
THIAMINE DEFICIENCY WAS SOLVED  Fortification/enrichment eradicated thiamine deficiency in the west  Intake of processed foods provides sufficient thiamine (RDA 1.1 – 1.4mg)  Food intake surveys – only 5% of the population consumes insufficient thiamine  Average American consumes 4X (NIH) Right?
EVERY PUBLISHED STUDY “A severe depletion is not commonly seen, except in cases of inadequate nutrition and/or alcoholism.” “Cardiac beriberi, or heart failure due to thiamine deficiency, is considered rare in the developed world.” “Thiamine deficiency is rare in developed countries and is most commonly associated with chronic alcoholism. The other predisposing conditions include chronic dietary deprivation and impaired absorption or intake of dietary nutrients.” “Nowadays, in the developed world, it is relatively rare.” Suggests TD is rare and limited to certain populations or conditions
IF WE DIG A LITTLE DEEPER  Without processed foods  Over 40% of population does not consume enough thiamine (or other nutrients)  If we look at the research  A large portion of the population is either frankly or functionally deficient  Frank deficiency – lab confirmed  We rarely measure – so how would we know?  And there problems with the labs – see Hiding  Functional deficiency – problems with thiamine or OXPHOS machinery; magnesium deficiency; high consumption/exposure to anti-thiamine factors e.g. modern foods and medications; chronic or severe illness that demands much higher intake of thiamine It’s not rare at all
Especially with hyperglycemia  ‘Healthy’ individuals see a reduction in thiamine beginning at 55% carb intake  Standard American Diet > 55% carbs  Type 1 and 2 diabetics are frequently deficient in thiamine  ~75% lower thiamine than controls  98% diabetics were deficient  ~10% of population is diabetic (NIH) Hyperglycemia increases demand “…prevalence of low plasma thiamine (<70 nmol/L [[23]]) was 98% in the diabetes group with microalbuminuria and 100% in the diabetes group without microalbuminuria and in the control group.”
Just how common is thiamine deficiency?  15-29% of obese patients pre- bariatric surgery, higher post surgery (~49%)  No data on those not seeking surgery  20-50% of community dwelling elderly, 45% of elderly patients in acute care  30% psychiatric patients  20% ER patients (random sample)  10% ICU patients upon admission (small, prospective study)  20% after 3 days  70% if septic  Up to 91% congestive heart failure patients  38% pregnant women  47-63% hyperemesis (likely more, not often measured until WE is present) Quite common, it appears.
WHY THE DISCREPANCY?  We assume it is was solved, so we don’t look for it  We look at intake only and ignore basic kinetics and dynamics  Absorption/transport  Metabolism (activation)  Utilization  We disregard the myriad of anti- thiamine factors or that increased energetic demands require increased intake – e.g. illness
Many roads to thiamine deficiency  Increased dietary demand  Low thiamine relative to sugar intake or toxicant load  Poor absorption  Dysbiosis, dysmotility disorders, leaky gut  Dietary deactivation/inactivation  Alcohol, tobacco, coffee, tea, other common foods  Mg2+ deficiency  Genetic factors  SNPs in transporters or enzymes  Medications & environmental chemicals  Block thiamine transporters, degrade the molecule, increase excretion, or just damage mitochondria (requiring more) Two most common: diet and medications
Common medications that deplete thiamine  Metformin [167]  92 million prescriptions in 2020 (Statista)  Psychiatric medications [168]  13% of adults (CDC)  Metronidazole [169], trimethoprim [170] and other antibiotics  NSAIDs, acetaminophen, and aspirin [172]  Proton pump inhibitors [173]  Diuretics [174]  Chemotherapeutic drugs [175] Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine Deficiency. Cells, 10(10), p.2595.
A key mechanism “Overall, our comprehensive study was able to identify 146 inhibitors of ThTR-2, most of which were not previously known .”
Environmental threats to mitochondrial function “However, although many of these chemicals cause effects other than mitochondrial toxicity, the importance of the mitochondrial effects is in some cases supported by the fact that there is overlap in the pathologies observed after exposures and mitochondrial diseases.”
What does all of this mean?  Thiamine sufficiency is more than just intake  All sorts of threats to thiamine stability  Deficiency is more common than recognized  Lots of folks are walking around with inadequate thiamine  Impairs metabolism of food into energy  Derails the metabolism of fatty acids, proteins and carbohydrates (metabolic syndrome)  Diminishes mitochondrial function and oxidative capacity > forces the switch to glycolysis  Increases hypoxia molecules  Drives inflammation, among other things It doesn’t look like we think it does.
“There is often something sinister about familiar concepts. The more familiar or ‘natural’ they appear, the less we wonder what they mean; but because they are widespread and well-known, we tend to act as if we know what we mean when we use them.” Devisch, I. and Murray, S.J., 2009. ‘We hold these truths to be self‐evident’: deconstructing ‘evidence‐based’medical practice. Journal of evaluation in clinical practice, 15(6), pp.950-954.
Identifying modern thiamine deficiency ITS ALL ABOUT ENERGY – OR LACK THEREOF
What does TD look like?  Depends upon severity and chronicity of the deficiency  Classical descriptions depict later stage deficiency  By the time we get to white matter lesions TD has been chronic and/or severe  TD is a long process with ↑morbidity/↓ mortality  Frequently begins in the gut  With caloric sufficiency/excess, one may live with TD for years before presenting classical symptoms, and may not present with classical symptoms at all  Symptoms may also wax and wane in parallel with periods of thiamine deficiency/sufficiency
A series of studies in the 1930-1940s Looked at TD across time in a female inpatient population. There were 3 studies in total, two with four women each and one with 11 women maintained on a diet of .15mg of thiamine per day for 147 days, .45mg of thiamine for 88 days, and 11 women at ~.15 – .2mg thiamine per day plus 1mg of thiamine given intermittently for up to 196 days, respectively. (RDA is 1.2mg) In the third study, where additional thiamine was provided, when averaged, the total thiamine consumed was ~.175mg per 1000 calories of food or .35mg for a 2000 calorie per day diet. Also, in this study, 5 of the 11 women were maintained on the diet for an undisclosed period before resuming a normal diet, while the remaining 6 were kept on the diet for as long as 196 days. This is approximately 30% of the recommended daily allowance needed to stave off deficiency symptoms and syndromes. https://www.hormonesmatter.com/are-thiamine-deficiency-symptoms-too-narrowly-focused/
Case notes on two women First few weeks: emotional instability, irritability, moodiness, anxiety, agitation, depression, reduced activity, and numerous, often vague, somatic complaints. Weakness and anorexia begin to present. 30 days: anorexia, weight loss, epigastric distress, increasing weakness, periodic vomiting 50 days: nausea and vomiting after meals, progressive weakness from low energy to bedridden, sometimes constipation 70 days: constant nausea, severe weakness, apathy, confusion, numbness, and tingling in extremities 90 days: inability to read or focus, aberrant to absent sensory recognition, tender calves, inability to stand from squatting position, hypoactive Achilles tendon reflex, nausea progresses to regular vomiting after meals 110 days: appetite fails, apathy, vagueness and confusion, low blood pressure and heart rate at rest, rapid increase upon ordinary exertion, aberrant and absent sensory perceptions, aberrant and reduced reflexes, reduced flexion of ankles and knees, ataxia, inability to stand on toes. 120 days: impaired pain perception on legs, loss of patellar and Achilles reflex, weakness in abduction, adduction, and flexion of thighs, weakness in the legs with limited ability to extend legs with quadriceps, inability to stand or walk without support, ankle and knee clonus absent, Babinski response absent. How many of your patients present with some of these symptoms?
Outcome One of these two subjects developed severe neurological defects at 120 days and so the experiment was stopped. The researchers noted that appetite had completely failed and remarked that ‘inanition seemed imminent’. They also remarked that with 60-80mg of thiamine given orally and parenterally many, but not all, of the deficits resolved. Appetite returned and strength was regained within the first week, and within 30 days, the less severely ill of the two women was mostly recovered. At 60 days, one of the women was fully recovered. For the other women, recovery was incomplete, even after 120 days of treatment. Of note, it was the younger and more active woman who suffered the most serious neurological deficits and who was unable to fully recover.
Insights .45mg of thiamine for 88 days “We nevertheless are impressed by the degree of debility induced by the isolated withdrawal of thiamine. Fatigue, lassitude, and loss of interest in food developed early and increased progressively as the period of deficiency extended, to the point of intolerance for food. So great was this intolerance that uncontrollable vomiting, even after tube feeding and parenteral injection of solutions of sodium chloride and dextrose, automatically brought the observations to a close.” “The time of development of symptoms and the time of development of severe symptoms differed among the subjects and seemed to be related to physical activity. The subjects who were more active showed symptoms earlier and were more seriously affected later than others who from the beginning were less energetic.”
WHAT THESE STUDIES TELL US  Even with severe dietary restriction of thiamine  When calories/nutrients maintained, early (and even late) TD symptoms are non-specific  Food intolerance, dysbiosis and dysmotility are signs of TD  More active people affected more quickly and seriously  Hyperglycemia, obesity, sedentary behavior likely masks TD  Symptoms may wax and wane relative to changes in thiamine  When women given extra thiamine after periods of deficiency, recovered, at least temporarily  Recovery takes time
On the wax and wane of symptoms Marrs, C. and Lonsdale, D., 2021. Hiding in Plain Sight: Modern Thiamine Deficiency. Cells, 10(10), p.2595.
Thresholds and tipping points  Time course of cerebral TD relative WE in rodents (ataxia, loss of righting, rigid body arching)  2.5 wks: weight loss, progressive anorexia, hair loss and drowsiness  4.5 wks: rapid progression of symptoms and decline of health over next 5 days with incoordination with walking, impairment of the righting reflex, reluctance to walk, walking backwards in circles, imbalance, rigid posturing and eventually a total loss of righting activity and severe drowsiness  Neuro symptoms became apparent when cerebral thiamine concentrations reached 20% of normal.  Have to lose 80% of cerebral thiamine before WE symptoms become noticeable  Recovery began when concentrations climb to 26% of normal.
HOW LONG DOES IT TAKE TO LOSE 80% OF CEREBRAL THIAMINE AND INDUCE WE IN HUMANS?  With severe and consistent dietary restriction – weeks to months  But with modern diet, thiamine intake varies across time – it may be years before WE symptoms manifest  Poor intake/poor absorption plus excess elimination  Hyperemesis gravidarum: 2-3 weeks (not often tested until 6-8 weeks, if then, after serious brain damage has begun)  Non-pregnant, severe vomiting/diarrhea: 2-3 weeks depending upon other variables  Poor intake with hyper-metabolism of severe illness/injury  ICU – a few days Does the time frame really matter? If thiamine ↑ATP and ATP is needed for everything, shouldn’t we be providing support well before it reaches this point?
What does early TD look like  Mitochondrial in nature – mitochondria fuel everything – wide variety of symptoms  High energy organ systems impacted most dramatically  Nervous system  Cardiovascular system  Gastrointestinal  Musculature  Metabolic changes locally <> systemically  Recall the cell culture study where the heart cells ceased functioning after ~10 days Everything and nothing
Some symptoms • Fatigue, exercise intolerance, decreased wakefulness (orexin/hypocretin neurons) • Cyclic vomiting , gastroparesis, and pseudo bowel obstructions • Myalgia, myopathy, neuropathy • Migraines, seizures, syncope • Ataxia and tremors • Hormone disorders • Depression, mania, anxiety, psychosis • Cognitive impairment • Diabetes, metabolic, inflammatory and immune dysfunction
Biochemistry for Medics: http://www.slideshare.net/n amarta28/thiamin More symptoms
General autonomic instability  Inadequate energy supply to the ANS > inconsistent regulation.  Too much, too little, too soon, too late, too long, too short  Inability to adapt to stress of any kind  Dysautonomia  Even more oddball symptoms
When to consider thiamine  If the patient has a long list of medically unexplained symptoms that don’t quite fit any diagnosis, it’s probably related to poor mitochondrial function and insufficient thiamine.  If the history suggest repeat illnesses, poor healing, diet issues, chronic medication use – it’s probably related to thiamine.  Metabolic syndrome  Persistent fatigue  If the patient has been vomiting or has severe diarrhea, or a severely restricted diet due to food intolerances, they would benefit from thiamine  Pregnancy and especially hyperemesis  Severe illness or injury demanding increased energy to heal, they would likely benefit from thiamine  And any of the conditions listed earlier that have a high rate of thiamine deficiency Rules of thumb In other words, much of the population would benefit from extra thiamine.
“Thiamine deficiency impacts on the most basic survival mechanisms: oxygenation and oxidation. Both oxygenation of the blood and its delivery to the tissues for the process of cellular oxidation are dependent on thiamine. Its deficiency, particularly by its effects on the functions of the limbic system and brainstem, places the ANS front and center. Both endogenous and exogenous signals from the brain to body organs become chaotic, leading to a vast array of symptoms.” Lonsdale & Marrs, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition.
Neurological  Antonio Costantini’s work with Parkinson’s and dystonia patients  Research link  YouTube video library of patients before and after  Using thiamine in Alzheimer’s  Dozens of articles  Clinical trial underway  Huntington’s disease  Thiamine/biotin transporter to SLC19A3  TPK (enzyme that converts free thiamine to TPP) Brain thiamine deficiency without apparent nutritional deficiency “Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.”
How to test  Labs – See Hiding article or book for details  In the office: watch and listen  Too many symptoms, serious, unexplainable decline in health, marked by persistent fatigue  Subtle and not so subtle changes in gait, stability, muscle tone, speech, decrements cognitive or affective acuity or stability  Asymmetrical pulse pressure, postural hyper- or hypotension, general tachycardia (early stage), bradycardia (later stage)  Other irregularities in autonomic function  In the hospital or acute setting  History and severity of illness > ↑ energy demand ↑ need for thiamine  If not deficient on admission, likely to become deficient during stay
How to treat: option 1 Hard and fast  High dose, IV, IM - theory is to kick start downregulated enzymes  Warranted in acute care, with WE, severe neurological symptoms, and where oral intake and/or absorption is problematic  Dependent upon case and clinical experience  Refeeding responses are real and difficult to navigate  Need to manage electrolytes and cofactors esp. those with wet beriberi, affecting the heart  The patient may get worse before getting better – articles on HM  IV multivitamin/mineral useful Dosing ranges  Guidelines vary significantly  IV 100-500 mg 1-3X per day for several days to week followed by oral at a range of doses  Many patients need IV support for months, followed by high dose oral intake indefinitely  IM – Parkinson’s 100mg 2X per week for months followed by 1000-3000mg (thiamine HCL) orally indefinitely – per Costantini’s work.
How to treat: option 2 Low and slow  Start at a low dose and gradually increase over time in stair step fashion  Allows the body to reregulate over time  When IV/IM and regular clinical oversight are not available  ‘Refeeding’ still problematic and can last for weeks to months  The patient may get worse before getting better  Difficult with prolonged GI symptoms Dosing  Dosing varies significantly  Starting dose: from micro-doses, fractions of a mg to 100s of mgs even grams  How long the patient has to stay at each dose before increasing varies  What co-factors and electrolyte support is needed varies  Need a good multi plus good electrolyte support  What formulation of thiamine the patient can handle and respond to varies too
Oral thiamine supplements  Thiamine mononitrate  In cheap OTC vitamins – not recommended  Thiamine HCL (various brands)  Requires a transporter, lower potency, requires much higher dose  At high doses works well with Parkinson’s, CFS; easier to titrate up than TTFD or benfotiamine  Thiamine tetrahydrofurfuryl disulfide (TTFD) - Thiamax, Allithiamine, Lipothiamine  Chemically modified to cross cell barrier, doesn’t require a transporter, higher potency, requires lower dose than HCL  Works for a variety conditions, may be too potent for some to begin with, sometimes problematic for those with sulfur problems, low glutathione and/or high food sensitivities  Benfotiamine  Chemically modified to cross cell barrier, doesn’t require a transporter (different mechanism than TTFD), higher potency, requires lower dose than HCL  Works well for hyperglycemia, seems to be tolerated better by those with GI issues, by children with neurodevelopmental disorders (tastes better than TTFD and can be hidden in foods more easily) Which works best for the patient is highly individual. For info on chemistry of the different supplements see: Elliot Overton’s video.
Cofactors and electrolytes  As thiamine comes on board, it will unmask other deficiencies – usually other B vitamins and/or mineral deficiencies  Magnesium needed for thiamine activation  Potassium will be drawn into the cell more readily – increase intake  Calcium reregulation frequently requires additional Ca2+ , will see this with heart related symptoms, and elevated ‘anxiety’ type symptoms  Cal/Mg - 2/1 supplement typically counters this. See articles on HM.  Low phosphate diets need to be improved or hypophosphatemia  Sodium may need to increased (with POTS, migraine esp.)
Health requires energy ENERGY REQUIRES THIAMINE

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