Alimentary Pharmacology & Therapeutics | 2021
Letter: future studies of high‐dose thiamine should consider whether its effects on fatigue are related to the inhibition of carbonic anhydrase isoenzymes
Abstract
EDITORS, In confirming the efficacy of high-dose thiamine for patients with quiescent IBD, Bager et al have added critical rigor to an emerging body of research on high-dose thiamine and laid the groundwork for future research.1 Costantini et al previously published case studies documenting the apparent benefits of high-dose thiamine in relieving fatigue for patients with other conditions, including multiple sclerosis,2 fibromyalgia3 and Parkinson’s disease.4 In addition to further studies in patients with IBD, I would encourage randomised studies to assess the benefits of high-dose thiamine for these conditions, as well as myalgic encephalomyelitis/chronic fatigue syndrome and the neurological manifestations of Ehlers-Danlos syndrome, which are also characterised by marked fatigue. Bager et al suggested that high-dose thiamine works by facilitating the passive transport of thiamine in cases where the active transport mechanism is defective. In addition to studying this intriguing hypothesis, I would encourage consideration of the alternative hypothesis that the effects of high-dose thiamine are due to its role as a carbonic anhydrase inhibitor. In an in vitro study, Özdemir et al found that thiamine inhibited three carbonic anhydrase isoenzymes nearly as well as acetazolamide.5 Based on the pharmacokinetics of oral thiamine hydrochloride,6 it appears that the amounts of thiamine taken by subjects in the study by Bager et al roughly match those needed to inhibit at least two of these isoenzymes. The inhibition of carbonic anhydrase isoenzymes by high-dose thiamine and the resulting production of carbon dioxide could lead to reductions in fatigue and other symptomatic improvement through one or more of four potential pathways: (a) by reducing intracranial hypertension and/or ventral brainstem compression; (b) by increasing blood flow to the brain; (c) by facilitating aerobic cellular respiration and lactate clearance through the Bohr effect7; or (d) by dampening the pro-inflammatory Th-17 pathway,8 again through the Bohr effect, potentially mediated by reductions in hypoxia-inducible factor 1.9 Research is needed to assess whether high-dose thiamine inhibits carbonic anhydrase isoenzymes as well in vivo as suggested by Özdemir et al’s in vitro study. If so, there could potentially be applications in which thiamine might substitute for acetazolamide, reducing patient side effects. Such a finding would also suggest cautions that should be applied to the ongoing administration of high-dose thiamine, including the monitoring of electrolytes and kidney function. Finally, I would recommend that future research considers which specific sub-components of fatigue are alleviated by thiamine, such as general tiredness, difficulty with physical exertion or post-exertional malaise. It would also be useful to examine the effects of high-dose thiamine on other symptoms, including visual and mental acuity (commonly called “brain fog”), which might be responsive to reductions in intracranial hypertension.