Thiamine Absorption Research Articles

Antepartum Wernicke’s Encephalopathy: Common, and Yet Rarely Diagnosed. Discussion on the Disease and Its Treatment

This review article presents a comprehensive discussion on antepartum Wernicke’s encephalopathy (WE), a serious neurological disorder. This disorder stems from thiamine (Vitamin B1) deficiency, which is critical for normal metabolism and neuronal integrity. During pregnancy, women are more susceptible to this condition due to increased nutritional requirement and metabolic changes. In WE, inadequate thiamine (Vitamin B1) causes disruption of metabolism in cells and impedes neurotransmitter synthesis in the brain, ultimately causing adverse neural consequences. Key risk factors contributing to antepartum WE include conditions that hinder thiamine absorption or increase metabolic demand, such as hyperemesis gravidarum (intense antepartum vomiting), malnutrition, alcoholism, and post-bariatric surgery states. WE's classic triad of symptoms, confusion, ataxia (loss of balance and coordination), and ophthalmoplegia (occlumotor incoordination), are not commonly seen in antepartum WE. Therefore, diagnosing the disorder in pregnancy is challenging and the condition is often misdiagnosed. Pregnancy symptoms like nausea, vomiting, and fatigue often overlap with WE's presentation, complicating diagnosis and confounding treatment. While magnetic resonance imaging (MRI) can reveal characteristic lesions in brain areas such as the thalamus and mammillary bodies, these may not always appear in early stages, adding further diagnostic difficulty. Effective management of antepartum WE relies on early recognition and timely administration of high-dose thiamine, particularly parenteral administration for affected pregnant women. Prompt treatment is critical to preventing irreversible sequalae, neurological and otherwise in both the woman and the child. Once acute symptoms are managed, transitioning to oral thiamine supplementation is the norm to prevent recurrence and maintain normal thiamine levels. Balanced diet of macro-nutrients and maintaining fluid and electrolyte balance, also plays an essential role in recovery. In severe or treatment-resistant cases, more intensive, prolonged thiamine therapy and regular monitoring of maternal and fetal health are necessary, usually managed by a multidisciplinary medical team. This coordinated care approach aims to prevent recurrence and minimize risks associated with WE. The article emphasizes following clinical guidelines, which recommend regular thiamine monitoring and preventive measures in high-risk pregnancies, to improve maternal and fetal outcomes. By adhering to established protocols, healthcare providers can reduce the likelihood of severe complications associated with WE, ensuring better care and recovery for affected pregnant women. Categories: Pregnancy, Neurology, Nutrition.

Bacterial lipopolysaccharide inhibits free thiamin uptake along the intestinal tract via interference with membrane expression of thiamin transporters 1 and 2.

This study examined the effect of exposure of small and large intestinal epithelial cells to the bacterial lipopolysaccharide (LPS) on uptake of free form of vitamin B1, i.e., thiamin. The intestinal tract encounters two sources of thiamin: diet and the gut microbiota. Absorption of thiamin in both the small and large intestine occurs via a carrier-mediated process that involves thiamin transporters 1 and 2 (THTR-1 and -2). Complementary in vitro (human duodenal epithelial HuTu-80 cells and human colonic epithelial NCM460 cells), in vivo (mice), and ex vivo (human primary differentiated enteroid and colonoid monolayers) models were used. The results showed that exposure to LPS causes a significant inhibition in carrier-mediated [3H]-thiamin uptake by small and large intestinal epithelia, with no change in the levels of expression of THTR-1 and -2 mRNAs and their total cellular proteins. However, a significant decrease in the fractions of the THTR-1 and -2 proteins that are expressed at the cell membranes of these epithelial cells was observed. These effects of LPS appeared to involve a protein kinase A (PKA) signaling pathway as activating this pathway caused a reversal in the inhibition of thiamin uptake and level of expression of its transporters at the cell membrane. These findings demonstrate that exposure of gut epithelia to LPS (a situation that occurs under different pathological conditions) leads to inhibition in thiamin uptake due to a decrease in level of expression of its transporters at the cell membrane that is likely mediated via a PKA signaling pathway. NEW & NOTEWORTHY This study shows that the exposure of gut epithelial cells to bacterial LPS negatively impact the uptake process of the free form of vitamin B1 (i.e., thiamin). This appears to be mediated via suppression in the level of thiamin transporters 1 and 2 (THTR-1 and -2) expression at the cell membrane and involves a protein kinase A (PKA) signaling pathway.

Thiamine status and genes encoding intestinal thiamine transporters and transcription factors in obese subjects

Background and aimsThe inconsistent data on thiamine status in obese subjects necessitates an examination of genes associated with intestinal absorption of thiamine. We aimed to reveal thiamine status in obese subjects and examine the expression of SLC19A2/3 genes encoding thiamine transporters and Sp1 transcription factor. Methods and resultsThirty-five adult obese subjects and 11 healthy controls were included in this cross-sectional study. Small intestine epithelial cells were used for quantitative RT-PCR analysis of the gene expression. The daily thiamine and energy intake were assessed with a food frequency questionnaire. Thiamine phosphate esters were hydrolyzed to free thiamine, and liquid chromatography with a tandem mass spectrometry-based method was used to measure total thiamine in whole blood. Daily energy intake according to body weight and daily carbohydrate intake were not significantly different between groups after adjustment for sex. Although daily thiamine intake was significantly lower in the obesity group (p = 0.015), obese subjects had significantly higher whole blood thiamine levels than controls (44.96 ± 14.6 ng/mL and 33.05 ± 8.6 ng/mL, p = 0.002). There was a significant positive correlation between whole blood thiamine and BMI (r = 0.342, p = 0.020). SLC19A2 gene expression was lower in those with BMI ≥35 kg/m2 (p = 0.036). A significant positive correlation was found between SLC19A2 expression and whole blood thiamine level (r = 0.310, p = 0.038). ConclusionA possible association between intestinal thiamine intake and total thiamine in whole blood was determined. The transcriptional changes of genes encoding the high-affinity membrane thiamine transporters, especially SLC19A2, probably play a role in this relationship.

Effect of the bacterial lipopolysaccharide (LPS) on vitamin B1 (thiamin) uptake along the intestinal tract: inhibition mediated via reduction in level of expression of thiamin transporter-1 & -2 proteins at the cell membrane

Background: LPS is a potent bacterial virulence factor and is a source of considerable clinical morbidity and mortality. This endotoxin is a predominant component of the outer membrane of Gram-negative bacteria. The gut is exposed to high levels of LPS in conditions like Inflammatory Bowel Diseases, necrotizing enterocolitis, sepsis, and following infection with enteric pathogens. Studies have shown that exposure of gut epithelial/other cells to LPS exerts profound and differential effects on membrane transport processes. Nothing, however, is known about the effect of LPS on uptake of free thiamin in the small intestine (where absorption of dietary thiamin occurs), and the large intestine (where absorption of the microbiota-generated thiamin occurs). Aim: To examine the effect of LPS on the small and large intestinal uptake of free thiamin and to determine the mechanism(s) involved. Methods: We used in vitro (human duodenum-derived HuTu 80 cells and colon-derived non-transformed NCM460 cells), ex vivo (human differentiated polarized enteroid and colonoid monolayers), and in vivo (mouse) models in our studies. Uptake studies were performed using 3H-thiamin as substrate. Results: Treating intestinal HuTu 80 and colonic NCM460 epithelial cells with LPS led to a significant inhibition in carrier-mediated 3H-thiamin uptake. Similar results were obtained when human differentiated enteroid and colonoid monolayers ex vivo, and mouse in vivo were treated with LPS. No changes in total cellular levels of thiamin transporter-1 & -2 (THTR-1 and THTR-2, respectively) proteins and mRNAs were observed upon LPS treatments; however, a significant decrease in the fraction of the THTR-1 & THTR-2 proteins that are expressed at the cell membrane were observed. These findings suggest that the LPS inhibitory effect on thiamin uptake in the small and large intestine is likely mediated via a decrease in the fraction of the thiamin transporters that are expressed at the cell membrane. Conclusion: This study shows that bacterial LPS inhibits thiamin uptake along the intestinal tract, and that this inhibition is likely mediated via reduction in level of the THTR-1 & THTR-2 proteins at the cell membrane. Supported by NIH grants DK-56061 and AA-018071, and VA grants 101BX001142 & IK6BX006189. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Vitamin B1 Supplementation Ameliorates Obesogenic Effects of a High Fat Diet in Male Mice

Dietary deficiencies in vitamins such as thiamine (Vitamin B1) are common even in developed countries and can have a range of deleterious health effects. This trend in Vitamin B1 deficiency coincides with increased fat consumption in the American diet, particularly of soybean oil, the most widely consumed cooking oil in the U.S. which is also present in many processed foods. Here, we hypothesized that the concurrent malnutrition caused by a soybean oil-based high fat diet (SO-HFD) and a physiological deficiency in thiamine can exacerbate conditions such as obesity, diabetes, and fatty liver that are associated with consumption of HFDs. To test this, C57BL/6N male mice (N=8-10 per group) were fed either a low-fat chow or an SO-HFD, with or without supplementation with 640 mg/kg of the thiamine analog thiamine tetrahydrofurfuryl disulfide (TTFD), for 18 weeks. Our results showed that the SO-HFD supplemented with TTFD leads to significantly decreased weight gain and delayed the onset of glucose intolerance compared to SO-HFD without added TTFD (p<0.05). In contrast, TTFD supplementation did not have any effect on body weight or glucose intolerance in the context of a low-fat diet. Metabolomic analysis revealed that the SO-HFD decreased absolute thiamine levels both in the blood and liver tissue compared to the low fat control diet (p<0.05); this decrease was reversed by TTFD supplementation suggesting that some of the negative effects of the SO-HFD may be due to its impact on the Vitamin B1 pathway. Untargeted metabolomic analysis identified several other metabolites — such as amino acids, organic acids, methylamine osmolytes and those involved in nucleotide metabolism — that were also affected by TTFD supplementation, but in a beneficial fashion. Transcriptomic analysis of the liver and intestines revealed alterations in thiamine absorption and metabolic pathways by the SO-HFD; effects of TTFD on hepatic gene expression and fatty liver will be presented. TTFD supplementation given after the onset of SO-HFD-induced obesity was not able to reverse the phenotype, suggesting that the deleterious effects of the SO-HFD-induced Vitamin B1 deficiency may be permanent. In conclusion, our findings indicate that consumption of an SO-enriched diet, similar in fat content to what is consumed by most Americans, can result in a Vitamin B1 deficiency. Although TTFD supplementation may mitigate some of the adverse metabolic effects of this diet, this intervention must be done at an early stage. Funding: The Thiamine Advocacy Foundation Research Grant (FMS, PHD, PD); NIH R01DK127082 (FMS)Acknowledgements: UCR Genomics Core Facility, UCR Metabolomics Core Facility, UCR High Performance Computing Center (HPCC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A STUDY OF THIAMINE DEFICIENCY IN PATIENTS WITH ACUTE ONSETENCEPHALOPATHY

Introduction:Vitamin B1, also known as thiamine, and its crucial role in energy metabolism and proper functioning of the nervous and cardiovascular systems. Thiamine is an essential vitamin that must be obtained through diet since the body does not produce it naturally. It is stored in the liver but only lasts for about 18 days. Thiamine is absorbed in the duodenum and transported across the blood-brain barrier. The recommended daily intake varies based on age, health condition, and life stages.Thiamine plays a vital role in various biochemical pathways in the brain, including energy production, lipid metabolism, neurotransmitter synthesis, and synaptic transmission. Thiamine deficiency can have diverse clinical effects, affecting the nervous and cardiovascular systems most severely and potentially leading to death if left untreated.Different thiamine deficiency syndromes are identified, including dry beriberi (peripheral neurologic manifestations), wet beriberi (cardiac effects), gastrointestinal beriberi (digestive symptoms), and Wernickes encephalopathy (neuropsychiatric condition). While alcohol abuse-associated malnutrition is a common cause of Wernickes encephalopathy in developed countries, it can also occur due to other factors such as decreased thiamine absorption, increased body requirements, or thiamine loss in certain medical conditions.Thiamine deficiency is considered a potential public health concern, particularly in communities in South Asia and West Africa, where diets heavily reliant on polished rice or cassava may contribute to the risk. Studies have shown varying prevalence rates of thiamine deficiency in different populations, including healthy adults and pregnant/lactating mothers in South-East Asia and India. While specific population-based studies are lacking in the Kashmiri population, preliminary evidence suggests the presence of thiamine deficiency disorders in infants, peripartum females, and adults with diverse presentations. Objectives: Early detection and treatment of Patients with Encephalopathy related to Thiamine deficiency Study Design/ Methodology:The study was hospital-based and prospective in nature, conducted in the Department of General Medicine, SMHS, GMC - Srinagar from May 2021 to September 2022. The study was done on patients aged more than 18 years of age attending emergency department of Government Medical College, Srinagar with acute onset encephalopathy. Observations And Results:In this study, 96 patients with acute onset encephalopathy were recruited based on CAM score criteria. The patients were divided into two groups: a low thiamine group and a normal thiamine group, based on their whole-blood thiamine levels. Among the patients, 15.6% had normal thiamine levels, while 84.4% had low thiamine levels. The mean thiamine level in the normal thiamine group was 5.46±4.44 ug/dL, and in the low thiamine group, it was 1.35±0.42 ug/dL (p=0.0001). Patients with normal thiamine levels were excluded from further analysis, leaving a group of 84.4% of patients with thiamine deficiency.Within the thiamine deficiency group, patients were further divided into responders and non-responders based on their response to a thiamine challenge. The responders group comprised 17 patients, including 11 males, 6 females (including 3 pregnant females), with a mean age of 36.25±9.44. Non-responders had a mean age of 61.8±15. Among responders, 70.58% had recurrent vomiting compared to 37.5% in non-responders. Confusion was the most common initial presentation in both groups, followed by lethargy. Behavioural changes were seen in a higher percentage of responders compared to non-responders. Ataxia was more prevalent in the responders group.Various laboratory parameters were analyzed between responders and non-responders. There was no significant difference in mean pH, sodium, potassium, total protein, serum albumin, and blood sugar levels between the two groups. However, lactate levels and the drop in lactate following thiamine therapy were higher in responders. Responders had lower levels of serum urea and serum creatinine compared to non-responders.MRI brain findings suggestive of Wernickes encephalopathy were observed in 53% of responders. Polished rice consumption was common among all patients, with 85% of responders and 62% of non-responders consuming polished rice as their main staple diet. Traditional salt tea intake was also prevalent in both groups. Conclusions: Thiamine deficiency can manifest in various clinical scenarios, including recurrent vomiting, hypoxia, electrolyte imbalances (such as hyponatremia and hypernatremia), and systemic diseases like uremia, hepatic encephalopathy, and septic shock. Pregnant women, who experience increased demand and may have thiamine loss due to vomiting, are also at risk of developing thiamine deficiency.The diagnosis of thiamine deficiency is primarily clinical and is confirmed by the response of neurological signs to high-dose intravenous thiamine treatment. MRI is considered the most valuable paraclinical study for diagnosis. Elevated serum lactate levels and the response of lactate to high-dose parenteral thiamine can serve as surrogate markers for thiamine-responsive encephalopathy. It is crucial to administer high doses of parenteral thiamine immediately to patients suspected of having encephalopathy due to thiamine deficiency to prevent complications associated with Wernicke-Korsakoff syndrome.

The Effect of Trimethoprim on Thiamine Absorption: A Transporter-Mediated Drug-Nutrient Interaction.

Trimethoprim is predicted to inhibitseveral thiamine transporters, including the primary thiamine intestinal absorptive transporter, ThTR-2, and the hepatic and renal organic cation transporters, OCT1, OCT2, and MATEs. To investigate the effect of trimethoprim on thiamine absorption, studies were conducted in cells, mice, and healthy volunteers and supported by use of real-world data. In a randomized, crossover clinical study, seven healthy volunteers were given a single oral dose of thiamine or thiamine plus trimethoprim, followed by blood sampling. The thiamine area under the curve (AUC) increased with trimethoprim co-administration (P value = 0.031). Similar results were seen in mice. Trimethoprim appeared to act on thiamine absorption through inhibition of hepatic OCT1 as evidenced from its ability to modulate levels of isobutyrylcarnitine and propionylcarnitine, OCT1 biomarkers identified from metabolomic analyses. Real-world data further supported this finding, showing an association between trimethoprim use and higher levels of triglycerides, LDL cholesterol, and total cholesterol, consistent with OCT1 inhibition (P values: 2.2 × 10-16 , 5.75 × 10-7 , and 5.82 × 10-7 , respectively). These findings suggest that trimethoprim increases plasma levels of thiamine by inhibiting hepatic OCT1. Trimethoprim reduced urinary excretion and clearance of biomarkers for OCT2 and MATEs, consistent with inhibition of renal organic cation transporters. This inhibition did not appear to play a role in the observed increases in thiamine levels. This study highlights the potential for drug-nutrient interactions involving transporters, in addition to transporters' established role in drug-drug interactions.

Wernicke-Korsakoff Syndrome in pregnancy: a preventable complication (P4-4.005)

<h3>Objective:</h3> NA <h3>Background:</h3> Wernicke’s Encephalopathy (WE) is classically a triad of encephalopathy, ophthalmoplegia and gait ataxia resulting from thiamine (B1) deficiency. MRI shows symmetric white matter hyperintensities in the mammillary bodies, bilateral thalami, tectal plate and periaqueductal gray matter. WE is commonly associated with chronic alcohol use; however it can develop in any condition that limits intake or absorption of thiamine, including pancreatitis. Although rare, a number of cases of hyperemesis gravidarum in pregnancy leading to WE have been reported, however comorbid pancreatitis and progression to Korsakoff in this population have not. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 29-year-old woman of 11-weeks gestation, with multiple prior admissions for hyperemesis gravidarum and pancreatitis, was admitted for management of acute pancreatitis with a serum lipase over one-thousand. Her family initially noted symptoms of apathy, abulia, and cognitive changes which they ascribed to possession by a djinn (demon or spirit), according to an ethnomedical belief system. She also developed ataxia, identified by her family as a biomedical symptom, for which they sought medical care. Patient and her family speak Soninke, a Gambian dialect initially unavailable on hospital translation services. These factors delayed recognition of the patient’s clinical picture. Neurology was consulted on hospital day three for altered mentation, exam was notable for direction changing nystagmus, abulia, and somnolence. MRI showed a pattern typical in WE as well as cortical hyperintensities in the perirolandic cortex. Intravenous high dose thiamine improved patient’s abulia, but she continues to have residual retrograde and anterograde amnesia consistent with Korsakoff psychosis. <h3>Conclusions:</h3> Pregnant women are uniquely vulnerable to thiamine deficiency. Prompt IV thiamine repletion should be considered in hyperemesis or acute pancreatitis. Language barriers and ethnomedical beliefs can be concurrent with biomedical beliefs and limit communication and delay clinical diagnosis resulting in poor patient outcomes. <b>Disclosure:</b> Mr. Morris has nothing to disclose. Dr. Amirkhanashvili has nothing to disclose. Dr. Bhatia has nothing to disclose. Dr. Fields has nothing to disclose. Dr. Adsule has nothing to disclose. Dr. Haut has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nile AI. Dr. Haut has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB.

Metronidazole Induced Encephalopathy Responsive to High Dose Thiamine (P4-12.006)

<h3>Objective:</h3> NA <h3>Background:</h3> Metronidazole induced encephalopathy (MIE) is a complication of prolonged metronidazole use whose clinical and radiographic signs are well-documented. Metronidazole is generally a well-tolerated antibiotic but can rarely cause neurotoxicity in susceptible individuals. We report on a patient who developed MIE that did not initially resolve with metronidazole discontinuation, but which responded dramatically to high dose intravenous (IV) thiamine supplementation. <h3>Design/Methods:</h3> A 60-year-old woman developed confusion and gait disturbance two weeks prior to admission. She had presented to an outside hospital with colitis one month prior and was treated with a 28-day course of IV ciprofloxacin and metronidazole, along with TPN. She had developed confusion and dystaxia after initiation of IV antibiotics that persisted after metronidazole discontinuation, and which led her to return to hospital. Neurologic exam revealed confusion and dystaxia. Given the recent TPN use, a thiamine level was drawn, and she was treated empirically with thiamine 500mg IV daily. MRI brain revealed restricted diffusion of the splenium of corpus collosum and increased T2-signal of the bilateral dentate nuclei. After two doses of IV thiamine, her dystaxia and confusion improved, and she regained her neurologic baseline. The diagnosis of MIE complicated by thiamine deficiency was made. Her thiamine level in serum resulted as normal. <h3>Results:</h3> na <h3>Conclusions:</h3> The patient’s MRI brain revealed classic changes of MIE yet she did not improve after cessation of metronidazole as described in previously reported cases. Rather, she improved after treatment with high dose thiamine. Metronidazole acts as a thiamine analogue and inhibits the absorption of thiamine leading to a functional deficiency state. We hypothesize that metronidazole, in the context of the patient’s suspected malnutrition, led to a severe functional thiamine deficiency, despite having a normal thiamine serum level. This case highlights the importance of thiamine repletion in addition to metronidazole discontinuation when MIE is suspected. <b>Disclosure:</b> Dr. Matta has nothing to disclose. Dr. Reza has nothing to disclose. Dr. Bagert has nothing to disclose.

In Vivo Evaluation of Thiamine Hydrochloride with Gastro-Retentive Drug Delivery in Healthy Human Volunteers Using Gamma Scintigraphy

A floating tablet system containing thiamine hydrochloride, a model drug with a narrow absorption window, was evaluated. The tablet was found to have a floating lag time of less than 30 s with a sustained drug release over 12 h during in vitro dissolution studies. The gastro-retentive property of the tablet in relation to the bioavailability of thiamine was determined in healthy human volunteers using gamma scintigraphy under fasted and fed conditions. The gastro-retentive time of the floating tablet could be prolonged up to 10 h under the fed state, compared to about 1.8 h in the fasted state. The prolonged gastric retention under the fed state resulted in a 2.8-fold increase in oral bioavailability of thiamine compared to that of the fasted state. There was also a 1.4-fold increase in thiamine absorption compared to that of a conventional immediate release tablet in the fed state. In the fasted state, the extent of thiamine absorption from the floating tablet was only about 70% of that absorbed from the immediate release tablet. Thus, to achieve a better performance, such floating tablet systems should be administered under a fed condition, to prolong the gastric retention time.

Acute Dizziness Treated With Thiamine Supplement: A Case of Wernicke Encephalopathy

Wernicke encephalopathy (WE) is an uncommon but severe neurological disorder caused by thiamine (vitamin B1) deficiency. It is characterized by the sudden onset of altered consciousness, ophthalmoplegia, and ataxia. Apart from chronic alcoholism, a lot of other conditions causing malnutrition and decreasing thiamine absorption must be considered as predisposing factors. Due to its low prevalence and clinical heterogeneity, WE is often misdiagnosed, resulting in persistent dysfunctions or death. Therefore, early diagnosis and prompt treatment with intravenous thiamine supplement might prevent encephalopathy and other neurologic or systemic complications of thiamine depletion. We hereby report of our experience of a WE patient who presented with predominantly vestibular symptoms and signs; the patient was successfully diagnosed and treated with high-dose intravenous thiamine repletion.

Central pontine myelinolysis as a consequence of hyperemesis gravidarum: A case report

Few cases of central pontine mielinolysis (CPM) are reported in the literature, mainly linked to hyperemesis gravidarum which may cause incorrect absorption of thiamine. In this report we described the case of CPM in a 17 weeks pregnant woman with hyperemesis gravidarum.

Ontogenetic Dietary Changes and Thiamine Status of Lake Ontario Chinook Salmon, 2005–2006

AbstractIn the Great Lakes, an Alewife Alosa pseudoharengus diet has been reported to cause thiamine deficiency in salmonines as a result of high thiaminase activity. The ontogeny of thiamine deficiency and its relationship to Alewife consumption have not been determined in Chinook Salmon Oncorhynchus tshawytscha within this system. Using stable isotope mixing models along with muscle thiamine, we assessed ontogenetic changes in the diet and corresponding muscle thiamine status of Lake Ontario Chinook Salmon ranging in TL from 100 to 1,000 mm. Thiamine levels were highest in young of the year collected in a tributary of Lake Ontario but declined once Chinook Salmon entered Lake Ontario. In Lake Ontario, the diets of juvenile (200–400 mm; 97–99%) and adult (&gt;400 mm; 97–100%) Chinook Salmon consisted almost entirely of Alewives as estimated using mixing models. This Alewife diet was associated with an ontogenetic decline in muscle thiamine among Chinook Salmon. The asymptotic decline in thiamine concentration with increasing size plateaued at 720–758 pmol/g of muscle. The proportion of individuals below a thiamine threshold of 500 pmol/g (associated with a loss of equilibrium) increased with TL up to 799 mm and then declined between 800 and 1,000 mm. At these muscle concentrations, no outward signs of thiamine deficiency were observed. Calculation of total mass accumulation of body stores of thiamine (muscle concentration times body weight) showed an unexpected and significant increase with size. Although it appears that dietary Alewives affected thiamine status, there were undetermined factors, such as incomplete destruction of thiamine by thiaminase, gut synthesis of thiamine, gill absorption of water thiamine, and/or other factors, that contributed to the overall thiamine status of these Chinook Salmon.

Case Series of Potential Wernicke's Encephalopathy in Patients Treated with Fedratinib

Introduction:In the phase III study, JAKARTA I, the JAK2 inhibitor, fedratinib, elicited responses in 47% (400mg) and 50% (500mg) of patients with intermediate 2 or high risk myelofibrosis (MF). In JAKARTA II, 53% of MF patients who were resistant and 63% of patients who were intolerant to ruxolitinib responded to fedratinib, indicative of clinical benefit for the majority of patients not responding to standard therapy. Fedratinib development was discontinued after the FDA placed a clinical hold on November 15, 2013 as a result of neurological symptoms, suggestive of Wernicke's encephalopathy (WE) in 8 of 670 subjects, exposed to fedratinib.WE develops in the setting of thiamine deficiency and is typified by diplopia, ataxia, confusion and characteristic brain MRI findings. Confirming a diagnosis of WE is complicated by comorbidities in patients with myeloproliferative neoplasms (MPN) including a high incidence of stroke, hepatic encephalopathy secondary to hepatic extramedullary hematopoiesis or sepsis related to marrow failure in an elderly population. While autopsy studies indicate that rates of WE range from 0.8-2.8% of the general population, the incidence in MPN patients is reportedly 3-fold higher. WE can be diagnosed based on clinical signs and specific MRI findings; prevented by ensuring that nutritional status is not exacerbated by nausea and vomiting; and treated with thiamine.To evaluate the epidemiology of potential WE subjects treated with fedratinib, we conducted a retrospective analysis of the 8 fedratinib-treated subjects. Patient demographics, clinical signs together with thiamine levels, when available, and MRI scans were evaluated to determine the likelihood of WE and elucidate contributory factors by an independent expert panel.Results:Eight patients (1 male, 7 females) from 7 countries and 5 fedratinib trials were identified. Median age was 69.1 years (IQR 67-71). Of these patients, 6 had MF, 1 had polycythemia vera and 1 had metastatic head and neck cancer. Based on retrospective analysis of clinical reports, thiamine levels and MRI results the data was either inconclusive or not supportive of WE in three patients, one of which likely had hepatic encephalopathy. Of the remaining 5 patients, 1 clearly had WE, 2 likely had WE, and 2 had inconclusive diagnosis. All potential WE patients had preceding protracted nausea and vomiting suggesting this as a contributing factor to malnutrition and thiamine deficiency.Concerning the 3 subjects thought to have WE: one was severely malnourished and refused gastrostomy during study suggesting malnutrition as a cause of thiamine deficiency. The two other likely WE patients had preceding sustained nausea and vomiting with recovery from neurological deficits while continuing fedratinib treatment suggesting fedratinib did not inhibit thiamine uptake. Consistent with that, mean patient thiamine levels from 161 patients available at end of treatment were normal and in vitro experiments in the presence of human serum show fedratinib at physiologically achievable levels does not inhibit thiamine transport.The two other patients that may have had WE had preceding nausea and vomiting; one developed neurological symptoms while not on drug and the other developed disseminated metastases, including an edematous brain metastases, preceding neurological symptoms confounding the diagnosis.Conclusion:Across 9 fedratinib trials enrolling 670 MPN or solid tumor patients between 3 to 5 patients experienced WE (0.4-0.7%). The overall prevalence of WE observed was less than published levels for a patient population of this size. For the 5 potential WE patients, one subject had malnutrition related to protracted nausea and vomiting as well as clinical signs and MRI findings consistent with WE. Additionally, 2 other subjects likely experienced WE, both of which recovered without a dose interruption suggesting fedratinib does not inhibit thiamine absorption. The remaining 2 had an unclear diagnosis with 2 of 3 experts believing the data were either inconclusive or not supportive of WE. Notably, one of the patients was not on fedratinib at the time of neurological symptoms. In total, these data suggest that fedratinib does not increase the risk of thiamine deficiency beyond its potential to exacerbate malnutrition through poor management of preventable GI adverse events. DisclosuresHarrison:Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy; CTI: Speakers Bureau. Mesa:Galena Biopharma, Inc.: Consultancy; Promedico: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Gilead Sciences, Inc.: Research Funding; Incyte Corporation: Research Funding; Ariad: Consultancy. Hood:Impact Biomedicines, Inc.: Employment, Equity Ownership. Bykowski:Impact Biomedicines, Inc.: Consultancy, Honoraria. Zuccoli:Impact Biomedicines, Inc.: Consultancy, Honoraria. Brewer:Elan: Other: Advisory Board; Bristol-Myers Squibb: Other: Advisory Board; Avanir: Other: Advisory Board; Novartis: Other: Advisory Board; Genentech: Other: Advisory Board; Eli Lilly: Other: Advisory Board; CorTechs Labs, Inc.: Equity Ownership; Human Longevity, Inc.: Equity Ownership.

PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. MethodsSynthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. ResultsWe succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 μSv/MBq (range 5.2–5.7). ConclusionNovel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

Oral benfotiamine reverts cognitive deficit and increase thiamine diphosphate levels in the brain of a rat model of neurodegeneration.

It is well known that patients with Alzheimer's disease (AD) have imbalances in blood thiamine concentrations and lower activity of thiamine-dependent enzymes. Benfotiamine, a more bioavailable thiamine analog, has been proposed as an alternative to counteract these changes related to thiamine metabolism. Thus, our study aimed to analyze the effects of benfotiamine supplementation on brain thiamine absorption, as well as on parameters related to neuronal energy metabolism and disease progression in an experimental model of sporadic AD induced by intracerebroventricular injection of streptozotocin (STZ) in rats. The supplementation with 150 mg/kg of benfotiamine for 30 days increased the concentrations of thiamine diphosphate in the hippocampus and entorhinal cortex. This led to an improvement in mitochondria enzymes and insulin signaling pathway, with inactivation of GSK3α/β and ERK1/2, which are two tau-kinases related to the progression of AD, which could decrease tau hyperphosphorylation and apoptosis signaling. Besides, we observed an increased amount of Glun2b subunit of NMDA receptors, decreased inflammation, and improvement of cognitive deficit. Together, these results suggest that benfotiamine could be a potential therapeutic approach in the treatment of sporadic AD.

Thiamine Deficiency in People with Obesity (P18-060-19)

ObjectivesThiamine (vitamin B1) and other micronutrient deficiencies are commonly observed after bariatric surgery. However, there is evidence that patients with obesity may be deficient in thiamine even before surgery, possibly due to metabolic changes following recent weight loss or decreased intake through dietary restriction. Type II diabetes may also adversely affect thiamine absorption and increase urinary thiamine losses, placing patients with this condition at increased risk of deficiency. The purpose of this research is to (1) determine the prevalence of thiamine deficiency in patients at a bariatric surgery clinic and compare this across type II diabetes status, race, and gender; and (2) determine the relationship between recent weight loss and thiamine deficiency. MethodsThis is a retrospective observational study of patients with obesity who were evaluated at the preoperative bariatric surgery clinic at the Washington, DC VA Medical Center between January 1, 2012 and April 1, 2018. Patients who had prior bariatric surgery, current or recent history of alcohol abuse, current use of diuretics or vitamin supplements, or for whom no thiamine test was ordered were excluded. All patients had a BMI of 31.7–49.0 kg/m2. Thiamine deficiency was defined as a test value below the reference range. Weight data were collected at the initial evaluation and up to four months prior. ResultsOf 155 clinic patients, 107 met all inclusion criteria. Thiamine deficiency was found in 36 (33.6%) patients. Chi-square tests did not show any differences in prevalence between patients with type II diabetes and those without, or by gender or race. Preliminary logistic regression analyses indicated that the odds of thiamine deficiency were 14% higher per % increase in recent weight loss (OR = 1.14, 95% CI: 1.01–1.29). ConclusionsApproximately one third of those evaluated at the bariatric surgery clinic were found to have a test result indicating thiamine deficiency. This suggests that people with obesity, especially those engaging in weight loss efforts, may benefit from additional nutritional screening. Funding SourcesNone.

Thiamine status, metabolism and application in dairy cows: a review.

As the co-enzyme of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, thiamine plays a critical role in carbohydrate metabolism in dairy cows. Apart from feedstuff, microbial thiamine synthesis in the rumen is the main source for dairy cows. However, the amount of ruminal thiamine synthesis, which is influenced by dietary N levels and forage to concentrate ratio, varies greatly. Notably, when dairy cows are overfed high-grain diets, subacute ruminal acidosis (SARA) occurs and results in thiamine deficiency. Thiamine deficiency is characterised by decreased ruminal and blood thiamine concentrations and an increased blood thiamine pyrophosphate effect to >45 %. Thiamine deficiency caused by SARA is mainly related to the increased thiamine requirement during high grain feeding, decreased bacterial thiamine synthesis in the rumen, increased thiamine degradation by thiaminase, and decreased thiamine absorption by transporters. Interestingly, thiamine deficiency can be reversed by exogenous thiamine supplementation in the diet. Besides, thiamine supplementation has beneficial effects in dairy cows, such as increased milk and component production and attenuated SARA by improving rumen fermentation, balancing bacterial community and alleviating inflammatory response in the ruminal epithelium. However, there is no conclusive dietary thiamine recommendation for dairy cows, and the impacts of thiamine supplementation on protozoa, solid-attached bacteria, rumen wall-adherent bacteria and nutrient metabolism in dairy cows are still unclear. This knowledge is critical to understand thiamine status and function in dairy cows. Overall, the present review described the current state of knowledge on thiamine nutrition in dairy cows and the major problems that must be addressed in future research.

PET Imaging Analysis of Vitamin B1 Kinetics with [11C]Thiamine and its Derivative [11C]Thiamine Tetrahydrofurfuryl Disulfide in Rats.

Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart. Positron emission tomography (PET) imaging with [11C]thiamine and [11C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography. Accumulation of [11C]TTFD was significantly higher than that of [11C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15min after the injection of [11C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [11C]thiamine-injected group. PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [11C]thiamine and [11C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

66-Year-Old Woman With Falls and Confusion

66-Year-Old Woman With Falls and Confusion