Thiamine: An indispensable regulator of paediatric neuro-cardiovascular health and diseases.

The sustainable developmental goals emphasize good health, reduction in preventable neonatal and under-five mortalities, and attaining zero hunger. However, South Asian countries report a higher incidence of neonatal and under-five mortalities when compared to the Western world, many of which are attributed to maternal and perinatal micronutrient deficiencies. Isolated nutrient deficiency in the absence of calorie deficit poses a diagnostic challenge since such deficiencies present with acute multisystemic and enigmatic manifestations. Thiamine (vitamin B1) is a micronutrient of prime importance which exerts indispensable roles in energy metabolism. Deficiency of thiamine can lead to catastrophic consequences. This review provides insight into the biochemical actions of thiamine in energy metabolism, the compromised aerobic metabolism resulting from thiamine deficiency, and the crucial role of thiamine in the proper functioning of the nervous, cardiovascular, and immune systems. The review also explores the acute life-threatening consequences of thiamine deficiencies in neonates and infants and the speculative role of thiamine in other pathologies like encephalopathy, sepsis, and autism spectrum disorders. However, routine assessment of thiamine in pregnant women and neonates is yet to be implemented, due to the lack of affordable and automated diagnostic techniques, and the cost-intensive nature of mass spectrometry-based quantification. CONCLUSION: Physicians are recommended to have a low threshold for suspecting thiamine deficiency especially in vulnerable populations. Laboratory diagnosis of thiamine deficiency needs to be implemented as a standard of care, especially in endemic regions. Further, public health policies on food fortification, mandatory supplementation, and surveillance are imperative to eliminate thiamine deficiency-induced health hazards. WHAT IS KNOWN: • South Asian countries report a higher incidence of neonatal and under-five mortalities, many of which are attributed to maternal and perinatal micronutrient deficiencies. • Preventable causes of neonatal/ infantile deaths include birth factors (low birth weight, birth asphyxia), infectious diseases (pneumonia, diarrhoea, tetanus, tuberculosis, measles, diphtheria, malaria, acute infections), deficiency diseases and genetic diseases (vitamin & mineral deficiencies, IEMs, congenital heart disease, unexplained PPHN, SIDS etc). WHAT IS NEW: • Acute thiamine deficiency presenting as multisystemic syndromes, has unfortunately been a long standing unresolved public health concern. However, accessible surveillance and diagnostic strategies remain elusive in most clinical settings. • Despite decades of reports and emerging guidelines, diagnosis of thiamine deficiency is often missed and policy mandates at national level are yet to be implemented even in endemic countries. • This review provides a comprehensive summary of the biochemical role of thiamine, its key functions and effects on major organ systems, the diagnostic gap, the enigmatic presentation of acute thiamine deficiency, the plausible role of thiamine in other pathologies and the preventive measures at individual and community level.

Thiamine deficiency: a commonly unrecognised but easily treatable condition.

Thiamine is present in many foods and is well recognised as an essential nutrient critical for energy metabolism. While thiamine deficiency is commonly recognised in alcoholism, it can present in many other settings where it is often not considered and goes unrecognised. One challenging aspect to diagnosis is that it may have varied metabolic, neurological and cardiac presentations. Here we present an overview of the disorder, focusing on the multiple causes and clinical presentations. Interestingly, thiamine deficiency is likely increasing in frequency, especially among wildlife, where it is linked with changing environments and climate change. Thiamine deficiency should be considered whenever neurological or cardiological disease of unknown aetiology presents, especially in any patient presenting with lactic acidosis.

Wernicke encephalopathy and beriberi disease presenting as STEMI-equivalent.

Thiamine deficiency is commonly associated with malnutrition, alcoholism and bariatric surgery. Thiamine deficiency can manifest in different ways, especially in developing countries: as peripheric neuropathy, as Wernicke encephalopathy or as beriberi disease. The authors present the case of a 72-year-old male, with a hiatal hernia that led to thiamine deficiency due to malnutrition. The initial clinical manifestation was an ST-elevation myocardial infarct equivalent, an ECG with a shark-fin pattern that evolved to a Wellens type B pattern. The patient evolved with severe altered mental status. A Wernicke encephalopathy diagnosis was confirmed by MRI; the patient was medicated with high-dose thiamine, with quick recovery, both neurologic and cardiac. The clinical history and response to treatment confirm the diagnosis of Wernicke encephalopathy and beriberi disease.

Nonalcoholic Wernicke-Korsakoff Syndrome Resulting From Psychosis.

ABSTRACT: Wernicke encephalopathy (WE) results from thiamine deficiency. If undiagnosed or inadequately treated, WE evolves into Korsakoff syndrome (KS). We herein report a case of nonalcoholic Wernicke-Korsakoff syndrome (WKS) that resulted from malnutrition due to psychosis in a 42-years-old male patient. Thiamine deficiency was secondary to severe malnourishment due to poisoning delusions and daily life disorganization in a patient with previously unrecognized schizophrenia. Besides the presence of WE's classic triad of signs, brain magnetic resonance imaging showed also typical thalamic lesions. Furthermore, the patient also presented anterograde and retrograde amnesia, executive dysfunction, and confabulations, compatible with KS being already present. Intravenous treatment with thiamine was given for 37 days. Improvement in cognitive functions and brain imaging alterations was evident. Nevertheless, persistent WKS deficits were present. This case highlights the multiplicity of etiologies of WKS, namely, psychiatric, and its debilitating consequences if not promptly recognized and treated.

Missing the early signs of thiamine deficiency. A case associated with a liquid-only diet.

BACKGROUND: Wernicke encephalopathy (WE) predominantly occurs in alcoholic patients. Few case reports have described this diagnosis as a result of dieting. The diagnosis is often missed or delayed resulting in permanent and severe neurologic sequelae and even death. The typical neurological signs may be absent or missed during the early stages of thiamine deficiency. CASE REPORT: A 23-year-old female presented to the hospital with confusion, bilateral lateral rectus palsy, and ataxia. Based on the typical neurological triad, WE was suspected. The brain MRI was also typical for WE. Prompt clinical improvement was seen within days after intravenous thiamine supplementation. A detailed medical history revealed that during the past 3 months she had been following a liquid-only diet and had lost about 30 kg. During that time, she had visited the emergency department on multiple occasions due to fatigue, nausea, and vomiting. CONCLUSION: A high level of suspicion is required by physicians to recognize that fatigue, nausea, and vomiting may represent early signs of thiamine deficiency in patients at risk for nutritional deficiencies. Empirical thiamine supplementation may be reasonable in such cases.

Does thiamine protect the brain from iron overload and alcohol-related dementia?

Alcohol-related dementia (ARD) is a common and severe co-morbidity in alcohol use disorder (AUD). We propose brain iron overload (BIO) to be an important and previously neglected pathogenic process, accelerating cognitive decline in AUD. Furthermore, we suggest thiamine, which is frequently depleted in AUD, to be a key modulator in this process: Thiamine deficiency impairs the integrity of the blood-brain barrier, thereby enabling iron to pass through and accumulate in the brain. This hypothesis is based on findings from animal, translational, and neuroimaging studies, discussed in this article. To validate this hypothesis, translational studies focusing on brain iron homeostasis in AUD, as well as prospective clinical studies investigating prevalence and clinical impact of BIO in AUD, should be conducted. If proven right, this would change the understanding of ARD and may lead to novel therapeutic interventions in prevention and treatment of ARD.

Acute Shoshin beriberi syndrome immediately post-kidney transplant with rapid recovery after thiamine administration.

Pediatric kidney transplant surgery is usually well tolerated, despite suboptimal physical conditioning that may result from uremia and nutritional deficiencies that accompany end-stage kidney failure. Nutritional supplementation is used to overcome such deficiencies, especially for children needing dialysis. Thiamine, a water-soluble vitamin also known as vitamin B1, is a critical cofactor in energy metabolism and may be competitively inhibited by the antimetabolite oxythiamine, a uremic toxin that accumulates in kidney failure. We report a case of a thiamine deficiency syndrome leading to overwhelming cardiac dysfunction, metabolic instability, and hemodynamic compromise, after otherwise uneventful kidney transplant surgery. Prior to transplant, this 14-year-old boy was treated with peritoneal dialysis and received thiamine supplementation. Post-transplant, the patient first developed hyperglycemia, then lactic acidosis, and subsequently hemodynamic instability despite escalating treatment with volume resuscitation and inotropic medication. He made a rapid and complete recovery after administration of IV thiamine. This is the first reported case of Shoshin beriberi syndrome in a pediatric kidney transplant recipient. Inadequate dialysis may have been a key factor, with toxin accumulation and thiamine transporter downregulation contributing to his status. Functional thiamine deficiency should be considered as a potential treatable cause of early post-transplant hemodynamic instability.

Mechanisms of Non-coenzyme Action of Thiamine: Protein Targets and Medical Significance.

Thiamine (vitamin B1) is a precursor of the well-known coenzyme of central metabolic pathways thiamine diphosphate (ThDP). Highly intense glucose oxidation in the brain requires ThDP-dependent enzymes, which determines the critical significance of thiamine for neuronal functions. However, thiamine can also act through the non-coenzyme mechanisms. The well-known facilitation of acetylcholinergic neurotransmission upon the thiamine and acetylcholine co-release into the synaptic cleft has been supported by the discovery of thiamine triphosphate (ThTP)-dependent phosphorylation of the acetylcholine receptor-associated protein rapsyn, and thiamine interaction with the TAS2R1 receptor, resulting in the activation of synaptic ion currents. The non-coenzyme regulatory binding of thiamine compounds has been demonstrated for the transcriptional regulator p53, poly(ADP-ribose) polymerase, prion protein PRNP, and a number of key metabolic enzymes that do not use ThDP as a coenzyme. The accumulated data indicate that the molecular mechanisms of the neurotropic action of thiamine are far broader than it has been originally believed, and closely linked to the metabolism of thiamine and its derivatives in animals. The significance of this topic has been illustrated by the recently established competition between thiamine and the antidiabetic drug metformin for common transporters, which can be the reason for the thiamine deficiency underlying metformin side effects. Here, we also discuss the medical implications of the research on thiamine, including the role of thiaminases in thiamine reutilization and biosynthesis of thiamine antagonists; molecular mechanisms of action of natural and synthetic thiamine antagonists, and biotransformation of pharmacological forms of thiamine. Given the wide medical application of thiamine and its synthetic forms, these aspects are of high importance for medicine and pharmacology, including the therapy of neurodegenerative diseases.

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.

Vitamin B1 Deficiency Related to Excessive Soft Drink Consumption in Japan.

The aim of this study was to clarify the picture of vitamin B1 deficiency (VB1D) caused by excessive soft drink consumption in Japan. A nationwide survey of children with soft drink-induced VB1D was conducted using a structured research form. Patient information was obtained from 2 sources: training hospitals for board-certified pediatricians and those identified by a database search. We obtained data from 33 children. Twenty-one children had a nonnurturing home environment. The median duration of excessive soft drink intake was 3.5 months and the daily intake was 1000 mL or more in 25 children. Infection was the most common reason for excessive soft drink consumption. Only 4 children had the classical triad of Wernicke encephalopathy. One child died, and 12 had neurological sequelae. A majority of children with soft drink-induced VB1D did not have a nurturing home environment. It is imperative to establish measures to prevent future cases of VB1D.

A review of micronutrients in sepsis: the role of thiamine, l-carnitine, vitamin C, selenium and vitamin D.

Sepsis is defined as the dysregulated host response to an infection resulting in life-threatening organ dysfunction. The metabolic demand from inefficiencies in anaerobic metabolism, mitochondrial and cellular dysfunction, increased cellular turnover, and free-radical damage result in the increased focus of micronutrients in sepsis as they play a pivotal role in these processes. In the present review, we will evaluate the potential role of micronutrients in sepsis, specifically, thiamine, l-carnitine, vitamin C, Se and vitamin D. Each micronutrient will be reviewed in a similar fashion, discussing its major role in normal physiology, suspected role in sepsis, use as a biomarker, discussion of the major basic science and human studies, and conclusion statement. Based on the current available data, we conclude that thiamine may be considered in all septic patients at risk for thiamine deficiency and l-carnitine and vitamin C to those in septic shock. Clinical trials are currently underway which may provide greater insight into the role of micronutrients in sepsis and validate standard utilisation.

Attitudes of pediatricians toward Children's consumption of ionic beverages.

BACKGROUND: The aim of our study was to clarify the attitudes of pediatricians toward children's consumption of ionic beverages. METHODS: A questionnaire survey of pediatric practitioners' attitudes toward the consumption of ionic beverages was administered to 537 doctors under 60 years of age who were members of the Japanese Pediatric Society. RESULTS: We received 215 valid responses from 182 board-certified pediatric specialists and 31 non-specialists. Approximately 60% of respondents recommended ionic beverages either often or sometimes. About half of all respondents cautioned patients about excessive consumption. About 40% had experienced at least one instance of excessive consumption characterized by acute symptoms including vomiting, diarrhea, and pyrexia. Specialists were more likely to recommend ionic beverages for oral rehydration than did non-specialists. Non-specialists more often recommended ionic beverages to patients with pyrexia. CONCLUSIONS: Pediatricians' attitudes toward children's consumption of ionic beverages were generally appropriate. Pediatric specialists' attitudes were more appropriate than were those of non-specialists.

Adaptive regulation of pancreatic acinar mitochondrial thiamin pyrophosphate uptake process: possible involvement of epigenetic mechanism(s).

The essentiality of thiamin stems from its roles as a cofactor [mainly in the form of thiamin pyrophosphate (TPP)] in critical metabolic reactions including oxidative energy metabolism and reduction of cellular oxidative stress. Like other mammalian cells, pancreatic acinar cells (PAC) obtain thiamin from their surroundings and convert it to TPP; mitochondria then take up TPP by a carrier-mediated process that involves the mitochondrial TPP (MTPP) transporter (MTPPT; product of SLC25A19 gene). Previous studies have characterized different physiological/biological aspects of the MTPP uptake process, but little is known about its possible adaptive regulation. We addressed this issue using pancreatic acinar 266-6 cells (PAC 266-6) maintained under thiamin-deficient (DEF) and oversupplemented (OS) conditions, as well as thiamin-DEF and -OS transgenic mice carrying the SLC25A19 promoter. We found that maintaining PAC 266-6 under the thiamin-DEF condition leads to a significant induction in mitochondrial [3H]TPP uptake, as well as in the level of expression of the MTPPT protein and mRNA compared with thiamin-OS cells. Similar findings were observed in mitochondria from thiamin-DEF mice compared with thiamin-OS. Subsequently, we demonstrated that adaptive regulation of MTTP protein was partly mediated via transcriptional mechanism(s) via studies with PAC 266-6 transfected with the SLC25A19 promoter and transgenic mice carrying the SLC25A19 promoter. This transcriptional regulation appeared to be, at least in part, mediated via epigenetic mechanism(s) involving histone modifications. These studies report, for the first time, that the PAC mitochondrial TPP uptake process is adaptively regulated by the prevailing thiamin level and that this regulation is transcriptionally mediated and involves epigenetic mechanism(s).NEW & NOTEWORTHY Our findings show, for the first time, that the mitochondrial thiamin pyrophosphate (MTPP) uptake process is adaptively regulated by the prevailing thiamin level in pancreatic acinar cells and this regulation is mediated, at least in part, by transcriptional and epigenetic mechanism(s) affecting the SLC25A19 promoter.

Unpeeling the Evidence for the Banana Bag: Evidence-Based Recommendations for the Management of Alcohol-Associated Vitamin and Electrolyte Deficiencies in the ICU.

OBJECTIVE: Patients with a chronic alcohol use disorder presenting to the ICU may be deficient in important vitamins and electrolytes and are often prescribed a "banana bag" as a reflexive standard of therapy. The difficulty of diagnosing Wernicke's encephalopathy in the critical care setting is reviewed. Furthermore, whether the contents and doses of micronutrients and electrolytes in standard banana bags meet the needs of critically ill patients with an alcohol use disorder is assessed based on available evidence. DATA SOURCE: MEDLINE/PubMed (1966 to June 2015) database search, the Cochrane Database of Systematic Reviews, and manual selection of bibliographies from selected articles. STUDY SELECTION AND DATA EXTRACTION: Articles relevant to Wernicke's encephalopathy, vitamin and electrolyte deficiencies in patients with alcohol use disorders, and alcoholic ketoacidosis were selected. Articles were narratively synthesized for this review. DATA SYNTHESIS: Of these deficiencies, thiamine is the most important for the practicing clinician to assess and prescribe replacement in a timely manner. Based on a pharmacokinetic assessment of thiamine, the banana bag approach likely fails to optimize delivery of thiamine to the central nervous system. Folic acid and magnesium may also merit supplementation although the available data do not allow for as strong a recommendation as for prescribing thiamine in this setting. There is no available evidence supporting the prescription of a multivitamin. CONCLUSIONS: Based on the published literature, for patients with a chronic alcohol use disorder admitted to the ICU with symptoms that may mimic or mask Wernicke's encephalopathy, we suggest abandoning the banana bag and utilizing the following formula for routine supplementation during the first day of admission: 200-500 mg IV thiamine every 8 hours, 64 mg/kg magnesium sulfate (approximately 4-5 g for most adult patients), and 400-1,000 µg IV folate. If alcoholic ketoacidosis is suspected, dextrose-containing fluids are recommended over normal saline.

Wernicke Encephalopathy and Sleeve Gastrectomy: A Case Report and Literature Review.

As the number of obese patients increases, as will the number of bariatric procedures. Malabsorptive bariatric procedures have emerged as one of common causes of Wernicke encephalopathy (WE), an acute neuropsychiatric disorder due to thiamine deficiency. However, restrictive procedures such as sleeve gastrectomy (SG) are less prone to cause nutrient deficiencies. WE occurred after SG is an uncommon complication because the main absorptive sites for thiamine are intact after SG. Here, we report a case of WE after SG. With rapid increase in the use of SG for morbid obesity, this case deserves particular attention from clinicians.

DYSMICROBISM, INFLAMMATORY BOWEL DISEASE AND THYROIDITIS: ANALYSIS OF THE LITERATURE.

The human body is colonized by a large number of microbes that are collectively referred to as the microbiota. They interact with the hosting organism and some do contribute to the physiological maintenance of the general good health thru regulation of some metabolic processes while some others are essential for the synthesis of vitamins and short-chain fatty acids. The abnormal variation, in the quality and/or quantity of individual bacterial species residing in the gastro-intestinal tract, is called “dysmicrobism”. The immune system of the host will respond to these changes at the intestinal mucosa level which could lead to Inflammatory Bowel Diseases (IBD). This inflammatory immune response could subsequently extend to other organs and systems outside the digestive tract such as the thyroid, culminating in thyroiditis. The goal of the present study is to review and analyze data reported in the literature about thyroiditis associated with inflammatory bowel diseases such as Ulcerative Colitis (UC) and Crohn’s Disease (CD). It was reported that similarities of some molecular bacterial components with molecular components of the host are considered among the factors causing IBD through an autoimmune reaction which could involve other non-immune cell types. The axis dysmicrobism-IBD-autoimmune reaction will be investigated as a possible etiopathogenic mechanism to Autoimmune Thyroiditis. If such is the case, then the employment of specific probiotic strains may represent a useful approach to moderate the immune system.

Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: a pilot study.

OBJECTIVE: Thiamine deficiency has been documented in adults with diabetes and in a single report of reversible encephalopathy in a child with diabetic ketoacidosis. In children who present with severe diabetic ketoacidosis, one of the most serious complications is cerebral edema of which the primary symptom may be encephalopathy. Thiamine deficiency in other disease states has been clearly linked with acute encephalopathy, but there are no data on thiamine status in children with diabetic ketoacidosis. This study describes the prevalence of thiamine deficiency in children with type 1 diabetes mellitus who present with diabetic ketoacidosis and are admitted to the ICU. DESIGN: A prospective observational pilot study. SETTING: PICU in a tertiary care children's hospital. PATIENTS: Children 2-18 years admitted to the ICU for treatment of diabetic ketoacidosis. INTERVENTIONS: Treatment of diabetic ketoacidosis. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients were enrolled. The mean age was 13.7 ± 3.6 years. Five of 21 patients (23.8%) had thiamine deficiency prior to insulin administration. After 8 hours of insulin therapy, seven of 20 patients (35%) had thiamine deficiency, and four of these seven patients also had thiamine deficiency at presentation. Sixty-eight percent of patients had a decrease in thiamine levels after 8 hours of insulin therapy, with a mean fall of 20 ± 31.4 nmol/L. CONCLUSIONS: Thiamine deficiency is common in children with diabetic ketoacidosis, and this deficiency may be worsened by treatment. When metabolic acidosis persists despite appropriate treatment of diabetic ketoacidosis, other factors such as thiamine deficiency should be considered.

Nerve Fiber Layer Infarcts in Thiamine Deficiency.

Thiamine deficiency classically manifests as the triad of Wernicke encephalopathy: acute confusional state, ataxic gait, and ocular motor dysfunction. However, most patients do no present with this classic triad. Optic neuropathy in thiamine deficiency is a rare manifestation and is usually associated with fundus appearances of optic disc swelling or optic disc pallor. We present 2 unique cases of thiamine deficiency where the fundus demonstrated peripapillary retinal nerve fiber layer thickening without florid disc swelling or pallor.

A Therapeutic Fast for Lymphoma Resulting in Wernicke Encephalopathy.

BACKGROUND: Wernicke encephalopathy is an acute neurological emergency caused by thiamine (vitamin B1) deficiency. The syndrome is associated with a significant morbidity and mortality, and prompt recognition and treatment of the syndrome in the emergency department (ED) is essential to improving patient outcomes. Numerous factors and clinical settings have been identified that predispose a patient to thiamine deficiency and subsequent Wernicke encephalopathy. CASE REPORT: We present the rare case of a 42-year-old man with a recent diagnosis of non-Hodgkin lymphoma who opted against chemotherapy in favor of a 60-day therapeutic water-only fast. On day 53 of his fast, the patient arrived to our ED in a coma and respiratory failure. Moments after the administration of thiamine, the patient's mental status and respiratory status improved significantly. Prior to admission and transport to the medical intensive care unit, the patient was awake, alert, and following basic commands. He was ultimately diagnosed with Wernicke encephalopathy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: With the increasing incidence of patients choosing alternative medical therapies to treat a variety of diseases, numerous electrolyte, metabolic, and nutritional disorders are becoming increasingly more common in the ED setting. In some cases, patients may choose a therapeutic fast in an effort to combat a malignancy; the danger being that patients with cancers such as lymphoma are already at risk for thiamine deficiency as a result of the increased thiamine consumption associated with rapid cellular turnover. Wernicke encephalopathy is a life-threatening neurological emergency, and the emergency physician must be aware of the numerous predisposing factors to the condition, as early identification and treatment improves patient outcomes.