Subclinical thiamine deficiency: What is the most appropriate method of diagnosis and treatment?

OBJECTIVES: The symptoms of thiamine deficiency vary considerably and asymptomatic cases; i.e., subclinical thiamine deficiency (SCTD), are known to exist. However, there is no information available on the treatment of SCTD. METHODS: We report a patient who underwent intravenous thiamine replacement therapy for about a month after being diagnosed with SCTD, but who developed SCTD again about three weeks after finishing the treatment. RESULTS: The patient was a 64-year-old woman who, after starting treatment for cervical cancer, complained of anxiety and underwent an initial psychiatric examination. The psychiatric diagnosis was an adjustment disorder. Based on the possibility of SCTD complications due to her decreased appetite and weight loss, her serum thiamine concentration was measured and found to be low. Therefore, thiamine was administered intravenously for 29 days. At the end of treatment, thiamine administration was discontinued as there were no apparent neuropsychiatric symptoms or problems with appetite. Twenty-three days later, there were still no problems with appetite or neuropsychiatric symptoms, but a follow-up blood sample revealed that her serum thiamine was again below the normal range. SIGNIFICANCE OF RESULTS: Currently, there is no information available regarding the diagnosis and treatment of SCTD in cancer patients. In some cases, such as this case, the deficiency recurs without any symptoms indicative of SCTD; therefore, further examination for diagnosis and treatment is necessary.

Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

Prevalence and Improvement of Caine-Positive Wernicke-Korsakoff Syndrome in Psychiatric Inpatient Admissions.

BACKGROUND: Wernicke-Korsakoff Syndrome (WKS) resulting from thiamine deficiency is classically defined as including encephalopathy, ataxia, and ophthalmoplegia. Only 16% of autopsy-confirmed patients with WKS exhibit all three signs. Caine-positive WKS criteria include two or more of the following: nutritional deficiency, delirium or mild memory impairment, cerebellar dysfunction/ataxia, and oculomotor abnormalities. OBJECTIVE: We describe Caine-positive WKS prevalence among psychiatric inpatients and compare pretreatment-versus-posttreatment neurocognitive improvement to an unaffected group. METHODS: This 6-month quality-improvement evaluation included two-stage screening for Caine-positive WKS, administering high-dose intravenous thiamine (day 1: 1200 mg; days 2-4: 200 mg) with reexamination on day 5. We used descriptive statistics and fitted random effects models to examine rate-of-change differences in pre-/posttreatment Montreal Cognitive Assessment (MoCA), delayed 5-item recall, and gait/coordination scores between treated Caine-positive patients with WKS and untreated Caine-negative patients. RESULTS: Of 262 patients, 32 (12%) had Caine-positive WKS; 17 (53%) used alcohol currently. Treated Caine-positive WKS (n = 26) versus Caine-negative comparison (n = 34) before and after treatment observed a mean change (standard deviation) in the MoCA score of 3.6 (2.5) versus 1.8 (2.5) (P < 0.01); 5-item recall: 1.8 (1.4) versus 0.5 (1.4) (P < 0.001); gait/coordination scores: -0.6 (1.2) versus -0.1 (0.6) (P < 0.001). Oculomotor abnormalities were infrequent (n = 4 in Caine-positive WKS, n = 2 in Caine-negative comparison groups). CONCLUSIONS: Caine-positive WKS prevalence among psychiatric inpatients was 12%; only half used alcohol. Patients treated with high-dose thiamine demonstrated clinically significant neurocognitive improvement.

Thiamine deficiency observed in a cancer patient's caregiver.

OBJECTIVE: Thiamine deficiency (TD) is recognized in various kinds of disease with associated loss of appetite including cancer; however, TD has not been recognized in the family caregivers of cancer patients to date. METHOD: From a series of cancer patient caregivers, we reported an aged family caregiver who developed TD while caring for the cancer patient. RESULT: The caregiver was a 90-year-old male. He had been accompanying his wife, who was diagnosed with colon cancer 4 years previously, on hospital visits as the primary caregiver, but because of psychological issues, he was recommended to visit the psycho-oncology department's "caregiver's clinic" for a consultation. Detailed examination revealed that his appetite had been only about 50% of usual from about one year before, and he had lost 12 kg in weight in one year. The diagnosis of TD was supported by his abnormally low serum thiamine level. SIGNIFICANCE OF THE RESULTS: This report demonstrates that there is a possibility that care providers could develop TD from the burdens associated with caregiving. TD should be considered whenever there is a loss of appetite lasting for more than 2 weeks, and medical staff should pay careful attention to the physical condition of care providers to prevent complications resulting from TD.

[Thiamine-responsive megaloblastic anemia or Rogers syndrome: A literature review]. / L'anémie mégaloblastique thiamine dépendante ou syndrome de Rogers : une revue de la littérature.

Thiamine-responsive megaloblastic anemia (TRMA), also known as Rogers syndrome, is a rare autosomal recessive disease characterized by three main components: megaloblastic anemia, diabetes mellitus and sensorineural deafness. Those features occur in infancy but may arise during adolescence. Diagnosis relies on uncovering genetic variations (alleles) in the SLC19A2 gene, encoding for a high affinity thiamine transporter. This transporter is essentially present in hematopoietic stem cells, pancreatic beta cells and inner ear cells, explaining the clinical manifestations of the disease. Based on a multidisciplinary approach, treatment resides on lifelong thiamine oral supplementation at pharmacological doses, which reverses anemia and may delay development of diabetes. However, thiamine supplementation does not alleviate already existing hearing defects.

The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: A systematic review.

The WHO 2016 report indicates that worldwide obesity is rising, with over 600 million people in the obese range (BMI>30). The recommended daily calorie intake for adults is 2000 kcal and 2500 kcal for women and men respectively. The average American consumes 3770 kcal/day and the average person in the UK consumes 3400 kcal/day. With such increased caloric intake, there is an increased load on metabolic pathways, in particular glucose metabolism. Such metabolism requires micronutrients as enzyme co-factors. The recommended daily allowance (RDA) for thiamine is 1.3 mg/day and 0.5 mg thiamine is required to process 1000 kilocalories (kcal). Therefore, despite the appearance of being overfed, there is now increasing evidence that the obese population may nutritionally depleted of essential micronutrients. Thiamine deficiency has been reported to be in the region of 16-47% among patients undergoing bariatric surgery for obesity. Thiamine, in turn, requires magnesium to be in its active form thiamine diphosphate, (TDP). TDP also requires magnesium to achieve activation of TDP dependent enzymes, including transketolase (TK), pyruvate dehydrogenase (PDH) and alpha-keto glutaric acid dehydrogenase (AKGDH), during metabolism of glucose. Thiamine and magnesium therefore play a critical role in glucose metabolism and their deficiency may result in the accumulation of anaerobic metabolites including lactate due to a mismatch between caloric burden and function of thiamine dependent enzymes. It may therefore be postulated that thiamine and magnesium deficiency are under-recognized in obesity and may be important in the progress of obesity and obesity related chronic disease states. The aim of the present systematic review was to examine the role of thiamine dependent enzymes in obesity and obesity related chronic disease states.

Prevalence and predictors of postoperative thiamine deficiency after vertical sleeve gastrectomy.

BACKGROUND: As the vertical sleeve gastrectomy (VSG) becomes increasingly popular, its effect on postoperative micronutrient levels, such as thiamine, becomes more important. We previously found a 1.8% prevalence of thiamine deficiency in bariatric patients before surgery. OBJECTIVE: The aims of this study were to determine the prevalence of thiamine deficiency at our center after VSG and to explore possible predictors of postoperative thiamine levels. SETTING: University hospital, United States. METHODS: A retrospective chart review was performed on 147 bariatric patients between 18- and 65-years old who underwent VSG between April 2011 and February 2015. Demographic characteristics, preoperative body mass index (BMI), obesity-associated co-morbidities, alcohol intake, smoking habits, insurance type, calendar year of the procedure, occurrence of postoperative complications, and compliance with postoperative nutrition and follow-up appointment guidelines were extracted from clinical charts. We defined thiamine deficiency as<78 nM on any lab draw within 1 year after the VSG. The χ2, Fisher exact, and Mann-Whitney U tests, and multivariate logistic regression models were created to analyze the association of the above factors with thiamine deficiency after a VSG. RESULTS: Of 147 patients, 105 met inclusion criteria and were analyzed, of whom 27 (25.7%) had thiamine deficiency. Overall median age was 42 years (interquartile ratio: 36, 49). The majority of patients were either African Americans or Caucasian (47.6% and 44.8%, respectively), female (77.1%), and compliant with vitamins (81.0%). The overall mean preoperative BMI was 46.4 kg/m2. Patients with thiamine deficiency were more likely to be African American (66.7%, P = .024), have a larger preoperative BMI (P = .026), and to report repetitive episodes of nausea (59.3%, P = .002) and vomiting (44.4%, P = .001) at any of their postoperative appointments within 1 year after surgery. Compliance with vitamins did not differ between those with or without thiamine deficiency (70.4%, 84.6%, P = .10). After controlling for all factors, African American race (odds ratio [OR] 3.9, P = .019), higher preoperative BMI (OR 1.13, P = .001), nausea (OR 3.81, P = .02), and vomiting (OR 3.49, P = .032) were independent risk factors for the development of thiamine deficiency. CONCLUSIONS: We found an alarmingly high prevalence of thiamine deficiency in postoperative SG patients. This disorder may have serious consequences including Wernicke encephalopathy; hence, it is important to identify predictive demographic, postoperative, and behavioral factors so that appropriate measures can be taken to prevent thiamine deficiency in VSG patients.

Thiamine deficiency contributes to synapse and neural circuit defects

BACKGROUND: The previous studies have demonstrated the reduction of thiamine diphosphate is specific to Alzheimer's disease (AD) and causal factor of brain glucose hypometabolism, which is considered as a neurodegenerative index of AD and closely correlates with the degree of cognitive impairment. The reduction of thiamine diphosphate may contribute to the dysfunction of synapses and neural circuits, finally leading to cognitive decline. RESULTS: To demonstrate this hypothesis, we established abnormalities in the glucose metabolism utilizing thiamine deficiency in vitro and in vivo, and we found dramatically reduced dendrite spine density. We further detected lowered excitatory neurotransmission and impaired hippocampal long-term potentiation, which are induced by TPK RNAi in vitro. Importantly, via treatment with benfotiamine, Aß induced spines density decrease was considerably ameliorated. CONCLUSIONS: These results revealed that thiamine deficiency contributed to synaptic dysfunction which strongly related to AD pathogenesis. Our results provide new insights into pathogenesis of synaptic and neuronal dysfunction in AD.

Wernicke Encephalopathy in Adolescents After Bariatric Surgery: Case Report and Review.

Roughly 1% of all weight loss surgery is performed in adolescents. There is strong evidence demonstrating significant postsurgical weight loss, improvement in quality of life, and reduction in comorbidities such as hypertension and diabetes. Reports of postoperative complications in adolescents are few because of the small sample size in most series. Despite vitamin supplementation, nutritional deficiencies requiring hospitalization occur occasionally after Roux-en-Y gastric bypass. Wernicke encephalopathy, a triad of ophthalmoplegia, ataxia, and altered mental status, is a serious consequence of thiamine (vitamin B1) deficiency. Few cases of Wernicke encephalopathy after weight loss surgery have been reported in the literature and even fewer in the pediatric population. Here we describe a teenage girl who develops vomiting after Roux-en-Y gastric bypass and presented with nystagmus, irritability, and ataxia. The clinical presentation, diagnosis, and treatment of Wernicke encephalopathy in adolescents after bariatric surgery are discussed.

Differential cortical neurotrophin and cytogenetic adaptation after voluntary exercise in normal and amnestic rats.

Voluntary exercise (VEx) has profound effects on neural and behavioral plasticity, including recovery of CNS trauma and disease. However, the unique regional cortical adaption to VEx has not been elucidated. In a series of experiments, we first examined whether VEx would restore and retain neurotrophin levels in several cortical regions (frontal cortex [FC], retrosplenial cortex [RSC], occipital cortex [OC]) in an animal model (pyrithiamine-induced thiamine deficiency [PTD]) of the amnestic disorder Wernicke-Korsakoff syndrome. In addition, we assessed the time-dependent effect of VEx to rescue performance on a spontaneous alternation task. Following 2-weeks of VEx or stationary housing conditions (Stat), rats were behaviorally tested and brains were harvested either the day after VEx (24-h) or after an additional 2-week period (2-wk). In both control pair-fed (PF) rats and PTD rats, all neurotrophin levels (brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF], and vascular endothelial growth factor) increased at the 24-h period after VEx in the FC and RSC, but not OC. Two-weeks following VEx, BDNF remained elevated in both FC and RSC, whereas NGF remained elevated in only the FC. Interestingly, VEx only recovered cognitive performance in amnestic rats when there was an additional 2-wk adaptation period after VEx. Given this unique temporal profile, Experiment 2 examined the cortical cytogenetic responses in all three cortical regions following a 2-wk adaptation period after VEx. In healthy (PF) rats, VEx increased the survival of progenitor cells in both the FC and RSC, but only increased oligodendrocyte precursor cells (OLPs) in the FC. Furthermore, VEx had a selective effect of only recovering OLPs in the FC in PTD rats. These data reveal the therapeutic potential of exercise to restore cortical plasticity in the amnestic brain, and that the FC is one of the most responsive cortical regions to VEx.

Thiamine deficiency induces oxidative stress in brain mitochondria of Mus musculus.

The present investigation evaluates the changes in the levels of antioxidant enzymes, lipid peroxidation (LPO), and protein carbonyl content (PCC) in brain mitochondria following thiamine deficiency (TD). The study was carried out on Mus musculus allocated into three groups, namely control and thiamine-deficient group for 8 (TD 8) and 10 (TD 10) days. The LPO was measured in terms of reduced glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). Antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured biochemically. A significant increase in the TBARS (p < 0.0001) and PCC (p < 0.001) levels in group II (TD 8) and group III (TD 10) animals was observed in comparison to controls. The GSH levels were found to be reduced in both the treated groups compared to the control. A significant reduction in the activities of SOD was also observed in group II (p < 0.01) and group III (p < 0.0001) animals in comparison to the control. Enzymatic activities of CAT (p < 0.001) and GPx (p < 0.05) were found to be significantly reduced in group III (TD 10) in comparison to the control. In conclusion, reduction in the activities of antioxidant enzymes as well as an increase in LPO and PCC following TD implies oxidative stress in brain mitochondria that may further leads to neurodegeneration.

HIF1-α-mediated gene expression induced by vitamin B1 deficiency.

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

Nystagmus: an uncommon neurological manifestation of thiamine deficiency as a serious complication of sleeve gastrectomy.

Wernicke encephalopathy--a debilitating acute or subacute neurological disorder-is caused by a deficiency in thiamine (vitamin B(1)). It is characterized by a classical clinical triad of symptoms: ocular impairment, cerebellar dysfunction, and confusion. Although bariatric surgery can certainly improve the overall health of an obese individual, it can also make him or her more susceptible to serious nutrition deficiencies. Following surgery, inadequate caloric intake, rapid and excessive weight loss, food intolerance, lack of adherence to nutrition supplementation, and/or the onset of prolonged vomiting can lead to severe nutrition deficiencies. It is generally believed that the more malabsorptive the surgery proves, the more likely is it that such a deficiency will occur. The case presented here shows that after sleeve gastrectomy (SG), a patient may also develop dangerous nutrition deficits that can negatively affect his or her life. In this particular case, a patient presented with a severe vitamin B(1) deficiency following SG for morbid obesity. Although patients may exhibit pathophysiologies similar to Wernicke encephalopathy after this surgery, only 2 cases of severe vitamin B(1) deficiency following sleeve gastrectomy have been reported. The grave consequences of thiamine deficiency observed in this patient underscore the importance of supplementation after SG.

Loss of astrocytic glutamate transporters in Wernicke encephalopathy.

Wernicke encephalopathy (WE), a neurological disorder caused by thiamine deficiency (TD), is characterized by structural damage in brain regions that include the thalamus and cerebral cortex. The basis for these lesions is unclear, but may involve a disturbance of glutamatergic neurotransmission. We have therefore investigated levels of the astrocytic glutamate transporters EAAT1 and EAAT2 in order to evaluate their role in the pathophysiology of this disorder. Histological assessment of the frontal cortex revealed a significant loss of neurons in neuropathologically confirmed cases of WE compared with age-matched controls, concomitant with decreases in alpha-internexin and synaptophysin protein content of 67 and 52% by immunoblotting. EAAT2 levels were diminished by 71% in WE, with levels of EAAT1 also reduced by 62%. Loss of both transporter sites was confirmed by immunohistochemical methods. Development of TD in rats caused a profound loss of EAAT1 and EAAT2 in the thalamus accompanied by decreases in other astrocyte-specific proteins. Treatment of TD rats with N-acetylcysteine prevented the downregulation of EAAT2 in the medial thalamus, and ameliorated the loss of several other astrocyte proteins, concomitant with increased neuronal survival. Our results suggest that (1) loss of EAAT1 and EAAT2 glutamate transporters is associated with structural damage to the frontal cortex in patients with WE, (2) oxidative stress plays an important role in this process, and (3) TD has a profound effect on the functional integrity of astrocytes. Based on these findings, we recommend that early treatment using a combination of thiamine AND antioxidant approaches should be an important consideration in cases of WE.

Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells.

To clarify the mechanism of yokukansan (TJ-54), a traditional Japanese medicine, against glutamate-mediated excitotoxicity, the effects of TJ-54 on glutamate uptake function were first examined using cultured rat cortical astrocytes. Under thiamine-deficient conditions, the uptake of glutamate into astrocytes, and the levels of proteins and mRNA expressions of glutamate aspartate transporter of astrocytes significantly decreased. These decreases were ameliorated in a dose-dependent manner by treatment with TJ-54 (100-700 microg/ml). The improvement of glutamate uptake with TJ-54 was completely blocked by the glutamate transporter inhibitor DL-threo-beta-hydroxyaspartic acid. Effects of TJ-54 on glutamate-induced neuronal death were next examined by using cultured PC12 cells as a model for neurons. Addition of 17.5 mM glutamate to the culture medium induced an approximately 50% cell death, as evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. TJ-54 (1-1000 microg/ml) inhibited the cell death in a dose-dependent manner. Furthermore, competitive binding assays to glutamate receptors showed that TJ-54 bound potently to N-methyl-D-aspartate receptors, in particular, to its glutamate and glycine recognition sites. These results suggest that TJ-54 may exert a neuroprotective effect against glutamate-induced excitotoxicity not only by amelioration of dysfunction of astrocytes but also by direct protection of neuronal cells.

Neurologic complications of gastric bypass surgery for morbid obesity.

BACKGROUND: The number of bariatric procedures is rapidly growing as the prevalence of obesity in the USA is increasing. Such procedures are not without complications, and those affecting the nervous system are often disabling and irreversible. We now describe our experience with these complications and review the pertinent literature. METHODS: We describe 26 patients with major neurologic conditions that seemed causally related to bariatric surgery encountered in the neurology service of a tertiary referral university medical center over a decade. RESULTS: The neurologic complications affected most regions of the nervous system: encephalopathy, optic neuropathy, myelopathy, polyradiculoneuropathy, and polyneuropathy. Myelopathy was the most frequent and disabling problem; symptoms began about a decade after surgery. Encephalopathy and polyradiculoneuropathy were acute and early complications. Except for vitamin B(12) and copper deficiencies in patients with myelopathy, we could not correlate specific nutritional deficiencies to the neurologic complications. All patients had multiple nutritional deficiencies, but their correction did not often yield dramatic results. The best result was achieved in one patient after surgical revision to reduce the bypassed jejunum. CONCLUSIONS: A wide spectrum of serious neurologic conditions may follow bariatric surgery. These complications may occur acutely or decades later.