Serum thiamine is not a reliable indicator of overall thiamine levels in the body, as only 0. Thiamine deficiency may result from inadequate dietary intake, administration of total parenteral nutrition without adequate vitamin replacement, impaired intestinal absorption, small intestinal bacterial overgrowth, 40 , 41 genetic metabolic diseases, 42 increased losses of thiamine or increased physiological requirements, or consumption of antithiamine factors, antacids, sulfites, or sodium bicarbonate food preservatives.
Risk factors for decreased thiamine intake include protracted vomiting, bariatric or gastrointestinal surgery, malnutrition, hyperemesis gravidarum, anorexia, and alcoholism. Examples of foods that can lead to inadequate thiamine intake upon prolonged consumption include sago, cassava flour, unfortified white bread, or highly refined cereals such as polished white rice.
The consumption of a diet composed mainly of refined carbohydrates or one that includes high alcohol intake also reduces body thiamine stores. To attain maximal erythrocyte transketolase activity, at least 0. Most humans will develop symptoms of thiamine deficiency when intake is below 0.
Whole wheat flour contains 0. Adding baking powder sodium bicarbonate to wholemeal flour when baking bread reduces the thiamine content. Washing white rice in water prior to cooking reduces the thiamine content by half. Thiamine is heat labile, chlorine sensitive, and water soluble, so discarding the rice water after cooking or using chlorinated water for cooking or washing rice contributes to thiamine loss from the diet.
Rice parboiling distributes the thiamine content from the bran and aluerone layer to the endosperm prior to milling. This is why beriberi is rare in India, where parboiled rice is the primary form of rice consumed. After , mechanical roller milling of wheat and polishing of rice became widespread. Consumption of mass-produced, polished white rice as the staple diet in East Asian countries led to epidemics of beriberi polyneuritis endemica in the s and s.
Mandatory fortification of wheat flour with the thiamine mononitrate vitamer was introduced in Australia in Since then, Wernicke-Korsakoff syndrome has become very uncommon in Australia. The thiamine mononitrate vitamer is used because it is non-hygroscopic and more stable than thiamine hydrochloride. Folate deficiency may indirectly contribute to thiamine deficiency, as folate is required for the regeneration of reduced nicotinamide adenine dinucleotide NADH by dihydrofolate reductase.
Antithiamine factors include thiaminases, mycotoxins, thiamine antagonists, and hemin. These factors can precipitate a thiamine deficiency crisis in susceptible individuals. Ingestion of foods containing antithiamine factors particularly thiaminase I is associated with mass mortality in fish and birds, cerebrocortical necrosis in ruminants, equine encephalomyelitis blind staggers in horses, and acute beriberi in humans. Thiaminases, which are structurally similar to hemin, split thiamine at the methylene linkage.
Similarly, the source of thiaminase I ingested by herbivores is thought to be bacteria in fern rhizomes. Both elevated thiaminase I activity and associated Bacillus thiaminolyticus have been found in the feces of patients with beriberi. Thiamine antagonists are found in tea and betel nuts tannic acid , coffee chlorogenic acid, caffeic acid , bracken fern caffeic acid , and pigmented polyphenol-containing foods such as red cabbage, blueberries, red currants, and red beets. These cause oxidation of the thiazole ring of thiamine, forming nonabsorbable thiamine disulfide.
Thiamine is unstable under alkaline conditions produced by food additives such as preservatives and antacids eg, sodium bicarbonate , which cause disruption of the thiamine methylene bridge. Sulfite-type food preservatives include sulfur dioxide, sodium sulfite, sodium and potassium bisulfite, and sodium and potassium metabisulfite.
These are used extensively in the production and preservation of foods and beverages, including dried fruit, ready-to-eat salad vegetables, frozen fried potatoes, wine, beer, soft drinks, packaged fruit juices, shellfish, and pickled and pureed foods. Sulfites possess antioxidant and antimicrobial activities, which inhibit the enzymatic and nonenzymatic browning spoiling of food. This preserves the color, freshness, flavor, and crispness of food but substantially reduces the available thiamine.
Sulfite disruption of the methylene bridge of thiamine. Increased losses of ingested thiamine can be caused by drug-related polyuria or diarrhea, drug interactions, or chronic excessive alcohol consumption. Thiamine is a polar, water-soluble vitamin and is not protein bound, which allows it to be easily dialyzed or filtered in the glomerulus. Increased urine flow, loop diuretics, or dialysis can all cause thiamine deficiency.
Thiamine deficiency is associated with drugs such as omeprazole, phenytoin, 5-fluorouracil, metformin, alcohol, antibiotics, furosemide, and thiazide diuretics. This is associated with an increase in the TPP effect in vitro and in whole blood. Small intestinal bacterial overgrowth can be treated specifically with certain oral antibiotics such as rifaximin, neomycin, and metronidazole, which can improve postoperative thiamine deficiency in Roux-en-y gastric bypass patients.
Formation of thiamine antimetabolites from metronidazole, which can occur particularly with high cumulative doses or prolonged use of metronidazole, can inhibit thiamine pyrophosphokinase, leading to irreversible, painful, peripheral neuropathy. Patients with congestive heart failure who receive chronic therapy with furosemide or thiazide diuretics can also develop thiamine deficiency.
Effects of drugs and antithiamine agents on thiamine 32 , 34 , 41 , 54 , 59 , 61 , 68 , Thiamine requirements increase in rapidly dividing or metabolically active cells or during the mobilization of energy substrates.
This occurs during infancy, adolescent growth, pregnancy, lactation, hyperthyroidism, fever, sepsis, strenuous exercise, major surgery, refeeding syndrome, or rapid growth of cancers.
Administering oral, enteral, or parenteral nutrition to these patients without concomitant thiamine supplementation can result in fulminant beriberi or acute refeeding syndrome. Thiamine is a vital cofactor for the production of energy in cells.
Both NADH and flavin adenine dinucleotide are produced in cells during cytosolic glycolysis and in mitochondria via the Krebs cycle. These are strong reducing agents that are oxidized in mitochondria to generate ATP.
NADH transport from the cytosol to the mitochondria is mediated by the malate—aspartate and glycerol phosphate shuttles. The lactate then diffuses out of the muscle and is transported to the liver, where it is converted back to pyruvate by lactate dehydrogenase and glucose by gluconeogenesis Cori cycle. Oxidative phosphorylation is more efficient than anaerobic glycolysis, producing a net yield of 34 molecules of ATP per molecule of glucose compared with a net yield of 2 molecules of ATP from 1 molecule of glucose.
Therefore, over a given time period, the net amount of ATP generated may be comparable when either fermentation or oxidative phosphorylation of glucose is utilized.
The fermentation of glucose to lactate, even in the presence of adequate oxygen, is used by cancer cells for proliferation, a process known as the Warburg effect. The active form of thiamine is TPP, also known as thiamine diphosphate. Hypomagnesemia may exacerbate thiamine deficiency, particularly in patients with beriberi or refeeding syndrome. For example, concomitant administration of intravenous magnesium sulfate and thiamine in alcoholic patients significantly improved erythrocyte transketolase activity compared with intravenous thiamine alone.
Pyruvate dehydrogenase links cytosolic glycolysis to mitochondrial aerobic metabolism during oxidative phosphorylation and ATP production. Pyruvate cannot be utilized in the Krebs cycle in thiamine deficiency and is converted to lactate by lactate dehydrogenase. Lactic acidosis, depletion of cellular ATP, and venous hyperoxia ensues.
This may manifest in abdominal pain, nausea, and vomiting, known as gastrointestinal beriberi. The production of mitochondrial ATP by oxidative phosphorylation in the Krebs cycle is necessary for maintenance of transmembrane electrochemical gradients, sodium—potassium pumps, myosin—actin interactions, and cellular metabolism. The neurotransmitter acetylcholine is produced from choline and acetyl coenzyme A. Red blood cells lack mitochondria and cannot store glycogen. They are entirely dependent on facilitated diffusion of glucose and anaerobic glycolysis for their energy needs.
Erythrocyte metabolism of glucose occurs through the hexokinase glycolysis pathway, the hexose monophosphate shunt or pentose phosphate pathway, and the Rappaport—Luebering glycolytic shunt. Thiamine pyrophosphate is a coenzyme for the transketolase reaction, which has an essential function in the pentose phosphate pathway.
The oxidative branch of the pentose phosphate pathway converts 1 molecule of glucose 6-phosphate to ribulose 5-phosphate and produces 2 molecules of nicotinamide adenine dinucleotide phosphate NADPH. Because mammalian erythrocytes lose their mitochondria during the third phase of erythropoiesis, they have no other way of producing NADPH apart from the pentose phosphate pathway.
NADPH is required for the reduction of glutathione, which preserves the erythrocyte cytoskeleton and cell membrane structure and maintains hemoglobin in the ferrous state. This is necessary for successful delivery of oxygen by erythrocytes to the body. The pentose phosphate pathway also provides a large reserve of NADPH in synaptosomes to prevent oxidative stress and to remove hydrogen peroxide produced by the action of monoamine oxidase on neurotransmitters released at neuronal synapses.
This is possibly due to neuronal dependence on the pentose phosphate pathway—based use of glucose and neuronal inability to sustain prolonged glycolysis. Neurons are also dependent on reduced glutathione, produced by astrocytes, for redox homeostasis and removal of reactive oxygen species. Lactate produced by astrocyte glycolysis and lactate dehydrogenase 1 is shuttled to neurons the astrocyte—neuron lactate shuttle to provide the substrate for production of oxidative mitochondrial energy.
Neurons take up this lactate via monocarboxylate transporter 2 and convert it back to pyruvate with lactate dehydrogenase 5, which spares neuronal glucose to be directed into the pentose phosphate pathway.
While TPP is essential for utilization of normal energy substrates, thiamine triphosphate is required for neurotransmission and normal function of high-conductance chloride channels and neuromuscular acetylcholine receptors in excitable tissues.
Thiamine deficiency thus causes neuronal loss, neuromuscular dysfunction, and oxidative stress, which can lead to muscle weakness, areflexia, and progressive sensorimotor neuropathy dry beriberi , along with confusion, nystagmus, ataxia, and ophthalmoplegia Wernicke encephalopathy.
Failure of rapid thiamine administration in Wernicke encephalopathy leads to irreversible damage to the thalamus, mammillary bodies, basal forebrain, and cerebellum, characterized by anterograde and retrograde amnesia, confabulation, cognitive impairment, and memory deficits Korsakoff psychosis. Cardiovascular manifestations of thiamine deficiency include high-output cardiac failure, peripheral vasodilation, arteriovenous shunting of blood, activation of the renin-angiotensin-aldosterone system, dyspnea, edema, and dysrhythmias wet beriberi.
Severe sensorimotor polyneuropathy has also been described in patients who receive long-term treatment for hypercholesterolemia with statin drugs, including lovastatin, simvastatin, pravastatin, and atorvastatin.
Potential mechanisms include inhibition of hydroxylmethylglutaryl-coenzyme A reductase or mitochondrial dysfunction caused by decreased concentration or transport of ubiquinone.
Ubiquinone, or coenzyme Q10, is a key redox molecule in the mitochondrial respiratory chain required for neuronal function. Gastric surgery alters the dietary behavior of patients with regard to appetite, food selection, and satiety. Pylorus resection, vagotomy, achlorhydria, functional pancreatic exocrine insufficiency, and postcibal asynchrony all contribute to disruption of the normal neuroendocrine regulation of food digestion and absorption.
Malabsorption, dumping, and diarrhea post gastrectomy are particularly associated with total gastrectomy or Billroth II partial gastrectomy. Different subtypes of beriberi coexisted. This can be caused by small intestinal bacterial overgrowth, which can be diagnosed by glucose-hydrogen breath testing and treated by rotating oral antibiotics with thiamine replacement.
Because thiamine is not stored in appreciable amounts, patients with subclinical thiamine deficiency after gastric surgery may develop acute symptoms of thiamine deficiency during times of physical stress. Refeeding syndrome related to thiamine deficiency may occur immediately after surgery, particularly if the patient experienced substantial preoperative weight loss or received neoadjuvant chemotherapy or radiotherapy.
Such patients also require simultaneous administration of magnesium, potassium, and phosphate. This is why daily thiamine replacement after gastric surgery with a good-quality oral multivitamin supplement has been advocated by national bariatric and gastrointestinal surgical societies and is recommended in multiple nutritional guidelines. Thiamine requirements increase with surgery, aging, sepsis, fever, anorexia, physical exertion, and broad-spectrum antibiotic treatment.
This may explain the lag time of development of neuropathic symptoms after gastrectomy in some older patients. The early recognition and rapid administration of parenteral thiamine in suspected beriberi is crucial to prevent progression from Wernicke encephalopathy to Wernicke-Korsakoff syndrome and to minimize permanent neurological damage.
Patients may initially present with nonspecific symptoms such as lethargy, somnolence, depression, irritability, fatigue, headaches, or restlessness. Peripheral neuropathy may manifest with burning feet, paresthesia, muscle tenderness, or calf cramps.
Other symptoms may include anorexia, vomiting, dysphagia, abdominal pain, and constipation gastrointestinal beriberi. A single intravenous dose of thiamine is less likely to achieve sufficient brain tissue levels, and the bioavailability of oral thiamine hydrochloride is only 3. Subclinical thiamine deficiency can develop after both malabsorptive Roux-en-Y gastric bypass, biliopancreatic diversion and restrictive laparoscopic adjustable gastric band, laparoscopic sleeve gastrectomy types of bariatric surgery.
Among individuals who undergo bariatric surgery and subsequently present with Wernicke encephalopathy, noncompliance with oral vitamin supplementation is common Noncompliance may be exacerbated by the impaired cognition, the apathy, or the progressive encephalopathy associated with chronic or acute thiamine deficiency.
This can be related to a poorly adjusted laparoscopic adjustable gastric band, marginal ulcer or gastrojejunal anastomotic stricture, gastric volvulus, intra-abdominal abscess, hiatal hernia, or sleeve stenosis after laparoscopic sleeve gastrectomy.
This is important from both a clinical and a medicolegal perspective. Clinical progression of initial symptoms of Wernicke encephalopathy to chronic Korsakoff syndrome occurred in Micronutrient deficiencies also occur preoperatively in patients undergoing bariatric surgery.
This consistent finding from academic bariatric units in different countries is related to poor-quality, high-calorie diets with low micronutrient intake. This was despite postoperative vitamin supplementation. In a US study of thiamine levels in patients prior to Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding, 47 This is an important finding, as perioperative diets are very low in carbohydrates, low in meat, and often based on dairy or fruit products, which may exacerbate a preexisting thiamine deficiency Table 1.
Female patients were found to have lower mean preoperative thiamine levels Beriberi is a nutritional complication of gastric surgery with devastating clinical consequences. Thiamine is absorbed in the duodenum and proximal jejunum, which therefore places patients who undergo total gastrectomy, Billroth II gastrectomy, or Roux-en-Y diversion at particular risk. Beriberi has also been described after restrictive procedures such as laparoscopic sleeve gastrectomy, gastroplasty, and laparoscopic adjustable gastric banding.
Patients often have subclinical thiamine deficiency after upper gastrointestinal surgery. Thiamine deficiency leads to impaired glucose metabolism, decreased delivery of oxygen by red blood cells, cardiac dysfunction, axonopathy, failure of neurotransmission, and neuronal death.
Beriberi may also be precipitated by acute illness such as sepsis or poor dietary intake. This may occur very soon or many years after gastric surgery, even in apparently well-nourished patients.
Other contributing factors include anorexia, vomiting or food avoidance, malabsorption, drug interactions, increased thiamine requirements, thiamine losses, ingestion of antithiamine agents, and consumption of alcohol or highly processed carbohydrates.
The diagnosis of beriberi relies on treating physicians and dietitians being aware of not only the association between gastric surgery and thiamine deficiency but also the variable clinical presentations of beriberi. Long-term follow-up of nutritional status in gastrectomy and bariatric surgical patients, including vitamin and mineral assessment, is recommended Box 1. Box 1 Summary of thiamine for prevention and treatment of beriberi after gastric surgery. Thiamine vitamin B 1 is a water-soluble vitamin that, unlike fat-soluble vitamins vitamins A, D, E, K , cannot be stored in the body.
Thiamine deficiency results in sensorimotor peripheral neuropathy; Wernicke encephalopathy; Korsakoff psychosis dry beriberi ; and cardiac failure, edema, and arrhythmia wet beriberi. Bariatric surgery results in changes in food choices, disruption in absorption of thiamine, and decreased thiamine intake.
The incidence of peripheral neuropathy related to deficiency of B-complex vitamins B 1 , B 2 , B 6 , B 12 after bariatric surgery including Roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion is 0. Risk factors for thiamine deficiency include poor oral intake, dysphagia, nausea, anorexia, prolonged vomiting, female gender, sepsis, aging, consumption of highly processed carbohydrates, alcohol consumption, and use of antithiamine agents.
Postoperative bariatric surgery patients should receive thiamine supplementation as part of routine multivitamin therapy 12—50 mg orally, twice daily. Preoperative micronutrient deficiency including vitamin D, thiamine, magnesium, and vitamin C in morbidly obese patients is common.
Bariatric surgery patients should receive preoperative supplementation with a good-quality multivitamin to prevent postoperative complications, including beriberi and scurvy.
Thiamine mononitrate is a more stable form of thiamine than thiamine hydrochoride in sterile solutions, compressed tablets, multivitamin capsules, and dry-filled capsules. Long-term nutritional follow-up of both gastric and bariatric surgery patients is recommended. Author contributions. The submitted article represents the original work of the author. Declaration of interest.
The author has no relevant interests to declare. The peripheral neuropathy of vitamin B 12 deficiency. J Neurol Sci. Google Scholar. Short-term changes in bone and mineral metabolism following gastrectomy in gastric cancer patients. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep. Indication for pancreatic enzyme substitution following gastric resection. Tovey FI , Hobsley M. Post-gastrectomy patients need to be followed up for years.
World J Gastroenterol. Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med. Fundectomy-evoked osteopenia in pigs is mediated by the gastric-hypothalamic-pituitary axis. Exp Biol Med Maywood. Polyneuropathy and folate deficiency. Arch Neurol. Severe ataxia, myelopathy, and peripheral neuropathy with acquired copper deficiency in a patient with history of gastrectomy.
Pancytopenia complicated with peripheral neuropathy due to copper deficiency: clinical diagnostic review. So YT. Deficiency diseases of the nervous system. Bradley's Neurology in Clinical Practice. Updated by: Linda J. Editorial team. There are two major types of beriberi: Wet beriberi: Affects the cardiovascular system.
Dry beriberi and Wernicke-Korsakoff syndrome : Affects the nervous system. Beriberi can occur in infants when they are: Breastfed and the mother's body is lacking in thiamine Fed unusual formulas that don't have enough thiamine Some medical treatments that can raise your risk of beriberi are: Getting dialysis Taking high doses of diuretics water pills. Exams and Tests. A physical examination may show signs of congestive heart failure , including: Difficulty breathing, with neck veins that stick out Enlarged heart Fluid in the lungs Rapid heartbeat Swelling in both lower legs A person with late-stage beriberi may be confused or have memory loss and delusions.
A neurological exam may show signs of: Changes in the walk Coordination problems Decreased reflexes Drooping of the eyelids The following tests may be done: Blood tests to measure the amount of thiamine in the blood Urine tests to see if thiamine is passing through the urine. Your provider may also suggest other types of vitamins. Outlook Prognosis. Untreated, beriberi can be fatal. With treatment, symptoms usually improve quickly.
Possible Complications. Complications may include: Coma Congestive heart failure Death Psychosis. When to Contact a Medical Professional. Beriberi is extremely rare in the United States.
However, call your provider if: You feel your family's diet is inadequate or poorly balanced You or your children have any symptoms of beriberi. Alternative Names. Beriberi involving the brain Wernicke-Korsakoff syndrome results when short-term severe deficiency is superimposed on chronic deficiency. The early stage is called Korsakoff syndrome and the person is confused, has difficulty talking and confabulates makes things up to cover for loss of memory. Blood flow to the brain is decreased and coma and eventually death result.
Cardiovascular beriberi wet beriberi takes two forms. In the first form the person experiences a fast heart beat, sweating and the skin is warm. As the disease progresses, heart failure occurs. The second form is called Shoshin disease and is very rare. In this case the onset of symptoms is sudden and overwhelming, and death through total cardiovascular collapse may occur in days or even hours.
There are various biochemical tests to detect thiamine deficiency. These include the measurement of blood thiamine and other related substances and the measurement of the amount of thiamine excreted in the urine. The most reliable diagnostic investigation is the measurement of whole blood or red blood cell transketolase activity.
Transketolase is an enzyme for which thiamine acts as a co-enzyme enhancing its activity in a particular metabolic pathway. If the activity of this enzyme increases as a result of adding another form of thiamine —— thiamine diphosphate —— TPP , this is called the TPP effect and is expressed as a percentage. Another way of diagnosing thiamine deficiency is by giving someone with the clinical signs of beriberi thiamine and seeing how they respond.
Beriberi can be prevented by an adequate intake of thiamine, which therefore requires eating a balanced diet or ensuring that patients at risk of thiamine deficiency anorexia nervosa, orthorexia, post-bariatric surgery are given vitamin B complex supplements that contain thiamine. Care must be taken to ensure that patients receiving TPN and formula-fed infants receive feeds that have an adequate thiamine content. Thiamine deficiency is treated by giving large amounts of the vitamin as soon as a deficiency is suspected.
After this, 2. Larger amounts are not usually absorbed. All patients should also receive other water-soluble vitamins in the correct dose, because B complex vitamins, including thiamine, work more efficiently when given in combination.
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