Vitamin B1 (Thiamin)

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Vitamin B1

Vitamin B1

Vitamin B1 also known as thiamin or thiamine, is one of the water-soluble B vitamins. Vitamin B1 or thiamine is naturally present in some foods, added to some food products, and available as a dietary supplement. Vitamin B1 or thiamine plays a critical role in energy metabolism and, therefore, in the growth, development, and function of cells ¹. Foods rich in vitamin B1 or thiamine include whole grains, brown rice, lean pork, poultry, eggs, fish, soybean, nuts, dried beans, peas, and fortified or enriched grain products such as cereals, infant formulas, and bread ², ³, ⁴. Multivitamins will provide an additional 1.5 mg of thiamine on top of a diet rich in thiamine ⁵.

Ingested vitamin B1 or thiamine from food and dietary supplements is absorbed by the small intestine through active transport at nutritional doses and by passive diffusion at pharmacologic doses ⁶, ¹. Most dietary vitamin B1 or thiamine is in phosphorylated forms, and intestinal enzyme phosphatase hydrolyzes them to free thiamin before the vitamin is absorbed by the small intestine ¹. The remaining dietary vitamin B1 or thiamine is in free (absorbable) form ¹, ⁷. Thiamine, a water-soluble vitamin, cannot be stored in appreciable amounts ⁸. Humans store vitamin B1 or thiamine primarily in the liver, but in very small amounts (approximately 30 mg) ⁹. Vitamin B1 or thiamine has a short half‐life of 14 to 18 days and body stores are limited, so people require a continuous supply of thiamine from the diet ¹⁰, ⁶, ¹¹.

Vitamin B1 or thiamine is present in the body as free thiamine, as well as in several phosphorylated forms: thiamine monophosphate (TMP), thiamine diphosphate (TDP also known as thiamin pyrophosphate (TPP)), and thiamine triphosphate (TTP) ¹², ¹³, ¹⁴. About 80% of the approximately 25–30 mg of vitamin B1 or thiamine in the adult human body is in the form of thiamin pyrophosphate (TPP) also known as thiamin diphosphate (TDP), the main metabolically active form of vitamin B1 or thiamine. Bacteria in the large intestine also synthesize free thiamin and thiamin pyrophosphate (TPP), but their contribution, if any, to thiamin nutrition is currently unknown ¹⁵. Thiamin pyrophosphate (TPP) serves as an essential cofactor for five enzymes involved in glucose, amino acid (proteins), and fatty acids (lipids) metabolism (Figure 1) ¹⁶, ¹, ⁹.

Levels of vitamin B1 or thiamine in the blood are not reliable indicators of thiamin status. Thiamine status is often measured indirectly by assaying the activity of the transketolase enzyme, which depends on thiamin pyrophosphate (TPP), in red blood cell hemolysates in the presence and absence of added thiamin pyrophosphate (TPP) ⁹. The result, known as the “TPP effect,” reflects the extent of unsaturation of transketolase with TPP. The result is typically 0%–15% in healthy people, 15%–25% in those with marginal deficiency, and higher than 25% in people with thiamine deficiency. Another commonly used measure of vitamin B1 or thiamine status is urinary thiamine excretion, which provides data on dietary intakes but not tissue stores ¹⁷. For adults, excretion of less than 100 mcg/day vitamin B1 or thiamine in urine suggests insufficient thiamine intake, and less than 40 mcg/day indicates an extremely low intake ¹⁸.

Figure 1. Vitamin B1 (thiamine) function

Footnote: Major biochemical reactions requiring vitamin B1 or thiamine as a cofactor (a compound that is essential for the activity of an enzyme).

[Source ¹⁹ ]

What does vitamin B1 (Thiamine) do?

Vitamin B1 or thiamine helps turn the food you eat into the energy you need. Thiamine is important for the growth, development, and function of the cells in your body.

About 80% of the approximately 25–30 mg of vitamin B1 or thiamine in the adult human body is in the form of thiamin pyrophosphate (TPP) also known as thiamin diphosphate (TDP), the main metabolically active form of vitamin B1 or thiamine. The synthesis of thiamin pyrophosphate (TPP) from free thiamine requires magnesium, adenosine triphosphate (ATP), and the enzyme, thiamin pyrophosphokinase ¹⁹. In humans, thiamin pyrophosphate (TPP) serves as an essential cofactor for five enzymes involved in glucose, amino acid (proteins), and fatty acids (lipids) metabolism (Figure 1) ¹⁶, ¹, ⁹. Forms of thiamine are also needed for ribose synthesis and for α-oxidation of 3-methyl-branched fatty acids ¹⁹.

Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, and branched-chain α-ketoacid dehydrogenase (BCKDH) each comprise a different enzyme complex found within cellular organelles called mitochondria ¹⁹. They catalyze the decarboxylation of pyruvate, α-ketoglutarate, 2-oxoadipate, and branched-chain amino acids (BCAAs) to form acetyl-coenzyme A (CoA), succinyl-CoA, glutaryl-CoA, and derivatives of branched-chain amino acid (BCAA), respectively (Figure 1). All products play critical roles in the production of energy from food through their connection to the citric acid (Krebs) cycle ²⁰. Branched-chain amino acid (BCAA), including leucine, isoleucine, and valine, are eventually degraded into acetyl-CoA and succinyl-CoA to fuel the citric acid cycle. The catabolism of the three branched-chain amino acids (BCAAs) also contributes to the production of cholesterol and donates nitrogen for the synthesis of the neurotransmitters, glutamate and g-aminobutyric acid (GABA) ²¹. In addition to the thiamin coenzyme (thiamin pyrophosphate), each dehydrogenase complex requires a niacin-containing coenzyme (NAD), a riboflavin-containing coenzyme (FAD), and lipoic acid.

Transketolase catalyzes critical reactions in another metabolic pathway occurring in the cytosol, known as the pentose phosphate pathway ¹⁹. One of the most important intermediates of this pathway is ribose-5-phosphate, a phosphorylated 5-carbon sugar required for the synthesis of the high-energy ribonucleotides, such as ATP and guanosine triphosphate (GTP). Nucleotides are the building blocks of nucleic acids, DNA, and RNA ¹⁹. The pentose phosphate pathway also supplies various anabolic pathways, including fatty acid synthesis, with the niacin-containing coenzyme NADPH ²², ²³. Because transketolase decreases early in thiamine deficiency and, unlike most thiamine-dependent enzymes, is present in red blood cells, measurement of its activity in red blood cells has been used to assess thiamine nutritional status ²⁰, ²⁴, ²⁵.

2-Hydroxyacyl-CoA lyase is a thiamin pyrophosphate-dependent enzyme in peroxisomes that catalyzes the catabolism of 3-methyl-branched fatty acids through the process of α-oxidation, the oxidative removal of a single carbon atom from fatty acids like phytanic acid ²⁶.

What are some effects of vitamin B1 on health?

Scientists are studying vitamin B1 or thiamine to better understand how it affects health. Here are some examples of what this research has shown.

Cataracts

A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of thiamin intake were 40% less likely to have nuclear cataracts than those in the lowest quintile ²⁷. In addition, a study in 408 US women found that higher dietary intakes of vitamin B1 or thiamine were inversely associated with five-year change in lens opacification ²⁸. However, these cross-sectional associations have yet to be elucidated by studies of causation.

Diabetes

People with diabetes have been reported to have low plasma concentrations and high renal clearance of thiamine, suggesting that individuals with type 1 or type 2 diabetes are at increased risk for thiamine deficiency ²⁹, ³⁰. Two thiamin transporters, thiamin transporter-1 (THTR-1) and thiamin transporter-2 (THTR-2), are involved in thiamine uptake by enterocytes in the small intestine and re-uptake in the proximal tubules of the kidneys. One study suggested that high blood sugar level (hyperglycemia) in patients with diabetes could affect thiamine re-uptake by decreasing the expression of thiamin transporters in the kidneys ³¹. Conversely, thiamine deficiency appears to impair the normal endocrine function of the pancreas and worsens hyperglycemia. Early studies showed that insulin synthesis and secretion were altered in the endocrine pancreatic cells of thiamine-deficient rats ³², ³³. In humans, thiamine deficiency caused by recessive mutations in the gene encoding thiamin transporter-1 (THTR-1) leads to diabetes mellitus in the thiamine-responsive megaloblastic anemia syndrome ¹⁹.

The proportion of people with type 1 or type 2 diabetes who have poor thiamine status based on erythrocyte transketolase activity ranges from 17% to 79% in studies conducted to date ³⁴. In a study of 76 consecutive patients with type 1 or type 2 diabetes, for example, 8% had mild thiamine deficiency and 32% had moderate thiamine deficiency based on assays of the transketolase enzyme ³⁵.

Some small studies have shown that oral high-dose thiamine supplementation with 150–300 mg/day vitamin B1 or thiamine can decrease glucose levels in patients with type 2 diabetes or impaired glucose tolerance ³⁶, ³⁷. Vitamin B1 or thiamine supplementation prevented any further increase in fasting glucose and insulin concentrations compared with placebo treatment but did not reduce the hyperglycemia ³⁷. One study suggested that vitamin B1 or thiamine supplementation might improve fasting glucose concentrations in in early stages of type 2 diabetes (i.e., pre-diabetes) ³⁶. However, the authors of these studies did not assess the potential clinical significance of these findings ¹⁷.

A few small randomized studies have assessed the effects of benfotiamine (man made thiamine) supplements on diabetic neuropathy. Three studies found that, compared to placebo, 120–900 mg/day benfotiamine with or without other B-vitamins decreased the severity of neuropathy symptoms and lowered urinary albumin excretion (a marker of early-stage diabetic nephropathy) ³⁸, ³⁹, ⁴⁰. However, another study found no effect of 900 mg/day benfotiamine on urinary excretion of albumin or kidney injury molecule-1, a marker of kidney injury ⁴¹.

Well-designed studies with larger sample sizes and longer durations are required to determine whether vitamin B1 or thiamine supplements can reduce glucose levels in patients with diabetes or decrease diabetic compications ¹⁷.

Heart failure

Severe thiamine deficiency (wet beriberi) can lead to impaired cardiac function and ultimately congestive heart failure ¹⁹. The rates of poor vitamin B1 or thiamine status in patients with congestive heart failure have ranged in studies from 21% to 98% ⁴. Explanations for this association include older age, comorbidities, insufficient dietary intake, treatment with diuretics, and frequent hospitalizations ⁴², ⁴³, ⁴⁴. Patients with congestive heart failure might also have altered thiamine metabolism, including reduced absorption of thiamine in the small intestine ⁴⁵. A 2015 meta-analysis of nine observational studies found a 2.5 times higher risk of thiamine deficiency in patients with heart failure compared to control subjects ⁴⁵. As in the general population, older patients with congestive heart failure were found to be at higher risk of thiamine deficiency than younger ones ⁴⁶.

The authors of one study reported that 33% of 100 patients with chronic heart failure had thiamine deficiency compared to 12% of 50 healthy volunteers ⁴³. Rates of thiamine deficiency were even higher when the investigators excluded those who used thiamine supplements. The different rates of thiamine deficiency in patients with heart failure in these and other studies are probably due to differences in nutrition status, comorbidities, medications and dietary supplements used, and techniques used to measure thiamine status ⁴².

An important measure of heart function in congestive heart failure is the left ventricular ejection fraction (LVEF), which can be assessed by echocardiogram. One study in 25 patients found that furosemide use at doses of 80 mg/day or greater was associated with a 98% prevalence of thiamine deficiency ⁴⁷. In a randomized, double-blind study of 30 patients with congestive heart failure, all of whom had been taking furosemide (80 mg/day) for at least three months, intravenous (IV) thiamine therapy (200 mg/day) for seven days resulted in an improved left ventricular ejection fraction (LVEF) compared to IV placebo ⁴⁸. When all 30 of the congestive heart failure patients in that study subsequently received six weeks of oral vitamin B1 or thiamine therapy (200 mg/day), the average left ventricular ejection fraction (LVEF) improved by 22%. This finding may be relevant because improvements in left ventricular ejection fraction (LVEF) have been associated with improved survival in congestive heart failure patients ⁴⁹. However, clinical trials of oral vitamin B1 or thiamine supplementation in heart failure patients have not found any benefit. In a randomized, double-blind, placebo-controlled trial in 52 patients with systolic heart failure, 300 mg/day of supplemental thiamin for one month did not improve LVEF compared to placebo ⁵⁰. A randomized, double-blind, placebo-controlled trial in 64 patients with heart failure reported that 200 mg/day or supplemental thiamin for six months did not improve LVEF ⁵¹.

The authors of a systematic literature review and meta-analysis found two randomized, double-blind, placebo-controlled trials of vitamin B1 or thiamine supplementation in people with heart failure that met their eligibility criteria ⁵². In these trials, vitamin B1 or thiamine supplements significantly improved net change in left ventricular ejection fraction (LVEF). However, the authors did not assess the clinical significance of this finding ¹⁷.

Although little evidence supports the routine use of supplemental vitamin B1 or thiamine in congestive heart failure patients and some authors suggest that it may be prudent to screen patients on long-term diuretic therapy for thiamine deficiency and treat accordingly ⁵³.

In summary, more research is needed to determine whether vitamin B1 or thiamine supplements might benefit people with heart failure, even if they have normal thiamine status.

Alzheimer’s disease

Some older adults are at increased risk for developing subclinical thiamine deficiency secondary to poor dietary intake, reduced gastrointestinal absorption, and multiple medical conditions ⁵⁴, ⁵⁵. Since thiamine deficiency can result in a form of dementia called Wernicke-Korsakoff syndrome, its relationship to Alzheimer’s disease and other forms of dementia have been investigated. Alzheimer’s disease is characterized by a decline in cognitive function in elderly people, accompanied by pathologic features that include beta-amyloid plaque deposition and neurofibrillary tangles formed by hyperphosphorylated Tau protein ⁵⁶.

Scientists are studying the possibility that thiamine deficiency could affect the dementia of Alzheimer’s disease. Whether thiamine supplements may help mental function in people with Alzheimer’s disease.

According to animal model studies, thiamine deficiency might play a role in the development of Alzheimer’s disease ⁵⁷. For example, thiamine deficiency produces oxidative stress in neurons, death of neurons, loss of memory, plaque formation, and changes in glucose metabolism—all markers of Alzheimer’s disease. Autopsy studies have shown that transketolase and other thiamine-dependent enzymes have decreased activity in the brains of people with Alzheimer’s disease ⁵⁸, ⁵⁹.

Few studies have assessed the prevalence of thiamine deficiency in people with Alzheimer’s disease. One of these studies found that 13% of 150 patients with cognitive impairment and acute-onset behavioral disturbances were considered thiamine deficient based on plasma levels ⁶⁰.

The authors of a 2001 Cochrane review assessed three double-blind, randomized trials (including two crossover trials) that compared the effects of 3 g/day oral thiamine to placebo on cognitive function in patients with Alzheimer’s type dementia ⁶¹. The three studies randomly assigned fewer than 20 patients each, and the two crossover studies did not include a washout period ⁶², ⁶³, ⁶⁴. The review authors stated that it was not possible to draw any conclusions from these three studies because they were small and the publications describing them did not provide enough detail to combine these data in a meta-analysis ⁶¹.

Larger, well-designed studies are needed to determine whether vitamin B1 or thiamine supplements are beneficial for Alzheimer’s disease.

Thiamine has not been shown to cause any harm.

Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons. Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. A recent study found decreased levels of the thiamin transporter-2 (THTR-2) protein in the striatum and frontal cortex of patients with Huntington’s disease compared to age-and sex-matched healthy controls ⁶⁵. Compared to control subjects, this study also found lower concentrations of thiamin pyrophosphate (TPP) in the striatum and lower concentrations of thiamin monophosphate (TMP) in the cerebrospinal fluid of patients with Huntington’s disease ⁶⁵. Mutations in the SLC19A3 gene that encodes THTR-2 causes biotin-thiamin-responsive basal ganglia disease, which is treated with high-dose co-supplementation with biotin and thiamine for life. In a mouse model of Huntington’s disease, high-dose supplementation with both biotin and thiamine vitamins improved neuropathological and motor deficits but had no effect on lifespan ⁶⁵. A phase 2, open-label clinical trial evaluating the effect of combined thiamine-biotin supplementation, at moderate (600 mg/day of thiamine and 150 mg/day of biotin) and high (1,200 mg/day of thiamine and 300 mg/day of biotin) dosages, in Huntington’s disease is currently underway ⁶⁶.

Wernicke-Korsakoff syndrome

Wernicke-Korsakoff syndrome is caused by vitamin B1 or thiamine deficiency and is one of the most severe neuropsychiatric consequence of alcohol abuse primarily seen in alcoholics ⁶⁷. Wernicke-Korsakoff syndrome patients classically present with a clinical triad of altered mental status (i.e., confusion or dementia), nystagmus (or ophthalmoplegia), and ataxia ⁶⁸. However, less than a third of patients present with this complete triad ⁶⁹, ⁷⁰, ⁷¹.

The authors of a 2013 Cochrane review of thiamine to treat or prevent Wernicke-Korsakoff syndrome found only two studies that met their inclusion criteria, and one of these studies has not been published ⁶⁷. These randomized, double-blind, placebo-controlled trials compared 5 mg/day by mouth for 2 weeks or daily intramuscular doses of 5 to 200 mg/day thiamine over 2 consecutive days in a total of 177 people with a history of chronic alcohol use. The Cochrane review authors concluded that the evidence from randomized clinical trials is insufficient to guide health care providers in selecting the appropriate dose, frequency, duration, or route of thiamine supplementation to treat or prevent Wernicke-Korsakoff syndrome in patients with alcohol abuse ⁶⁷.

The authors of the European Federation of Neurological Societies guidelines for diagnosing, preventing, and treating Wernicke’s encephalopathy note that even high doses of oral vitamin B1 or thiamine supplements might not be effective in raising blood thiamin levels or curing Wernicke’s encephalopathy ⁷². They recommend 200 mg thiamine, preferably intravenously, three times daily (total of 600 mg/day) until the signs and symptoms stop, along with a balanced diet. In its guidelines for managing Wernicke’s encephalopathy in emergency departments, the Royal College of Physicians in London supports the administration of oral thiamin hydrochloride (100 mg three times a day) in patients with adequate dietary intakes of thiamin and no signs or symptoms of Wernicke’s encephalopathy ⁷³. However, the authors recommend parenteral thiamin supplementation for patients at high risk, such as those with ataxia, confusion, and a history of chronic alcohol misuse, because oral supplementation is unlikely to produce adequate blood levels.

Cancer

Thiamine deficiency and Wernicke-Korsakoff syndrome have been observed in some cancer patients with rapidly growing tumors ⁷⁴, ⁷⁵. Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamine ⁷⁶. All rapidly dividing cells require nucleic acids at an increased rate, and some cancer cells appear to rely heavily on the TPP-dependent enzyme, transketolase, to provide the ribose-5-phosphate necessary for nucleic acid synthesis. One study found that the levels of THTR-1, transketolase, and TPP mitochondrial transporters were increased in samples of human breast cancer tissue compared to normal tissue, suggesting an adaptation in thiamin homeostasis in support of cancer metabolism ⁷⁷. Other studies have found that the gene encoding THTR-2 is downregulated in certain cancers ⁷⁸. Moreover, use of the chemotherapeutic drug, 5-fluorouracil, inhibits phosphorylation of thiamin to thiamin pyrophosphate and may thus lead to thiamin deficiency ⁷⁹, ⁸⁰.

Vitamin B1 or thiamine supplementation in cancer patients is common to prevent thiamine deficiency, but Boros et al. ⁸¹ caution that too much thiamine may actually fuel the growth of some malignant tumors, suggesting that thiamin supplementation be reserved for those cancer patients who are actually deficient in thiamine. Presently, there is no evidence available from studies in humans to support or refute this theory. However, it would be prudent for individuals with cancer who are considering vitamin B1 or thiamine supplementation to discuss it with their clinician managing their cancer therapy. Intravenous, high-dose thiamine has been suggested as a treatment for cancer patients with confirmed Wernicke-Korsakoff syndrome ⁷⁵.

Sepsis

Sepsis is a life-threatening medical emergency caused by the body’s extreme response to an infection ⁸². Sepsis happens when an infection you already have triggers a chain reaction throughout your body. Infections that lead to sepsis most often start in the lung, urinary tract, skin, or gastrointestinal tract. Without timely treatment, sepsis can rapidly lead to tissue damage, organ failure, and death ⁸². Because thiamine deficiency is common among septic patients ⁸³, several studies have investigated the treatment effect of intravenous thiamine – alone or in combination with other agents like vitamin C and hydrocortisone.

Observational studies examining the association of intravenous thiamine as a monotherapy have mainly looked at its association with lactic acidosis, which commonly occurs in both thiamine deficiency and sepsis, and with mortality. One retrospective study in 123 septic patients and 246 matched controls found that intravenous thiamin administration within 24 hours of hospital admission was linked to improvements in both lactate clearance and 28-day mortality ⁸⁴. In a small retrospective study of 53 alcohol-use disorder patients presenting with septic shock, lower mortality was observed in the 34 patients who received intravenous thiamin compared to the 19 patients who did not ⁸⁵.

A few randomized controlled trials have evaluated the effect of intravenous thiamine in the treatment of sepsis. A randomized, double-blind, placebo-controlled trial in 88 patients with sepsis and elevated blood concentrations of lactate reported that intravenous thiamine (200 mg twice daily for seven days or until discharge from the hospital) did not decrease lactate concentrations at 24 hours post initiation of treatment – the primary endpoint of the trial ⁸⁶. No differences between the treatment and placebo groups were found for the secondary endpoints, which included survival ⁸⁶. In a subsequent analysis of data from this trial, the septic patients that were given parenteral thiamin (n=31) had lower creatinine concentrations throughout the treatment and were less likely to need renal replacement therapy compared to placebo (n=39) ⁸⁷.

A 2020 meta-analysis of four studies – one observational and three randomized controlled trials – found no benefit of intravenous thiamine for improving lactate concentrations, length of hospital stay in intensive care, or overall survival ⁸⁸. Large-scale clinical trials are needed to determine whether parenteral administration of thiamin is beneficial in the treatment of sepsis. Administering thiamin in combination with vitamin C and corticosteroids may be more efficacious to treat sepsis ⁸⁹; some clinical trials of such treatments are currently underway ¹⁹.

Metabolic diseases

Vitamin B1 or thiamine supplementation is included in the clinical management of genetic diseases that affect the metabolism of carbohydrates and branched-chain amino acids (BCAAs).

Thiamin-responsive pyruvate dehydrogenase deficiency

Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid (lactic acidosis) in the body and a variety of neurological problems ⁹⁰. Signs and symptoms of pyruvate dehydrogenase deficiency usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking ⁹⁰. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking ⁹⁰. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain ⁹⁰. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood ⁹⁰.

The genes involved in pyruvate dehydrogenase deficiency each provide instructions for making a protein that is a component of a group of proteins called the pyruvate dehydrogenase complex. This complex plays an important role in the pathways that convert the energy from food into a form that cells can use. The pyruvate dehydrogenase complex converts a molecule called pyruvate, which is formed from the breakdown of carbohydrates, into another molecule called acetyl-CoA. This conversion is essential to begin the series of chemical reactions that produce energy for cells.

The pyruvate dehydrogenase complex is made up of multiple copies of several enzymes called E1, E2, and E3, each of which performs part of the chemical reaction that converts pyruvate to acetyl-CoA. In addition, other proteins included in the complex ensure its proper function. One of these proteins, E3 binding protein, attaches E3 to the complex and provides the correct structure for the complex to perform its function. Other associated proteins control the activity of the complex: pyruvate dehydrogenase phosphatase turns on (activates) the complex, while pyruvate dehydrogenase kinase turns off (inhibits) the complex.

The patients who respond to vitamin B1 or thiamine treatment (from a few mg/day to doses above 1,000 mg/day) exhibit pyruvate dehydrogenase complex (PDHC) deficiency due to the decreased affinity of pyruvate dehydrogenase complex (PDHC) deficiency for TPP ⁹¹, ⁹². Although vitamin B1 or thiamine supplementation can reduce lactate accumulation and improve the clinical features in thiamin-responsive patients, it does not constitute a cure ⁹³.

Maple syrup urine disease

Maple syrup urine disease is an inherited disorder in which the body is unable to process branched-chain amino acid (BCAA) properly ⁹⁴. Maple syrup urine disease gets its name from the distinctive sweet odor of affected infants’ urine. Alterations in the branched-chain amino acid (BCAA) catabolic pathway result in neurologic dysfunction caused by the accumulation of branched-chain amino acids (leucine, isoleucine, and valine) and their derivatives, branched-chain ketoacids (BCKA). Maple syrup urine disease is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death ⁹⁴.

Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated.

Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease ⁹⁴. The BCKDHA, BCKDHB, and DBT genes provide instructions for making proteins that work together as part of a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs.

Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease.

Researchers are studying other genes related to the same protein complex that may also be associated with maple syrup urine disease.

The therapeutic approach includes a synthetic diet with reduced branched-chain amino acid (leucine, isoleucine, and valine) content, and thiamine (10-1,000 mg/day) is supplemented to patients with mutations in the E2 subunit of the BCKDH complex ⁹⁵. In thiamine-responsive individuals, the supplementation has been proven effective to correct the phenotype without recourse to the branched-chain amino acid (BCAA) restriction diet.

Thiamine-responsive megaloblastic anemia

Mutations in the SLC19A2 gene that encodes THTR-1 impairs intestinal thiamine uptake and causes thiamine deficiency, leading to thiamine-responsive megaloblastic anemia ⁹⁶. Thiamine-responsive megaloblastic anemia syndrome also called thiamin metabolism dysfunction syndrome-1, is characterized by megaloblastic anemia, diabetes mellitus, and deafness. A review of 30 cases reported additional neurologic, visual, and cardiac impairments ⁹⁷. High-dose oral supplementation with thiamine (up to 300 mg/day) helps to maintain health and correct hyperglycemia in prepubescent children. A recent study in 32 individuals with found no additional benefit of oral doses above 150 mg/day ⁹⁸. After puberty, a decline in pancreatic function results in the requirement of insulin together with thiamine to control the hyperglycemia. One study also reported that the treatment of a four-month-old girl with 100 mg/day of thiamin did not prevent hearing loss at 20 months of age ⁹⁹. Early diagnosis of the thiamine-responsive megaloblastic anemia syndrome and early treatment with thiamin is important for a better prognosis ⁹⁸.

Biotin-thiamin-responsive basal ganglia disease

Biotin-thiamin-responsive basal ganglia disease, also called biotin-responsive basal ganglia disease, thiamin transporter-2 deficiency, and thiamin metabolism dysfunction syndrome-2, is caused by an autosomal recessive mutation in the SLC19A3 gene that codes for THTR-2. The disease usually presents around 3 to 10 years of age ¹⁰⁰, but an early infantile form of the disease exists with onset as early as one month of age ¹⁰¹. Clinical features include subacute encephalopathy (confusion, drowsiness, altered level of consciousness), ataxia, and seizures.

A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises ¹⁰². Often associated with poor outcomes, acute crises were not observed for a five-year follow-up period following thiamin supplementation (300-400 mg/day) – early diagnosis and immediate treatment with biotin and thiamin led to positive outcomes ¹⁰². Recent studies have found supplemental thiamin to be important in treating the condition. In an open-label study of 20 pediatric patients with the disease, supplemental thiamin alone was as effective as combined biotin-thiamin supplementation when given for 30 months ¹⁰³. Lifelong high-dose supplementation with a combination of biotin and thiamin is generally the treatment for biotin-thiamin-responsive basal ganglia disease ¹⁰⁰. Early diagnosis and treatment is important to ensure a better prognosis ¹⁰¹, ¹⁰⁴.

Other thiamine metabolism dysfunction syndromes

Supplemental thiamine has limited utility in treating other inborn errors of thiamin metabolism. Mutations in the SLC25A19 gene that codes for the mitochondrial TPP transporter can result in either thiamine metabolism dysfunction syndrome-3 (THMD3) or thiamine metabolism dysfunction syndrome-4 (THMD4). Of these rare syndromes, thiamine metabolism dysfunction syndrome-3 (THMD3), also called Amish-type microcephaly or Amish lethal microcephaly, has the more severe phenotype, resulting in a congenital microcephaly, elevated concentrations of α-ketoglutarate in urine, and usually death in infancy ¹⁰⁵. Thiamine metabolism dysfunction syndrome-4 (THMD4) is characterized by episodic encephalopathy and weakness, which often presents following a viral infection or febrile illness in childhood. Some patients affected with THMD4 may respond to high-dose thiamin supplementation ¹⁰⁶.

Mutations in the TPK1 gene result in thiamin pyrophosphokinase 1 deficiency and thiamine metabolism dysfunction syndrome-5 (THMD5), which usually manifests in early childhood. While the clinical presentation of THMD5 varies, affected individuals often experience episodic ataxia, dystonia, and lactic acidosis ¹⁰⁷. Only a few cases of thiamine metabolism dysfunction syndrome-5 (THMD5) have been reported to date; two of these patients experienced limited improvement of symptoms upon supplementation with thiamin, in conjunction with adherence to a high-fat diet ¹⁰⁸.

How much vitamin B1 do I need?

The amount of vitamin B1 or thiamine you need depends on your age and sex ¹⁰⁹. Average daily recommended amounts are listed in Table 1 below in milligrams (mg). The Recommended Dietary Allowance (RDA) is average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals ¹¹⁰. Table 1 lists the current Recommended Dietary Allowance (RDA) for vitamin B1 or thiamine ¹¹⁰. For infants from birth to 12 months, the Food and Nutrition Board at the Institute of Medicine of the National Academies established an adequate intake (intake at this level is assumed to ensure nutritional adequacy; adequate intake is established when evidence is insufficient to develop an RDA). for vitamin B1 or thiamine that is equivalent to the mean intake of vitamin B1 or thiamine in healthy, breastfed infants ¹⁷.

Most people in the United States consume the recommended amounts of vitamin B1 or thiamine ¹⁷. An analysis of data from the 2003-2006 National Health and Nutrition Examination Survey showed that only 6% of the U.S. population has a usual intake below the estimated average requirement (average daily level of intake estimated to meet the requirements of 50% of healthy individuals. It is usually used to assess the adequacy of nutrient intakes in populations but not individuals) ³.

Among children and teens, the average daily vitamin B1 or thiamine intake from foods is 1.27 mg for ages 2–5 years, 1.54 mg for ages 6–11 years, and 1.68 mg for ages 12–19 years ¹¹¹. In adults aged 20 and older, the average daily vitamin B1 or thiamine intake from foods is 1.95 mg in men and 1.39 mg in women. The average daily vitamin B1 or thiamine intake from foods and supplements in children and teens is 1.51 mg for ages 2–5 years, 1.76 mg for ages 6–11 years, and 1.95 mg for ages 12–19 years. In adults aged 20 and older, the average daily vitamin B1 or thiamine intake from foods and supplements is 4.89 mg in men and 4.90 mg in women ¹⁷.

No current data on rates of thiamine deficiency in the U.S. population are available ¹⁷.

Most people in the United States get enough vitamin B1 or thiamine from the foods they eat. Thiamine deficiency is rare in this country. However, certain groups of people are more likely than others to have trouble getting enough vitamin B1 or thiamine:

People with alcohol dependence
Older individuals
People with HIV/AIDS
People with diabetes
People who have had weight loss surgery

Table 1. Recommended Dietary Allowances (RDAs) for vitamin B1 or thiamine

Life Stage	Recommended Amount
Birth to 6 months	0.2 mg
Infants 7–12 months	0.3 mg
Children 1–3 years	0.5 mg
Children 4–8 years	0.6 mg
Children 9–13 years	0.9 mg
Teen boys 14–18 years	1.2 mg
Teen girls 14–18 years	1.0 mg
Men	1.2 mg
Women	1.1 mg
Pregnant teens and women	1.4 mg
Breastfeeding teens and women	1.4 mg

[Source ¹⁰⁹ ]

What happens if I don’t get enough vitamin B1?

You can develop thiamine deficiency if you don’t get enough vitamin B1 or thiamine in the foods you eat or if your body eliminates too much or absorbs too little vitamin B1 or thiamine.

Thiamine deficiency can cause loss of weight and appetite, confusion, memory loss, muscle weakness, and heart problems. Severe thiamine deficiency leads to a disease called beriberi with the added symptoms of tingling and numbness in the feet and hands, loss of muscle, and poor reflexes. Beriberi is not common in the United States and other developed countries.

A more common example of thiamine deficiency in the United States is Wernicke-Korsakoff syndrome, which mostly affects people with alcoholism. It causes tingling and numbness in the hands and feet, severe memory loss, disorientation, and confusion.

What foods provide vitamin B1?

Vitamin B1 or thiamine is found naturally in many foods and is added to some fortified foods. You can get recommended amounts of vitamin B1 or thiamine by eating a variety of foods, including the following ⁷:

Whole grains and fortified bread, cereal, pasta, and rice
Meat (especially pork) and fish
Legumes (such as black beans and soybeans), seeds, and nuts

Breads, cereals, and infant formulas in the United States and many other countries are fortified with thiamine ⁷. The most common sources of vitamin B1 or thiamine in the U.S. diet are cereals and bread ². Pork is another major source of the vitamin. Dairy products and most fruits contain little vitamin B1 or thiamine ⁹. About half of the vitamin B1 or thiamine in the U.S. diet comes from foods that naturally contain thiamin; the remainder comes from foods to which thiamine has been added ³.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central website (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B1 or thiamine arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/Thiamin-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/Thiamin-Food.pdf).

Heating foods containing vitamin B1 or thiamine can reduce their thiamin content. For example, bread has 20%–30% less vitamin B1 or thiamine than its raw ingredients, and milk pasteurization reduces thiamin content (which is very small to begin with) in milk by up to 20% ⁹. Because vitamin B1 or thiamine dissolves in water, a significant amount of the vitamin is lost when cooking water is thrown out ⁹. Processing also alters vitamin B1 or thiamine levels in foods; for example, unless white rice is enriched with thiamin, it has one tenth the amount of thiamin in unenriched brown rice ¹¹².

Data on the bioavailability of vitamin B1 or thiamine from food are very limited ¹¹³. Some studies do show, however, that thiamin absorption increases when intakes are low ¹.

Several food sources of thiamine are listed in Table 2.

Table 2. Vitamin B1 (thiamine) food sources

Food	Milligrams (mg) per serving	*Percent Daily Value (DV)**
Breakfast cereals, fortified with 100% of the Daily Value (DV) for thiamine, 1 serving	1.2	100
Egg noodles, enriched, cooked, 1 cup	0.5	42
Pork chop, bone-in, broiled, 3 ounces	0.4	33
Trout, cooked, dry heat, 3 ounces	0.4	33
Black beans, boiled, ½ cup	0.4	33
English muffin, plain, enriched, 1 muffin	0.3	25
Mussels, blue, cooked, moist heat, 3 ounces	0.3	25
Tuna, Bluefin, cooked, dry heat, 3 ounces	0.2	17
Macaroni, whole wheat, cooked, 1 cup	0.2	17
Acorn squash, cubed, baked, ½ cup	0.2	17
Rice, brown, long grain, not enriched, cooked, ½ cup	0.2	17
Rice, white, long grain, enriched, cooked, ½ cup	0.1	8
Bread, whole wheat, 1 slice	0.1	8
Orange juice, prepared from concentrate, 1 cup	0.1	8
Sunflower seeds, toasted, 1 ounce	0.1	8
Beef steak, bottom round, trimmed of fat, braised, 3 ounces	0.1	8
Yogurt, plain, low fat, 1 cup	0.1	8
Oatmeal, regular and quick, unenriched, cooked with water, ½ cup	0.1	8
Corn, yellow, boiled, 1 medium ear	0.1	8
Milk, 2%, 1 cup	0.1	8
Barley, pearled, cooked, 1 cup	0.1	8
Cheddar cheese, 1½ ounces	0	0
Chicken, meat and skin, roasted, 3 ounces	0	0
Apple, sliced, 1 cup	0	0

Footnote: *DV = Daily Value. Daily Values were developed by the U.S. Food and Drug Administration (FDA) to help consumers compare the nutrient contents of products within the context of a total diet. The DV for thiamine is 1.5 mg for adults and children age 4 and older. Foods providing 20% or more of the Daily Value are considered to be high sources of a nutrient.

[Source ¹¹⁴ ]

Vitamin B1 (Thiamine) Supplements

Vitamin B1 or thiamine is also available in many dietary supplements. Multivitamin or multimineral supplements with vitamin B1 or thiamine typically provide about 1.5 mg thiamine (100% of the Daily Value) and sometimes more ¹¹⁵. Supplements containing B-complex vitamins (including thiamin) or thiamine only are also available. The most commonly used forms of vitamin B1 or thiamine in supplements are thiamine mononitrate and thiamin hydrochloride, which are stable and water soluble ¹, ¹¹⁵.

Benfotiamine is a synthetic thiamine derivative that is used in some dietary supplements. Benfotiamine is not water soluble and is converted to thiamine in the body ¹¹⁶.

Thiamine (Vitamin B1) Deficiency

Thiamine deficiency, also called vitamin B1 deficiency, is a rare disorder that occurs if the recommended daily intake of vitamin B1 or thiamine is not maintained ¹¹⁷, ¹¹⁸. Populations and cultures that rely heavily upon rice based diets are at increased risk of thiamine deficiency ¹¹⁹. Thiamine deficiency may also occur due to impaired intestinal absorption or high excretion rates, such as in people with alcohol dependency, acquired immunodeficiency syndrome (AIDS), and malnutrition ¹²⁰, ¹²¹. Individuals with certain medical and non-medical conditions are more susceptible to vitamin B1 deficiency, e.g., alcohol dependency, older age, diabetes, post-weight loss surgery, cancers that have spread throughout the body, cancer chemotherapy with poor dietary intake, gastrointestinal disease, pregnancy with hyperemesis gravidarum (severe nausea and vomiting during pregnancy), lactation, fasting, starvation, use of unbalanced diets, malnourished patients with intestinal obstruction or malabsorption syndromes, hyperthyroidism (overactive thyroid), kidney failure on hemodialysis, and systemic infections ¹²², ¹²³, ¹¹⁹.

Thiamine is important for the growth, development, and function of the cells in your body. In the human body, thiamine or vitamin B1 exists mainly in the form of thiamin pyrophosphate (TPP). This is the main active form of thiamine and serves as a cofactor for many enzymes during the metabolism of glucose, branched-chain amino acids (protein), and fatty acids (lipids) (see Figure 1 above) ¹⁶. Thiamine or vitamin B1 deficiency can lead to severe (or even fatal) cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium ¹²⁴, ²¹.

Thiamin deficiency causes degeneration of peripheral nerves, thalamus, mammillary bodies, and cerebellum. Cerebral blood flow is markedly reduced, and vascular resistance is increased.
The heart may become dilated; muscle fibers become swollen, fragmented, and vacuolized, with interstitial spaces dilated by fluid. Vasodilation occurs and can result in edema in the feet and legs. Arteriovenous shunting of blood increases. Eventually, high-output heart failure may occur.

Most people have no symptoms and signs of thiamine deficiency or vitamin B1 deficiency; therefore, it must be suspected in the appropriate clinical setting ¹²⁵. Thiamine deficiency or vitamin B1 deficiency early symptoms and signs are often nonspecific and vague, such as fatigue. However, early symptoms mainly arise from neurological, heart and gastrointestinal systems, where patients may experience weight loss, anorexia, confusion, short-term amnesia, malaise, muscle weakness, and heart symptoms due to heart failure ¹²⁶.

Generally, heart effects are referred to as “wet beriberi”, the peripheral neurological signs and symptoms are called “dry beriberi”, and delirium, mental confusion and abnormal eye movements (due to ophthalmoplegia, which is paralysis or weakness of the eye muscles), stance and gait ataxia are termed “cerebral beriberi” or Wernicke’s encephalopathy ¹²⁷, ²³, ¹⁹. “Gastrointestinal beriberi” is caused by lactic acidosis, a condition resulting from the accumulation of lactate and is often associated with nausea, vomiting, and severe abdominal pain ¹²⁸.

Beriberi is the classic diet related thiamine deficiency which can present as wet or dry types. “Wet beriberi” presents as a right sided high-output heart failure with signs of peripheral swelling (edema), an enlarged heart, warm extremities, rapid heart rate (tachycardia), and respiratory distress ¹²⁶. “Dry beriberi” is predominantly a neurological complication involving the peripheral nervous system and presents with painful peripheral neuropathy, malaise, muscle weakness, seizures, or brisk tendon reflexes ¹²³. Infants and children are susceptible to vitamin B1 deficiency too, presenting as infantile or childhood beriberi. Usually, infants present with swelling (edema), ill-looking appearance, pallor, anorexia, coffee ground vomiting, and diarrhea ¹²⁶. Neurological signs include a hoarse cry due to vocal cord paralysis, head lag, seizures, coma, and sudden infant death syndrome. “Juvenile beriberi” is uncommon and often misdiagnosed due to overlapping symptoms of meningitis ¹⁶.

If thiamine deficiency or vitamin B1 deficiency is prolonged or left untreated, an individual is at risk of advanced-stage symptoms due to irreversible neurological damage called Wernicke-Korsakoff syndrome ¹²⁹, ¹³⁰. Wernicke-Korsakoff syndrome is more common in the United States and 8 to 10 times more common among people with chronic alcohol consumption/misuse, severe gastrointestinal disorders, cancers, drug use, and AIDS ¹²⁶. Wernicke-Korsakoff syndrome presents in two phases. Wernicke’s encephalopathy occurs early and presents with polyneuropathy, ataxia, abnormal eye movements due to ophthalmoplegia (paralysis or weakness of the eye muscles), and gait abnormalities. Korsakoff’s syndrome also called Korsakoff psychosis, Korsakoff’s dementia, Korsakoff’s amnesia, or amnestic confabulatory syndrome, is a residual syndrome in patients who suffered from a Wernicke encephalopathy, but did not receive immediate and adequate treatment with thiamine or vitamin B1 replacement therapy ¹³⁰, ¹³¹, ¹³², ¹³³. The most conspicuous symptom of Korsakoff’s syndrome is global short-term amnesia, which can be very profound. In combination with other cognitive and behavioral deficits such as disorientation, confabulation, and hallucinations, which may have far-reaching effects on daily life ¹³⁴, ¹³⁵, ¹³⁶. Wernicke encephalopathy is acute and often reversible while Korsakoff syndrome is chronic and may be irreversible ¹³⁷. The most common cause of Korsakoff syndrome is chronic alcohol abuse ¹³⁸. Alcohol interferes with gastrointestinal tract absorption of thiamine as well as interfering with the liver’s ability to store thiamine. Additionally, accompanying malnutrition often compounds the effects of alcoholism leading to further thiamine deficiency. Other causes of Korsakoff syndrome include eating disorders, chronic vomiting (including hyperemesis gravidarum), psychiatric disorders, chemotherapy, and cancer ¹³⁹, ¹⁴⁰. As Korsakoff syndrome is advanced-stage symptoms of thiamine deficiency, parenteral thiamine treatment does not lead to recovery in about one-quarter of patients ¹³⁶.

To treat mild thiamine deficiency, the World Health Organization (WHO) recommends daily oral doses of 10 mg thiamine for a week, followed by 3–5 mg/daily for at least 6 weeks ¹⁴¹. For patients at risk of thiamine deficiency or with confirmed thiamine deficiency, parenteral (intravenously or intramuscularly) thiamine of 100 mg and 200 mg 3 times a day has been used, respectively, in clinical practice ⁷². The recommended treatment for severe thiamine deficiency consists of 25–30 mg intravenously in infants and 50–100 mg in adults, then 10 mg daily administered intramuscularly for approximately one week, followed by 3–5 mg/day oral thiamine for at least 6 weeks ¹⁷.

Thiamine (Vitamin B1) Deficiency causes

Thiamine deficiency or vitamin B1 deficiency may result from inadequate dietary thiamine intake, administration of total parenteral nutrition without adequate thiamine replacement, increased physiological requirements for thiamine, excessive loss of thiamine from the body, impaired intestinal absorption, small intestinal bacterial overgrowth (SIBO), consumption of anti-thiamine factors (ATF) in food, antacids, sulfites, or sodium bicarbonate food preservatives or a combination of these factors ¹⁴², ¹⁴³, ¹⁴⁴, ¹⁹.

The maximum body store of thiamine is 30 mg, which is rapidly depleted within 2 weeks of beginning a thiamine-deficient diet ⁸. Risk factors for decreased thiamine intake include protracted vomiting, weight loss surgery or gastrointestinal surgery, malnutrition, extreme nausea and vomiting during pregnancy (hyperemesis gravidarum), anorexia, and alcoholism ⁴².

Other conditions that may cause thiamine deficiency or vitamin B1 deficiency include:

HIV/AIDS
Cancers that have spread throughout the body
Extreme nausea and vomiting during pregnancy (hyperemesis gravidarum)
Heart failure (when treated with long-term diuretic therapy)
Long periods of intravenous (IV) nutrition without receiving thiamine supplements
Long-term dialysis
Taking high doses of diuretics (water pills)
Very high thyroid hormone levels (thyrotoxicosis)
Breastfed infants whose mother is lacking in thiamine
Infants fed unusual formulas that don’t have enough thiamine.

In rare cases, thiamine deficiency or vitamin B1 deficiency can be a genetic metabolic disease ¹⁴⁵, ¹⁴⁶. This condition is passed down through families. People with this condition lose the ability to absorb thiamine from foods. This can happen slowly over time. The symptoms occur when the person is an adult. However, this diagnosis is often missed. This is because health care providers may not consider thiamine deficiency in nonalcoholics ¹⁴⁶.

Inadequate dietary thiamine or vitamin B1 intake

Inadequate consumption of thiamine or vitamin B1 is the main cause of thiamine deficiency in developing countries ²⁰. Thiamine deficiency is common in low-income populations whose diets are high in carbohydrate and low in thiamine. 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 ⁸. The consumption of a diet composed mainly of refined carbohydrates or one that includes high alcohol intake also reduces body thiamine stores ⁸.

To attain maximal erythrocyte transketolase activity, at least 0.6 mg of thiamine per 1000 kcal of carbohydrate is required ⁸. Most humans will develop symptoms of thiamine deficiency when intake is below 0.2 mg of thiamine per 1000 kcal. Whole wheat flour contains 0.55 mg of thiamine per 100 g, brown rice 0.33 mg per 100 g, and highly milled white rice only 0.08 mg per 100 g ⁸. Adding baking powder (sodium bicarbonate) to wholemeal flour when baking bread reduces the thiamine content ⁸. 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 ¹⁴². Parboiling (partly cook food by boiling) of rice was originally developed in India but is not practiced in Southeast Asia or Japan, where milled white rice is preferred. 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 ¹⁴².

After 1878, mechanical roller milling of wheat and polishing of rice became widespread ¹⁴⁷. Consumption of mass-produced, polished white rice as the staple diet in East Asian countries led to epidemics of thiamine deficiency (beriberi) in the 1800s and 1900s ¹⁴⁸, ¹⁴⁷. Polished rice and milled wheat were also popular because removal of the oil-rich bran layer from rice or the wheat bran from wheat grains prolonged storage times, minimized rancidity, and reduced the susceptibility to weevils. Mandatory fortification of wheat flour with the thiamine mononitrate vitamer was introduced in Australia in 1991. 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 ¹⁴⁹. Mandatory fortification of bread with iodine and folate was commenced in Australia in 2009. Folate deficiency may indirectly contribute to thiamine deficiency, as folate is required for the regeneration of reduced nicotinamide adenine dinucleotide (NADH) by dihydrofolate reductase. NADH is necessary for the regeneration of TPP ¹⁵⁰. Vitamin C may protect against the development of symptoms of thiamine deficiency ¹⁴².

Breast-fed infants whose mothers are thiamine deficient are vulnerable to developing infantile beriberi. Alcoholism, which is associated with low intake of thiamine among other nutrients, is the primary cause of thiamine deficiency in industrialized countries. Some of the non-alcoholic conditions associated with Wernicke-Korsakoff syndrome include anorexia nervosa, bariatric surgery (weight-loss surgery), gastrointestinal malignancies, and malabsorption syndromes ¹⁵¹, ¹⁵², ¹⁵³, ¹⁵⁴. Obese individuals may also be at heightened risk of thiamine deficiency ¹⁵⁵, ¹⁵⁶. Moreover, cases of Wernicke’s encephalopathy have been linked with hyperemesis gravidarum (severe nausea and vomiting during pregnancy) ¹⁵⁷, ¹⁵⁸, and with parenteral nutrition lacking vitamin supplementation ¹⁵⁹, ¹⁶⁰.

Increased thiamine or vitamin B1 requirement

Conditions resulting in an increased requirement for thiamine or vitamin B1 include strenuous physical exertion, fever, severe infection or sepsis, hyperthyroidism, pregnancy, breast-feeding, adolescent growth, major surgery, refeeding syndrome, or rapid growth of cancers ⁶, ¹⁶¹, ¹⁶², ⁷⁴, ¹⁶³, ¹⁶⁴, ¹⁶⁵, ¹⁶⁶, ¹⁶⁷. Such conditions place individuals with marginal thiamine intake at risk for developing symptomatic thiamine deficiency.

Fever can critically increase the requirement for thiamine, as a rise in core body temperature of 1°C will increase the basal metabolic rate by 10% ¹⁶⁸. Consumption of a high-fat or a high-carbohydrate diet results in increased metabolic consumption of thiamine ¹⁵⁰. This is particularly relevant in individuals with preexisting thiamine deficiency, such as refugees, prisoners of war, persons with alcoholism, oncology patients, and postoperative bariatric surgery or gastrectomy patients. Administering oral, enteral, or parenteral nutrition to these patients without concomitant thiamine supplementation can result in fulminant beriberi or acute refeeding syndrome ¹⁴², ¹⁶⁹, ¹⁷⁰, ¹⁷¹, ¹⁷².

Malaria patients in Southeast Asia were found to be thiamine deficient more frequently than non-infected individuals ¹⁷³, ¹⁷⁴. Malarial infection leads to a large increase in the metabolic demand for glucose. Because thiamine is required for enzymes involved in glucose metabolism, the stresses induced by malarial infection could exacerbate thiamin deficiency in predisposed individuals. HIV-infected individuals, whether or not they had developed AIDS, were also found to be at increased risk for thiamine deficiency ¹⁷⁵. Furthermore, chronic alcohol abuse impairs intestinal absorption and utilization of thiamine ²³; therefore, alcoholics have increased requirements for thiamine or vitamin B1. Thiamine deficiency is also observed as a complication of the refeeding syndrome: the introduction of carbohydrates in severely starved individuals leads to an increased demand for thiamine in glycolysis and the citric acid cycle that precipitates thiamine deficiency ¹⁷⁶.

Anti-thiamin factors

The presence of anti-thiamin factors (ATF) in foods contributes to the risk of thiamin deficiency. Certain plants contain anti-thiamin factors (ATF), which react with thiamine to form an oxidized, inactive product. Consuming very large amounts of tea or coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, might lower thiamin status due to the presence of anti-thiamin factors (ATF) ¹⁷⁷, ¹⁷⁸. Anti-thiamin factors (ATF) include mycotoxins (molds), thiaminases that break down thiamin in food, thiamine antagonists, and hemin ⁸. Individuals who habitually eat certain raw fresh-water fish, raw shellfish, or ferns are at higher risk of thiamine deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking ²³, ²⁴, ¹⁷⁹, ¹⁸⁰, ¹⁸¹. In Nigeria, an acute, neurologic syndrome (seasonal ataxia) has been associated with thiamine deficiency precipitated by a thiaminase in African silkworms (Anaphe species), a traditional, high-protein food for some Nigerians ¹⁸².

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 ⁸. These cause oxidation of the thiazole ring of thiamine, forming nonabsorbable thiamine disulfide ¹⁴². For example, consumption of 1 g of dry tea leaves boiled in 100 mL of water for 5 minutes caused thiamine loss of 0.21 mg per hour ¹⁸³. Vitamin C and cysteine can protect thiamine from degradation caused by organic acids and polyphenols ¹⁸⁴. Outbreaks of beriberi in the wet season in some countries may be related to low availability of food, importation of poor-quality rice or milled white rice, seasonal variations in plant tannin levels, or the mycotoxin citreoviridin, produced by rice mold ¹⁸⁵, ¹⁶², ¹⁸⁶.

Food additives and thiamine

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 ⁸. Sulfite-type food preservatives include sulfur dioxide, sodium sulfite, sodium and potassium bisulfite, and sodium and potassium metabisulfite ⁸. 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. For example, respective thiamine loss from cabbage blanched with sulfite-treated water versus untreated water was 45% vs 15% ¹⁴². The use of sulfiting agents in foods recognized as important sources of thiamine is prohibited by the US Food and Drug Administration ¹⁸⁷, ¹⁸⁸, ¹⁸⁹, ¹⁹⁰.

Excessive loss of thiamine caused by thiamine-drug interactions

Excessive loss of thiamine may precipitate thiamine deficiency. Increased losses of ingested thiamine can be caused by drug-related polyuria or diarrhea, drug interactions, or chronic excessive alcohol consumption ⁸. 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 ⁴². By increasing urinary flow, diuretics may prevent reabsorption of thiamine by the kidneys and increase its excretion in the urine ¹⁹¹, ¹⁹². The risk of thiamine deficiency is increased in diuretic-treated patients with marginal thiamine intake ¹⁹³ and in individuals receiving long-term, diuretic therapy ⁴⁷. Patients with congestive heart failure who receive chronic therapy with furosemide or thiazide diuretics can also develop thiamine deficiency. The prevalence of thiamine deficiency in this patient population varies from 21% to 98% ⁸. Supplementation with thiamine has been shown to improve left ventricular ejection fraction by 22%, New York Heart Association Functional Classification, and TPP effect (from 11.7% to 5.4%) in these patients ⁴⁸. Mechanisms for exacerbation of heart failure by diuretics include increased thiamine loss in urine, furosemide-related inhibition of cardiac myocyte thiamine uptake, furosemide-induced anorexia, furosemide inhibition of intestinal absorption or cellular uptake of thiamine, and hypomagnesemia ⁴². Unrecognized thiamine deficiency in heart failure patients treated with long-term diuretic therapy may result in Shoshin beriberi ¹⁹⁴.

Individuals with kidney failure requiring hemodialysis lose thiamine at an increased rate and are at risk for thiamine deficiency ¹⁹⁵. Alcoholics who maintain a high fluid intake and high urine flow rate may also experience increased loss of thiamine, exacerbating the effects of low thiamine intake ¹⁹⁶.

Omeprazole a proton pump inhibitor because of its azole analogue molecular structure may cause inactivation of pyruvate decarboxylase and human erythrocyte transketolase, resulting in antagonism of thiamine ¹⁹⁷. Omeprazole may inhibit gastric proton pumps by competing with thiamine for binding to hydrogen/potassium adenosine triphosphatase ¹⁴⁵, ¹⁹⁷. Proton pump inhibitor drugs or Roux-en-Y gastric bypass surgery may also worsen subclinical thiamine deficiency by promoting small intestinal bacterial overgrowth, which alters luminal thiamine levels ¹⁹⁸, ¹⁴⁴. Hypomagnesemia induced by proton pump inhibitors can contribute to functional thiamine deficiency, as magnesium is a required cofactor for the formation of TPP and acetyl coenzyme A ¹⁹⁸. 5-Fluorouracil decreases hepatic thiamine levels and thiamine-dependent transketolase activity. This is associated with an increase in the TPP effect in vitro and in whole blood ¹⁹⁹. 5-Fluorouracil is catabolized to fluoroacetate, which blocks the Krebs cycle and ATP production, leading to neurotoxicity, ammonia formation, and encephalopathy ²⁰⁰, ²⁰¹, ²⁰². Metformin, a substrate and inhibitor of the human thiamine transporter 2, reduces both intestinal absorption of thiamine and levels of thiamine in tissues and liver ²⁰³, ²⁰⁴, ²⁰⁵. Alcohol decreases carrier-mediated thiamine transport in the brush border and basolateral membrane of enterocytes in the jejunum (thiamine transporter 1) and potentially decreases thiamine production by intestinal flora in the lumen ²⁰⁶

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 ²⁰⁷, ¹⁴³, ¹⁴⁴. The use of broad-spectrum antibiotics (penicillins, cephalosporins, aminoglycosides, tetracyclines, fluoroquinolones, sulfonamides, trimethoprim), however, can potentially cause thiamine deficit in some patients by reducing counts of normal intestinal bacteria that produce thiamine (eg, Escherichia coli, bifidobacteria, Lactobacillus spp) and by promoting the growth of pathogenic flora such as Clostridium spp, which produce thiaminases ²⁰⁸, ⁴². Metronidazole, a thiazole, has been shown to be a substrate for thiaminase 1. 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 ¹⁸⁴.

Table 3. Effects of drugs and antithiamine agents on thiamine

Drug family/antithiamine agent	Drug	Effect on thiamine
Alcohol	Ethanol	Decreased intestinal thiamine transport
Antibiotic	Metronidazole	Production of thiamine antimetabolites
Antibiotics	β-lactams, aminoglycosides, trimethoprim, quinolones	Decreased production of thiamine by intestinal microbiota
Chemotherapy	5-fluorouracil	Decreased production of hepatic thiamine, decreased TKT activity
Polyphenols (coffee, tea)	Caffeic acid, tannic acid	Oxidation of thiazole ring
Diuretics	Furosemide, thiazides	Increased renal excretion, decreased intestinal absorption
Flavonoids	Quercetin, rutin	Oxidation to thiamine disulfide
Food preservatives	Sulfites	Disruption of thiamine methylene bridge
Oral hypoglycemics (biguanide)	Metformin	THTR2 inhibitor, prevents active transport of thiamine
Proton pump inhibitors	Omeprazole	Inactivation of PDH, erythrocyte transketolase, and H/K ATPase

Abbreviations: H/K ATPase = hydrogen/potassium adenosine triphosphatase; PDH = pyruvate dehydrogenase; TKT = transketolase; THTR2 = thiamine transporter 2.

[Source ⁸ ]

Groups at risk of thiamine deficiency

The following groups are among those most likely to have inadequate thiamine status ¹⁷.

People with alcohol dependence

In highly industrialized countries, chronic alcohol use disorders appear to be the most common cause of thiamine deficiency ¹. Up to 80% of people with chronic alcoholism develop thiamine deficiency because ethanol reduces gastrointestinal absorption of thiamine, thiamine stores in the liver, and thiamine phosphorylation ⁹, ¹³². Also, people with alcoholism tend to have inadequate intakes of essential nutrients, including thiamine.

Older adults

Up to 20%–30% of older adults have laboratory indicators that suggest some degree of thiamine deficiency ⁷, ¹¹³. Possible reasons include low dietary intakes, a combination of chronic diseases, concomitant use of multiple medications, and low absorption of thiamin as a natural result of aging ²⁰⁹, ⁴⁶. Some small studies have found that the risk of deficiency is particularly high in elderly people who reside in an institution ⁵⁴, ⁶⁰.

People with HIV/AIDS

People with HIV infection have an increased risk of thiamin deficiency and its sequelae, including beriberi and Wernicke-Korsakoff syndrome ¹, ²¹⁰. Autopsies of 380 people with AIDS found that almost 10% had Wernicke’s encephalopathy ²¹¹, and some experts believe that thiamin deficiency is underdiagnosed in this population ²¹². The association between thiamin deficiency and HIV/AIDS is probably due to malnutrition as a result of the catabolic state associated with AIDS ¹⁷.

People with diabetes

Some small studies have found that thiamine levels in plasma are up to 76% lower in people with type 1 diabetes than in healthy volunteers and 50%–75% lower in people with type 2 diabetes ²¹³, ³⁰. Other studies have shown a higher risk of thiamine deficiency in people with type 1 and/or type 2 diabetes based on tests of erythrocyte transketolase activity ³⁵, ²¹⁴. These lower thiamine levels might be due to increases in clearance of thiamin by the kidneys. The relevance of these effects to clinical prognosis or outcomes is not known.

People who have undergone weight loss surgery

Weight loss surgery also called bariatric surgery for weight loss is associated with some risks, including severe thiamine deficiency due to malabsorption that can lead to beriberi or Wernicke’s encephalopathy ¹⁷. A 2008 literature review identified 84 cases of Wernicke’s encephalopathy after bariatric surgery (primarily gastric bypass surgery) between 1991 and 2008 ²¹⁵. About half of these patients experienced long-lasting neurologic impairments. Micronutrient supplements that include thiamine are almost always recommended for patients following weight loss surgery to avoid deficiencies ²¹⁶.

Thiamine deficiency prevention

Eating a proper diet that is rich in vitamins will prevent thiamine deficiency. Nursing mothers should make sure that their diet contains all vitamins. If your infant is not breastfed, make sure that the infant formula contains thiamine.

If you drink alcohol, try to cut down or quit. Also, take B vitamins to make sure your body is properly absorbing and storing thiamine.

Thiamine deficiency symptoms

Generally, heart effects of thiamine deficiency are referred to as “wet beriberi”, the peripheral neurological signs and symptoms of thiamine deficiency are called “dry beriberi”, and delirium, mental confusion and abnormal eye movements (due to ophthalmoplegia, which is paralysis or weakness of the eye muscles), stance and gait ataxia are termed “cerebral beriberi” or Wernicke’s encephalopathy ¹²⁷, ²³, ¹⁹. “Gastrointestinal beriberi” is caused by lactic acidosis, a condition resulting from the accumulation of lactate and is often associated with nausea, vomiting, and severe abdominal pain ¹²⁸.

Thiamine deficiency cardiovascular signs and symptoms are as follows:

Fast heart rate (tachycardia)
Chest pain
Wide pulse pressure
Heart failure (orthopnea with or without edema, warm skin due to vasodilation) ²¹⁷
Hypotension, shock

Thiamine deficiency gastroenterologic signs and symptoms are as follows:

Anorexia
Abdominal discomfort
Constipation
Difficulty swallowing (dysphagia) ²¹⁸

Thiamine deficiency neurologic signs and symptoms of thiamine deficiency are as follows ²¹⁹:

Poor memory, irritability, sleep disturbance
Wernicke encephalopathy and/or Korsakoff syndrome ²²⁰
Bilateral, symmetrical lower extremity paresthesias, burning pain
Muscle cramps
Decreased vibratory position sensation
Absent knee and ankle jerk
Muscle atrophy
Foot drop (late stage)
Abnormal eye movement (back and forth movements called nystagmus) – most common (early sign) ²²¹

Thiamine deficiency infantile beriberi signs and symptoms are as follows ²²²:

Congestive heart failure
Loss of voice (aphonia)
Absent deep tendon reflex.

A study by Mifsud et al ²²¹ described the characteristics of 56 cases of thiamine deficiency that were seen at a French tertiary hospital. A history of alcohol abuse was found in 45 patients (80%), and while neurologic symptoms were the basis for diagnosis in the majority of individuals, there were frequent instances of nonspecific and digestive symptoms. Moreover, the criteria for malnutrition were fulfilled in 34% of patients. Of the 54% of patients in whom brain magnetic resonance imaging (MRI) scans were performed, abnormal scans were found in 63% of cases ²²¹.

A study by Isenberg-Grzeda et al ²²³ indicated that thiamine deficiency may be a frequent occurrence among inpatients with cancer, even in those who are of normal weight or overweight, lack other vitamin deficiencies, and are receiving multivitamin supplements. The single-center study found thiamine deficiency in 55.3% of 217 patients, with risk factors for the deficiency including active cancer treatment and fluorouracil-based chemotherapy ²²³.

A literature review by Jain et al ⁴⁵ comparing the incidence of thiamine deficiency in patients with heart failure to that in controls reported an odds ratio of 2.53, with possible reasons for the deficiency in heart failure including diuretic use, dietary changes, and alterations in the absorption and metabolism of thiamine. The literature also indicated that thiamine supplementation may improve symptoms and ejection fraction in patients with heart failure ⁴⁵.

Beriberi signs and symptoms

Beriberi is a disease in which the body does not have enough thiamine or vitamin B1.

There are two major types of beriberi:

Wet beriberi: Thiamine deficiency with cardiovascular system involvement is termed wet beriberi. The chronic form of wet beriberi consists of 3 stages. In the first stage, peripheral vasodilation occurs, leading to a high cardiac output state. This leads to salt and water retention mediated through the renin-angiotensin-aldosterone system in the kidneys. As the vasodilation progresses, the kidneys detect a relative loss of volume and respond by conserving salt. With the salt retention, fluid is also absorbed into the circulatory system. The resulting fluid overload leads to edema of the dependent extremities.
Dry beriberi: Thiamine deficiency with nervous system involvement is termed dry beriberi. This presentation usually occurs when poor caloric intake and relative physical inactivity are present. The neurologic findings can be peripheral neuropathy characterized by symmetrical impairment of sensory, motor, and reflex functions of the extremities, especially in the distal lower limbs. Histologic analysis has shown that the lesions arise from a degeneration of the myelin in the muscular sheaths without inflammation ²²⁴.
Cerebral beriberi also known as Wernicke-Korsakoff syndrome that affects the nervous system ²²⁵.

Symptoms of “dry beriberi” include:

Difficulty walking
Loss of feeling (sensation) in hands and feet
Loss of muscle function or paralysis of the lower legs
Mental confusion
Pain
Speech difficulties
Strange eye movements (nystagmus)
Tingling
Vomiting

Symptoms of “wet beriberi” include:

Awakening at night short of breath
Increased heart rate
Shortness of breath with activity
Swelling of the lower legs

Wernicke-Korsakoff syndrome signs and symptoms

Wernicke encephalopathy and Korsakoff syndrome are often thought to be on a spectrum with one another as they are both due to thiamine or vitamin B1 deficiency. Wernicke’s encephalopathy causes brain damage in lower parts of the brain called the thalamus and hypothalamus ²²⁶. Korsakoff’s psychosis results from permanent damage to areas of the brain involved with memory ²²⁶. Therefore, clinicians should screen for them together. Wernicke encephalopathy classically presents with the triad of altered mental status, ophthalmoplegia, and ataxia. In reality, less than 20% of patients will present with all three of these findings ¹²⁹. Korsakoff syndrome or Korsakoff’s psychosis is a neuropsychiatric disorder associated with memory disturbances in which there are significant deficits in anterograde and retrograde memory. Immediate memory is maintained, but short-term memory is diminished with intact sensorium. The disorder is associated with patients fabricating stories in the setting of clear consciousness. Confabulations can be spontaneous or provoked with provoked confabulation commonly seen in chronic Korsakoff syndrome and spontaneous confabulation usually noted in the acute Wernicke’s encephalopathy ²²⁷, ²²⁸.

The following signs and symptoms should cause suspicion for Wernicke-Korsakoff syndrome ¹²⁹:

Altered mental status (up to 82% of patients) – amnesia, disorientation, confabulations
Oculomotor findings – most often horizontal nystagmus, retinal hemorrhage, ophthalmoplegia, cranial nerve IV palsy, conjugate gaze
Loss of muscular coordination (ataxia) – wide-based gait. Ataxia is likely to be a combination of polyneuropathy, cerebellar damage, and vestibular paresis. Vestibular dysfunction, usually without hearing loss, is universally impaired in the acute stages of Wernicke encephalopathy.

The cognitive impairments specific to Korsakoff syndrome vs. Wernicke encephalopathy include anterograde amnesia, profoundly limiting one’s learning capacity, retrograde amnesia, as well as executive deficits, resulting in decreased inhibition and difficulties with judgment, planning and problem-solving ²²⁹. Anterograde amnesia can result in the classic symptom of confabulations, replacing one’s gap in memory with untrue information ²³⁰.

Symptoms of Wernicke encephalopathy include:

Confusion and loss of mental activity that can progress to coma and death
Loss of muscle coordination (ataxia) that can cause leg tremor
Vision changes such as abnormal eye movements (back and forth movements called nystagmus), double vision, eyelid drooping
Alcohol withdrawal

Symptoms of Korsakoff syndrome include:

Inability to form new memories
Loss of memory, can be severe
Making up stories (confabulation)
Seeing or hearing things that are not really there (hallucinations)

Thiamine deficiency complications

Thiamine deficiency complications may include:

Coma
Congestive heart failure
Death
Psychosis

Thiamine deficiency diagnosis

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. The person may be less able to sense vibrations. The person may appear poorly nourished.

A physical examination of the nervous and muscular system may show signs of damage to many nerve systems:

Changes in walking
Coordination problems
Abnormal eye movement
Drooping of the eyelids
Decreased or abnormal reflexes
Fast pulse (heart rate)
Low blood pressure
Low body temperature
Muscle weakness and atrophy (loss of tissue mass)
Problems with walk (gait) and coordination.

For practical reasons, replacing thiamine as an initial test may be most feasible ²³¹. If the patient responds to thiamine administration, it is safe to assume that a measure of thiamine deficiency was responsible for the signs and symptoms ²³¹. Thiamine is not toxic in high levels, which means that this route carries little risk. In addition, time is saved in treating the patient and money is saved in testing. However, although observation of a patient’s clinical response to thiamine administration remains the easiest, least expensive form of testing, clinicians usually miss the subclinical forms of thiamine deficiency ²³¹.

The diagnosis of Wernicke’s encephalopathy is a histopathological diagnosis, made after a postmortem examination of the brain ²³², ²³³, ²³⁴.

The Caine criteria have been described to have a sensitivity or 85% and specificity of 100% for Wernicke encephalopathy, in the alcoholic population ²³⁵, ¹²⁹. Because of the strong overlap, the Caine criteria can be used to help screen for Korsakoff syndrome as well.

Caine criteria for the diagnosis of Wernicke encephalopathy in chronic alcoholics ²³⁵. When 2 out of these 4 criteria apply, the clinical diagnosis of Wernicke encephalopathy is made ¹²⁹, ²³⁵:

Dietary deficiencies
- Undernutrition (body mass index <2 SD below normal)
- A history of grossly impaired dietary intake
- An abnormal thiamine status
Oculomotor abnormalities
- Ophthalmoplegia
- Nystagmus
- Gaze palsy
Cerebellar dysfunction
- Unsteadiness or ataxia
- Abnormalities of past pointing
- Dysdiadokokinesia
- Impaired heel-shin testing
Either an altered mental state OR mild memory impairment
- Altered mental status
  - Disorientation in two of three fields
  - Confused
  - An abnormal digit span
  - Comatose
- Mild memory impairment
  - Failure to remember two or more words in the four-item memory test
  - Impairment on more elaborate neuropsychological tests of memory function

The following tests are used to check a person’s nutrition level:

Serum albumin (relates to person’s general nutrition)
Transketolase activity in red blood cells (reduced in people with thiamine deficiency). The serum level of thiamin is not a reliable indicator of thiamin status. However, thiamin function can be measured by red blood cells transketolase activity (erythrocytes transketolase activity or ETKA). Red blood cells transketolase activity (EKTA) of 0 to 15% is considered adequate, 15 to 25% is considered a moderate risk, and 25% or higher is considered high risk for thiamin deficiency ²³⁶, ²³⁷.
Serum vitamin B1 or thiamine levels. Direct measurement of erythrocyte thiamin pyrophosphate (TPP) can be done using whole-blood testing and has more sensitivity, specificity, precision, and robustness ²³⁶. The concentration of TPP in the whole blood ranges from 70 to 180 nmol/L ¹²³.
Urine tests to see if thiamine is passing through the urine. Urinary thiamine excretion can be used to measure adequate dietary intake. However, it does not reflect the thiamine stores in the body. In adults, urinary thiamine excretion of <100 mcg/day suggests inadequate intake, and less than 40 mcg/day suggests thiamin deficiency ¹⁸.
Liver enzymes may be high in people with a history of long-term alcohol abuse.

A brain MRI may show changes in the tissue of the brain. But if Wernicke-Korsakoff syndrome is suspected, treatment should start immediately. Usually a brain MRI exam is not needed.

Thiamine deficiency treatment

In suspected cases of thiamine deficiency, prompt administration of parenteral (intravenously or intramuscularly) thiamine is indicated.

The preferred dose of thiamine treatment for Wernicke encephalopathy may be as high as 500 mg intravenous thiamine given three times daily for 3 to 5 days, followed by intravenous thiamine, 250 mg/day for 3 to 5 days or until the symptoms disappear, and then further treatment with oral thiamine, 100 mg/day ²³⁸, ²²⁵. The rationale for using three times daily dosing of intravenous thiamine in acute presentations is based on the short half-life of intravenous thiamine (96 minutes) and the slow, carrier mediated process of thiamine transport across the blood–brain barrier ⁸. A single intravenous dose of thiamine is less likely to achieve sufficient brain tissue levels, and the bioavailability of oral thiamine hydrochloride is only 3.7% to 5.3% ²³⁸.

All malnourished patient may need higher doses of thiamine ²²⁵. Thiamine is generally administered before or together with glucose solutions because the glucose oxidation can decrease thiamine levels thereby exacerbating the neurological symptoms of Wernicke encephalopathy ²²⁵. Patients with magnesium deficiency should also be treated as this can result in reduced recovery from Wernicke encephalopathy especially in patients with alcoholism ²³⁹, ²³⁰, ²⁴⁰. Following a review of 19 papers, it has been recommended not to delay in correcting hypoglycemia ²⁴¹. There are suggestions that prolonged and not acute replacement of glucose without thiamine supplementation increased the risk of Wernicke encephalopathy.

For Korsakoff syndrome high dose thiamine at 500 mg to 1500 mg, IV, three times daily for at least 3 days ¹²⁹. Electrolyte abnormalities should be corrected and fluids replaced. In particular, magnesium requires replacement, as thiamine-dependent enzymes cannot operate in a magnesium-deficient state. Many patients will present needing glucose replacement as well, and traditionally it was thought that replacing glucose before thiamine could exacerbate the patient’s symptoms ¹³⁸.

Thiamine, even at high concentrations, is not toxic in a person with normal kidney function ²⁴². No cases of thiamine toxicity have been reported from the use of thiamine at the dosages indicated, even in patients in critical condition ²⁴².

Once clinical symptoms improve, thiamine supplementation can switch to the oral route with a dose range of 50 to 100 mg per day ⁶. It is equally important in individuals with thiamine deficiency to require other nutrient supplementation such as magnesium, vitamin B2 (riboflavin), vitamin B3 (nicotinamide), vitamin B6 (pyridoxine), vitamin B12, vitamin C, potassium, and phosphate ¹⁷.

Support for cardiac function is necessary in cases of wet beriberi, because lack of cardiac support leads to low-output cardiac failure when the thiamine deficiency is corrected ²⁴².

Follow-up care until delivery of current pregnancy, intensive care for advanced cardiomyopathy, definitive care for hyperthyroidism, or further workup of intestinal derangement may be warranted in patients with thiamine deficiency ²⁴².

Blood tests may be repeated after the treatment is started. These tests will show how well you are responding to the medicine.

After the acute phase of vitamin and electrolyte replacement, there is mounting evidence that memory rehabilitation is beneficial in Korsakoff syndrome. Declarative memory (“knowing what”) seems to be most affected in Korsakoff syndrome, leading to many patients requiring lifelong care. Because procedural learning (“knowing how”) seems to remain somewhat maintained in Korsakoff syndrome, memory rehabilitation focussed in this area has shown promising outcomes. There has been some success in small Korsakoff syndrome patient populations in learning procedures and improving their autonomy ²²⁹.

Thiamine deficiency recovery time

Beriberi can be quickly fatal or can slowly rob an individual of almost all energy for even the simplest of daily activities. However, beriberi is one of the most easily treatable thiamine deficiency, with a remarkable recovery being possible even in severe cases ²⁴³. Therefore, the patient prognosis for beriberi is usually good, unless patients have established Korsakoff syndrome. While thiamine can induce partial improvement, the neuropsychological deficits persist in many cases. The confusional state usually improves when IV thiamine is administered but the learning and memory deficits only improve partially. A small number of patients fail to have any improvement and may develop Korsakoff psychosis or Korsakoff syndrome, which often requires institutionalization. Very few individuals recover at this point.

In cases of wet beriberi, clinical improvement can be observed within 12 hours of treatment, with normalization of heart function and size occurring in 1 or 2 days ²⁴³. The recovery is so dramatic that treatment with thiamine is a diagnostic test, which can be used in cases of acute heart failure and insidious peripheral neuropathy ²⁴³.

A retrospective study by Harel et al ²⁴⁴ indicated that thiamine deficiency in infancy can lead to long-term motor function problems. The study looked at children aged 5-6 years who, during the first 2 years of life, had been fed a faulty milk substitute that was deficient in thiamine, comparing them with age-matched controls. The Movement Assessment Battery for Children and the Zuk Assessment indicated that motor function difficulties existed in 56% and 59%, respectively, of the thiamine-deficient formula group, compared with 10% and 3%, respectively, of the control group. The results suggested that infantile thiamine deficiency affects gross and fine motor function, as well as balance skills ²⁴⁴.

Thiamine deficiency prognosis

Untreated, beriberi can be fatal. With treatment, symptoms usually improve quickly. Heart damage is usually reversible. A full recovery is expected in these cases. However, if acute heart failure has already occurred, the outlook is poor.

Nervous system damage is also reversible, if caught early. High suspicion for Wernicke’s encephalopathy is key to improving patient prognosis. Classically, the thinking was that once Korsakoff syndrome has set in, memory loss (amnesia) was generally irreversible, even with treatment ²⁴⁵, ²⁴⁶, ¹³⁸. Several case studies and eight double-blind trials have been published, where Korsakoff syndrome patients were treated with clonidine, fluvoxamine, reboxetine, or rivastigmine. Together, these studies did not produce any consistent evidence for the efficacy of any of these interventions ²⁴⁷. Therefore, until this date, no effective pharmacological treatment for Korsakoff syndrome is available ¹³⁰. More recent research has shown promise in memory rehabilitation including memory compensation techniques and error-less learning strategies ¹³⁰. If a person with Wernicke encephalopathy receives thiamine replacement, language problems, unusual eye movements, and walking difficulties may go away. However, Korsakoff syndrome or Korsakoff psychosis tends to develop as Wernicke symptoms go away.

Regarding neuroimaging, associations with cortical lesions have shown to correlate with a worse prognosis ¹²⁹.

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