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Thiamin (also spelled thiamine) is a water-soluble B vitamin, also known as vitamin B1 or aneurine (1). Isolated and characterized in the 1930s, thiamin was one of the first organic compounds to be recognized as a vitamin (2). Thiamin occurs in the human body as free thiamin and as various phosphorylated forms: thiamin monophosphate (TMP), thiamin triphosphate, adenosine thiamin triphosphate, and thiamin pyrophosphate (TPP), which is also known as thiamin diphosphate.
The synthesis of TPP from free thiamin requires magnesium, adenosine triphosphate (ATP), and the enzyme, thiamin pyrophosphokinase. In humans, TPP is required as a coenzyme in the metabolism of carbohydrates and branched-chain amino acids. Forms of thiamin are also needed for ribose synthesis and for α-oxidation of 3-methyl-branched fatty acids.
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. They catalyze the decarboxylation of pyruvate, α-ketoglutarate, 2-oxoadipate, and branched-chain amino acids (BCAA) to form acetyl-coenzyme A (CoA), succinyl-CoA, glutaryl-CoA, and derivatives of 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 (2). 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 BCAAs also contributes to the production of cholesterol and donates nitrogen for the synthesis of the neurotransmitters, glutamate and g-aminobutyric acid (GABA) (3). In addition to the thiamin coenzyme (TPP), 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. 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. The pentose phosphate pathway also supplies various anabolic pathways, including fatty acid synthesis, with the niacin-containing coenzyme NADPH (1, 4). Because transketolase decreases early in thiamin deficiency and, unlike most thiamin-dependent enzymes, is present in red blood cells, measurement of its activity in red blood cells has been used to assess thiamin nutritional status (2, 5, 6).
2-Hydroxyacyl-CoA lyase is a TPP-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 (7).
Beriberi, the disease resulting from severe thiamin deficiency, was described in Chinese literature as early as 2600 B.C. Thiamin deficiency affects the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems (2). Beriberi has been subdivided into dry, wet, cerebral, or gastrointestinal, depending on the systems affected by severe thiamin deficiency (1, 8).
The main feature of dry (paralytic or nervous) beriberi is peripheral neuropathy. Early in the course of the neuropathy, "burning feet syndrome" may occur. Other symptoms include abnormal (exaggerated) reflexes, as well as diminished sensation and weakness in the legs and arms. Muscle pain and tenderness and difficulty rising from a squatting position have also been observed (9).
In addition to neurologic symptoms, wet (cardiac) beriberi is characterized by cardiovascular manifestations of thiamin deficiency, which include rapid heart rate, enlargement of the heart, severe swelling (edema), difficulty breathing, and ultimately, congestive heart failure. The Japanese literature describes the acute fulminant form of wet beriberi as “shoshin” (10).
Cerebral beriberi may lead to Wernicke's encephalopathy and Korsakoff's psychosis, especially in people who abuse alcohol. The diagnosis of Wernicke's encephalopathy is based on a "triad" of signs, which include abnormal eye movements, stance and gait ataxia, and cognitive impairment. Due in part to an overlap of symptoms with alcoholic delirium, Wernicke’s encephalopathy is thought to be underdiagnosed (11). If left untreated, the irreversible neurologic damage can cause additional clinical manifestations known as Korsakoff’s psychosis. This syndrome – also called Korsakoff’s dementia, Korsakoff's amnesia, or amnestic confabulatory syndrome – involves a confused, apathetic state and a profound memory disorder, with severe amnesia and loss of recent and working memory.
Thiamin deficiency affecting the central nervous system is referred to as Wernicke's disease when the amnesic state is not present and Wernicke-Korsakoff syndrome (WKS) when the amnesic symptoms are present along with the eye-movement and gait disorders. Rarer neurologic manifestations can include seizures (12). Most WKS sufferers are alcoholics, although it has been observed in other disorders of gross malnutrition, including stomach cancer and AIDS. Administration of intravenous thiamin to WKS patients generally results in prompt improvement of the eye symptoms, but improvements in motor coordination and memory may be less, depending on how long the symptoms have been present. Evidence of increased immune cell activation and increased free radical production in the areas of the brain that are selectively damaged suggests that oxidative stress plays an important role in the neurologic pathology of thiamin deficiency (13).
TPP is critical for metabolic reactions that utilize glucose in glycolysis and the citric acid cycle (see Figure 1). A decrease in the activity of thiamin-dependent enzymes limits the conversion of pyruvate to acetyl-CoA and the utilization of the citric acid cycle, leading to accumulation of pyruvate and lactate. Lactic acidosis, a condition resulting from the accumulation of lactate, is often associated with nausea, vomiting, and severe abdominal pain in a syndrome described as gastrointestinal beriberi (8).
Thiamin deficiency may result from inadequate thiamin intake, increased requirement for thiamin, excessive loss of thiamin from the body, consumption of anti-thiamin factors in food, or a combination of these factors.
Inadequate consumption of thiamin is the main cause of thiamin deficiency in developing countries (2). Thiamin deficiency is common in low-income populations whose diets are high in carbohydrate and low in thiamin (e.g., milled or polished rice). Breast-fed infants whose mothers are thiamin deficient are vulnerable to developing infantile beriberi. Alcoholism, which is associated with low intake of thiamin among other nutrients, is the primary cause of thiamin deficiency in industrialized countries. Some of the non-alcoholic conditions associated with WKS include anorexia nervosa, bariatric surgery (weight-loss surgery), gastrointestinal malignancies, and malabsorption syndromes (14-17). Obese individuals may also be at heightened risk of thiamin deficiency (18, 19). Moreover, cases of Wernicke’s encephalopathy have been linked with hyperemesis gravidarum (severe nausea and vomiting during pregnancy) (20, 21), and with parenteral nutrition lacking vitamin supplementation (22, 23).
Conditions resulting in an increased requirement for thiamin include strenuous physical exertion, fever, pregnancy, breast-feeding, and adolescent growth. Such conditions place individuals with marginal thiamin intake at risk for developing symptomatic thiamin deficiency.
Malaria patients in Southeast Asia were found to be thiamin deficient more frequently than non-infected individuals (24, 25). Malarial infection leads to a large increase in the metabolic demand for glucose. Because thiamin 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 thiamin deficiency (26). Further, chronic alcohol abuse impairs intestinal absorption and utilization of thiamin (1); thus, alcoholics have increased requirements for thiamin. Thiamin 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 thiamin in glycolysis and the citric acid cycle that precipitates thiamin deficiency (27).
Excessive loss of thiamin may precipitate thiamin deficiency. By increasing urinary flow, diuretics may prevent reabsorption of thiamin by the kidneys and increase its excretion in the urine (28, 29). The risk of thiamin deficiency is increased in diuretic-treated patients with marginal thiamin intake (30) and in individuals receiving long-term, diuretic therapy (31). Individuals with kidney failure requiring hemodialysis lose thiamin at an increased rate and are at risk for thiamin deficiency (32). Alcoholics who maintain a high fluid intake and high urine flow rate may also experience increased loss of thiamin, exacerbating the effects of low thiamin intake (33).
The presence of anti-thiamin factors (ATF) in foods contributes to the risk of thiamin deficiency. Certain plants contain ATF, which react with thiamin 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 ATF (34, 35). ATF include mycotoxins (molds) and thiaminases that break down thiamin in food. Individuals who habitually eat certain raw fresh-water fish, raw shellfish, or ferns are at higher risk of thiamin deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking (1, 6). In Nigeria, an acute, neurologic syndrome (seasonal ataxia) has been associated with thiamin deficiency precipitated by a thiaminase in African silkworms, a traditional, high-protein food for some Nigerians (36).
The RDA for thiamin, revised in 1998 by the Food and Nutrition Board of the Institute of Medicine, was based on the prevention of deficiency in generally healthy individuals (37; Table 1).
| Life Stage | Age | Males (mg/day) | Females (mg/day) |
|---|---|---|---|
| Infants | 0-6 months | 0.2 (AI) | 0.2 (AI) |
| Infants | 7-12 months | 0.3 (AI) | 0.3 (AI) |
| Children | 1-3 years | 0.5 | 0.5 |
| Children | 4-8 years | 0.6 | 0.6 |
| Children | 9-13 years | 0.9 | 0.9 |
| Adolescents | 14-18 years | 1.2 | 1.0 |
| Adults | 19 years and older | 1.2 | 1.1 |
| Pregnancy | all ages | - | 1.4 |
| Breast-feeding | all ages | - | 1.4 |
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 (38). In addition, a study in 408 US women found that higher dietary intakes of thiamin were inversely associated with five-year change in lens opacification (39). However, these cross-sectional associations have yet to be elucidated by studies of causation.
Patients with diabetes mellitus have been reported to have low plasma concentrations and high renal clearance of thiamin (40, 41), suggesting that individuals with type 1 or type 2 diabetes are at increased risk for thiamin deficiency. Two thiamin transporters, thiamin transporter-1 (THTR-1) and THTR-2, are involved in thiamin uptake by enterocytes in the small intestine and re-uptake in the proximal tubules of the kidneys. One study suggested that hyperglycemia in patients with diabetes could affect thiamin re-uptake by decreasing the expression of thiamin transporters in the kidneys (42). Conversely, thiamin deficiency appears to impair the normal endocrine function of the pancreas and exacerbate hyperglycemia. Early studies showed that insulin synthesis and secretion were altered in the endocrine pancreatic cells of thiamin-deficient rats (43, 44). In humans, thiamin deficiency caused by recessive mutations in the gene encoding THTR-1 leads to diabetes mellitus in the thiamin-responsive megaloblastic anemia syndrome (see Metabolic diseases below).
In a randomized, double-blind pilot study, high-dose thiamin supplements (300 mg/day) were given for six weeks to hyperglycemic individuals (either glucose intolerant or newly diagnosed with type 2 diabetes). Thiamin supplementation prevented any further increase in fasting glucose and insulin concentrations compared with placebo treatment but did not reduce the hyperglycemia (45). However, one study suggested that thiamin supplementation might improve fasting glucose concentrations in early stages of type 2 diabetes (i.e., pre-diabetes) (46).
Some older adults are at increased risk for developing subclinical thiamin deficiency secondary to poor dietary intake, reduced gastrointestinal absorption, and multiple medical conditions (47, 48). Since thiamin deficiency can result in a form of dementia (Wernicke-Korsakoff syndrome), its relationship to Alzheimer's disease (AD) and other forms of dementia have been investigated. AD is characterized by a decline in cognitive function in elderly people, accompanied by pathologic features that include β-amyloid plaque deposition and neurofibrillary tangles formed by hyperphosphorylated Tau protein (49).
Using positron emission tomography (PET) scanning, reduced glucose metabolism has been observed in brains of AD patients (50). A large, multicenter PET study using a radiolabeled glucose analog, 18F-Fluoro-deoxyglucose (FDG), correlated a reduction in FDG uptake (a surrogate marker for glucose metabolism) with the extent of cognitive impairment in AD patients. This study, which included 822 subjects over 55 years of age that were cognitively normal (n=229), displayed mild cognitive impairment (n=405), or had mild AD (n=188), demonstrated that brain glucose utilization could predict the progression from mild cognitive impairment to AD (51). A nine-year longitudinal study associated the presence of diabetes mellitus in older people (above 55 years old) with an increased risk for developing AD (52). Emerging evidence links type 2 diabetes and AD, conditions that may involve insulin resistance in the brain (reviewed in 53).
A reduction in thiamin-dependent processes in the brain appears to be related to the altered glucose metabolism in patients with AD (54-56). Case-control studies have found blood levels of thiamin, TPP, and TMP to be lower in those with dementia of Alzheimer's type (DAT) compared to control subjects (57, 58). Moreover, several investigators have found evidence of decreased activity of TPP-dependent enzymes, α-ketoglutarate dehydrogenase and transketolase, in the brains of patients who died of AD (59). The finding of decreased brain levels of TPP in the presence of normal levels of free thiamin and TMP suggests altered TPP synthesis rather than poor thiamin bioavailability. However, it is not clear whether the activities of TPP-metabolizing enzymes (including thiamin pyrophosphokinase) are altered in AD patients (60, 61). Chronic administration of the thiamin derivative benfotiamine alleviated cognitive alterations and decreased the number of β-amyloid plaques in a mouse model of AD without increasing TMP and TPP levels in the brain. This suggested that the beneficial effects of benfotiamine in the brain were likely mediated by the stimulation of TPP-independent pathways (62). Chronic benfotiamine administration was also shown to decrease the number of neurofibrillary tangles in certain brain regions and improve survival in a mouse model (63). In a rat model of neurodegeneration, long-term oral benfotiamine supplementation increased thiamin pyrophosphate concentrations and led to improvements in insulin signaling and cognitive deficits (64).
Thiamin deficiency has been linked to increased β-amyloid production in cultured neuronal cells and to plaque formation in animal models (65, 66). These pathological hallmarks of AD could be reversed by thiamin supplementation, suggesting that thiamin could be protective in AD. Other disorders, including mitochondrial dysfunction and chronic oxidative stress, have been linked to both thiamin deficiency and AD pathogenesis and progression (13, 55, 67). Presently, there is only slight and inconsistent evidence that thiamin supplements are of benefit in AD. A double-blind, placebo-controlled study of 15 patients (10 completed the study) reported no beneficial effect of 3 grams/day of thiamin on cognitive decline over a 12-month period (68). A preliminary report from another study claimed a mild benefit of 3 to 8 grams of thiamin per day in DAT, but no additional data from that study are available (69). A mild beneficial effect in patients with AD was reported after 12 weeks of treatment with 100 mg/day of a thiamin derivative (thiamin tetrahydrofurfuryl disulfide), but this study was not placebo-controlled (70). A 2001 systematic review of randomized, double-blind, placebo-controlled trials of thiamin in patients with DAT found no evidence that thiamin was a useful treatment for the symptoms of Alzheimer's disease (71). More recently, a small uncontrolled study in five patients with mild-to-moderate AD reported cognitive improvement, measured by the Mini-Mental Status Examination, following supplementation with 300 mg/day of benfotiamine for 18 months (72). In a placebo-controlled study of 70 β-amyloid positive patients with either amnestic mild cognitive impairment (a precursor to AD) or mild AD, those receiving 600 mg/day of benfotiamine for 12 months experienced less cognitive decline compared to placebo, but the differences did not reach statistical significance (p=0.125; 73). Large-scale, randomized controlled trials are needed to determine whether supplemental thiamin or benfotiamine might help slow progression of cognitive decline in those with Alzheimer’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 (74). Compared to control subjects, this study also found lower concentrations of TPP in the striatum and lower concentrations of TMP in the cerebrospinal fluid of patients with Huntington’s disease (74). 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 thiamin for life (see Biotin-thiamin-responsive basal ganglia disease below). In a mouse model of Huntington’s disease, high-dose supplementation with both of these vitamins improved neuropathological and motor deficits but had no effect on lifespan (p=0.15) (74). A phase II, open-label clinical trial evaluating the effect of combined thiamin-biotin supplementation, at moderate (600 mg/day of thiamin and 150 mg/day of biotin) and high (1,200 mg/day of thiamin and 300 mg/day of biotin) dosages, in Huntington’s disease is currently underway (75).
Severe thiamin deficiency (wet beriberi) can lead to impaired cardiac function and ultimately congestive heart failure (CHF). Although cardiac manifestations of beriberi are rarely encountered in industrialized countries, CHF due to other causes is common, especially in the elderly. Loop diuretics used in the treatment of CHF, notably furosemide, increase thiamin excretion, potentially leading to thiamin deficiency (76, 77). Patients with CHF might also have altered thiamin metabolism, including reduced absorption of thiamin in the small intestine (78). A 2015 meta-analysis of nine observational studies found a 2.5 times higher risk of thiamin deficiency in patients with heart failure compared to control subjects (78). As in the general population, older CHF patients were found to be at higher risk of thiamin deficiency than younger ones (79).
An important measure of cardiac function in CHF is the left ventricular ejection fraction (LVEF), which can be assessed by echocardiography. One study in 25 patients found that furosemide use at doses of 80 mg/day or greater was associated with a 98% prevalence of thiamin deficiency (31). In a randomized, double-blind study of 30 CHF patients, all of whom had been taking furosemide (80 mg/day) for at least three months, intravenous (IV) thiamin therapy (200 mg/day) for seven days resulted in an improved LVEF compared to IV placebo (80). When all 30 of the CHF patients in that study subsequently received six weeks of oral thiamin therapy (200 mg/day), the average LVEF improved by 22%. This finding may be relevant because improvements in LVEF have been associated with improved survival in CHF patients (81). However, clinical trials of oral thiamin 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 (82). 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 (83).
Although little evidence supports the routine use of supplemental thiamin in CHF patients, trials specifically in CHF patients with marginal thiamin status have not been done, and some suggest that it may be prudent to screen patients on long-term diuretic therapy for thiamin deficiency and treat accordingly (84).
Chronic hyperglycemia in individuals with diabetes mellitus contributes to the pathogenesis of microvascular diseases. Diabetes-related vascular damage can affect the heart (cardiomyopathy), kidneys (nephropathy), retina (retinopathy), and peripheral nervous system (neuropathy). In subjects with diabetes, hyperglycemia alters the function of bone marrow-derived endothelial progenitor cells (EPC) that are critical for the growth of blood vessels (85). Interestingly, a higher daily intake of thiamin from the diet was correlated with more circulating EPC and with better vascular endothelial health in 88 individuals with type 2 diabetes (86). An inverse association has also been found between plasma concentrations of thiamin and the presence of soluble vascular adhesion molecule-1 (sVCAM-1), a marker of vascular dysfunction, in patients with diabetes (40, 87). Early markers of diabetic nephropathy include the presence of serum albumin in the urine, known as microalbuminuria. Administration of thiamin or benfotiamine (a thiamin derivative) prevented the development of renal complications in chemically-induced diabetic rats (88). A randomized, double-blind, placebo-controlled study conducted in 40 patients with type 2 diabetes with microalbuminuria found that high-dose thiamin supplementation (300 mg/day) decreased excretion of urinary albumin over a three-month period (87). Since thiamin treatment has shown promising results in cultured cells and animal models (89-91), the effects of thiamin and its derivatives on vascular complications should be examined in patients with diabetes.
Thiamin deficiency and Wernicke-Korsakoff syndrome have been observed in some cancer patients with rapidly growing tumors (92, 93). Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamin (94). 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 (95). Other studies have found that the gene encoding THTR-2 is downregulated in certain cancers (96). Moreover, use of the chemotherapeutic drug, 5-fluorouracil, inhibits phosphorylation of thiamin to thiamin pyrophosphate and may thus lead to thiamin deficiency (97, 98).
Thiamin supplementation in cancer patients is common to prevent thiamin deficiency, but Boros et al. caution that too much thiamin may actually fuel the growth of some malignant tumors (99), suggesting that thiamin supplementation be reserved for those cancer patients who are actually deficient in thiamin. 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 thiamin supplementation to discuss it with the clinician managing their cancer therapy. Intravenous, high-dose thiamin has been suggested as a treatment for cancer patients with confirmed Wernicke-Korsakoff (93).
Sepsis is a life-threatening critical illness caused by a dysregulated host response to an infection. The widespread inflammation can lead to tissue and organ damage and to death (100). Because thiamin deficiency is common among septic patients (101), several studies have investigated the treatment effect of intravenous thiamin – alone or in combination with other agents like vitamin C and hydrocortisone.
Observational studies examining the association of intravenous thiamin as a monotherapy have mainly looked at its association with lactic acidosis, which commonly occurs in both thiamin 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 (102). 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 (103).
A few randomized controlled trials have evaluated the effect of intravenous thiamin 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 thiamin (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 (104). No differences between the treatment and placebo groups were found for the secondary endpoints, which included survival (104). 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; 105).
A 2020 meta-analysis of four studies – one observational and three randomized controlled trials – found no benefit of intravenous thiamin for improving lactate concentrations, length of hospital stay in intensive care, or overall survival (106). 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 (107); some clinical trials of such treatments are currently underway (see clinicaltrials.gov/).
Thiamin supplementation is included in the clinical management of genetic diseases that affect the metabolism of carbohydrates and branched-chain amino acids (BCAAs).
Mutations in PDHC prevent the efficient oxidation of carbohydrates in affected individuals. PDHC deficiency is commonly characterized by lactic acidosis, neurologic and neuromuscular degeneration, and death during childhood. The patients who respond to thiamin treatment (from a few mg/day to doses above 1,000 mg/day) exhibit PDHC deficiency due to the decreased affinity of PDHC for TPP (108, 109). Although thiamin supplementation can reduce lactate accumulation and improve the clinical features in thiamin-responsive patients, it does not constitute a cure (110).
Inborn errors of BCAA metabolism lead to thiamin-responsive branched-chain ketoaciduria, also known as maple syrup urine disease. Alterations in the BCAA catabolic pathway result in neurologic dysfunction caused by the accumulation of BCAAs and their derivatives, branched-chain ketoacids (BCKA). The therapeutic approach includes a synthetic diet with reduced BCAA content, and thiamin (10-1,000 mg/day) is supplemented to patients with mutations in the E2 subunit of the BCKDH complex (111). In thiamin-responsive individuals, the supplementation has been proven effective to correct the phenotype without recourse to the BCAA restriction diet.
Mutations in the SLC19A2 gene that encodes THTR-1 impairs intestinal thiamin uptake and causes thiamin deficiency, leading to thiamin-responsive megaloblastic anemia (112). This syndrome, which is 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 (113). High-dose oral supplementation with thiamin (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 (114). After puberty, a decline in pancreatic function results in the requirement of insulin together with thiamin 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 (115). Early diagnosis of the syndrome and early treatment with thiamin is important for a better prognosis (114).
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 (116), but an early infantile form of the disease exists with onset as early as one month of age (117). 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. 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 (118). 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 (119). Lifelong high-dose supplementation with a combination of biotin and thiamin is generally the treatment for biotin-thiamin-responsive basal ganglia disease (116). Early diagnosis and treatment is important to ensure a better prognosis (117, 120).
Supplemental thiamin 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 thiamin metabolism dysfunction syndrome-3 (THMD3) or thiamin metabolism dysfunction syndrome-4 (THMD4). Of these rare syndromes, 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 (121). 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 (122).
Mutations in the TPK1 gene result in thiamin pyrophosphokinase 1 deficiency and thiamin 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 (123). Only a few cases of 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 (124).
Humans obtain thiamin from dietary sources and from the normal microflora of the colon, although the contribution of the latter towards the body’s requirement for thiamin is not clear (125).
A varied diet should provide most individuals with adequate thiamin to prevent deficiency. In the US the average dietary thiamin intake for young adult men is about 2 mg/day and 1.2 mg/day for young adult women. A survey of people over the age of 60 found an average dietary thiamin intake of 1.4 mg/day for men and 1.1 mg/day for women (37). However, institutionalization and poverty both increase the likelihood of inadequate thiamin intake in the elderly (126). Whole-grain cereals, legumes (e.g., beans and lentils), nuts, lean pork, and yeast are rich sources of thiamin (1). Because most of the thiamin is lost during the production of white flour and polished (milled) rice, white rice and foods made from white flour (e.g., bread and pasta) are fortified with thiamin in many Western countries. A number of thiamin-rich foods are listed in the table below, along with their thiamin content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central.
Thiamin is available in dietary supplements and in fortified foods, most commonly as thiamin hydrochloride or thiamin mononitrate (127). Multivitamin supplements typically contain at least 1.2 mg of thiamin, the Daily Value (DV) for adults and children 4 years and older (128).
Benfotiamine is a synthetic, lipid-soluble precursor of thiamin that is available as a dietary supplement. It has higher bioavailability compared to thiamin (129).
The Food and Nutrition Board did not set a tolerable upper intake level (UL) for thiamin because there are no well-established toxic effects from consumption of excess thiamin in food or through long-term, oral supplementation (up to 200 mg/day). A small number of life-threatening anaphylactic reactions have been observed with large intravenous doses of thiamin (37).
Reduced blood concentrations of thiamin have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time (130). 5-Fluorouracil, a drug used in cancer therapy, inhibits the phosphorylation of thiamin to TPP (131). Diuretics, especially furosemide, may increase the risk of thiamin deficiency in individuals with marginal thiamin intake due to increased urinary excretion of thiamin (29). Moreover, chronic alcohol abuse is associated with thiamin deficiency due to low dietary intake, impaired absorption and utilization, and increased excretion of the vitamin (1). Chronic alcohol feeding to rats showed a decrease in the active absorption of thiamin linked to the inhibition of thiamin membrane transporter THTR-1 in the intestinal epithelium (132). Alcohol consumption in rats also decreases the levels of THTR-1 and THTR-2 in renal epithelial cells, thus limiting thiamin re-uptake by the kidneys (133).
The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 1.2 mg/day of thiamin for men and 1.1 mg/day for women. A varied diet should provide enough thiamin for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement, containing 100% of the Daily Values (DV), will ensure an intake of at least 1.5 mg/day of thiamin.
Presently, there is no evidence that the requirement for thiamin is increased in older adults, but some studies have found inadequate dietary intake and thiamin insufficiency to be more common in elderly populations (126). Thus, it would be prudent for older adults to take a multivitamin/mineral supplement, which will generally provide at least 1.5 mg/day of thiamin.
Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in September 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in June 2013 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in July 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in October 2021 by:
Lucien Bettendorff, Ph.D.
Research Director, F.R.S.-FNRS
University of Liège, Belgium
Copyright 2000-2024 Linus Pauling Institute
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