Aetiology

Causes of vitamin B1 deficiency include alcohol-misuse disorders, inadequate intake of thiamine (e.g., fasting, starvation, malnutrition), malabsorptive conditions (e.g., gastrointestinal surgery, recurrent vomiting and/or diarrhoea), and conditions with increased demand for thiamine (e.g., cancer, infection).[13]

Alcohol

In the developed world, vitamin B1 deficiency presenting as Wernicke's encephalopathy occurs mainly in people with alcohol misuse disorders, particularly in the context of poor nutritional intake.[3]​ Alcohol may block the active-transport mechanism for the absorption of thiamine in the gastrointestinal tract.[3][14][15]

Diet

Vitamin B1 (thiamine) is an essential micronutrient obtained through the diet.[10]​ In countries where diets are low in thiamine, such as Southeast Asia where there is high consumption of thiamine-depleted polished rice, vitamin B1 deficiency is more common.[10][12]​​​​ The germ cells of whole grains and seeds are rich in thiamine.

Increased caloric intake, as seen in patients with obesity, results in an increased load on metabolic pathways and demand for micronutrients.[16]

Inadequate or absent thiamine supplementation in total parenteral nutrition can cause vitamin B1 deficiency.[17]

Infantile beriberi can occur in infants exclusively breastfed by mothers deficient in vitamin B1.[9]

Thiaminases break down thiamine in food, and thiamine antagonists can interfere with the absorption of thiamine. Certain foods that contain thiaminases (e.g., fermented fish, shellfish) or thiamine antagonists (e.g., tea, coffee, betel nuts, red cabbage) can result in vitamin B1 deficiency.[18]

Refeeding syndrome

There is increased demand for thiamine during refeeding (reinstitution of nutrition following a period of undernutrition) because it is a co-factor in glucose-dependent metabolic pathways. Vitamin B1 deficiency can, therefore, present as part of refeeding syndrome.[19][20]​​​​​ Patients with a lower body mass index, or with no oral intake for an extended period, are at increased risk for refeeding syndrome.[20][21]

Surgery

Gastrointestinal surgery, including bariatric surgery, may lead to vitamin B1 deficiency.[22][23][24][25]​​​​​​​​​ Deficiency can result from a decrease in the mucosal absorptive surface of the ileum following surgery, sustained postoperative vomiting, or poor oral intake.​[7][26]​​​ Vitamin B1 deficiency has been reported in 16% to 29% of patients planning to undergo bariatric surgery for obesity.[16]

Genetic causes

Several rare syndromes of thiamine metabolism dysfunction have been described. These syndromes result from genetic defects in thiamine transport and metabolism and are generally detected in younger individuals.[27][28]

Mutations in SLC19A2 (thiamine transporter-1), SLC19A3 (thiamine transporter-2), TPK1 (thiamine pyrophosphokinase), and SLC25A19 (mitochondrial thiamine pyrophosphate carrier) exhibit well-defined clinical phenotypes.[27]​ Thiamine-responsive megaloblastic anaemia (TRMA) syndrome is a rare disease characterised by thiamine-responsive anaemia, diabetes, and deafness; it is caused by recessively inherited mutations in the SLC19A2 gene.[28][29]​​​​ Mutations in SLC19A3, TPK1, and SLC25A19 genes predominantly result in neurological sequelae with episodic encephalopathy, often triggered by febrile illness or infection.[27][28]

Pre-existing conditions and their treatment

Malignancy can be associated with anorexia, nausea and vomiting, malabsorption, and accelerated metabolism of thiamine, placing patients with cancer at increased risk of vitamin B1 deficiency.[30][31]​​​ Patients with gastrointestinal and haematological malignancies are particularly at risk because there are multiple mechanisms by which these cancers can lead to vitamin B1 deficiency, either through increased metabolism of thiamine (by fast-growing cancer cells) or causes of inadequate thiamine supply (e.g., mucositis, gastrointestinal obstruction, gastrointestinal tract resection, total parenteral nutrition).[30]​ Some chemotherapeutic agents interfere with thiamine function.[30]

Renal replacement therapy causes loss of water soluble vitamins, such as vitamin B1.[32]​ This may occur due to losses in the effluent fluid, in addition to poor oral intake.[33]

Case reports suggest that women with hyperemesis gravidarum are at risk of vitamin B1 deficiency, which may lead to Wernicke’s encephalopathy if untreated, especially during refeeding.[34][35]

HIV infection and AIDS have been associated with increased risk of vitamin B1 deficiency.[36]

Magnesium is a co-factor for thiamine-containing enzymes.[16]​ Thus, an adequate supply of magnesium is required in order for thiamine to function optimally. Causes of magnesium deficiency include increased loss of magnesium (e.g., diarrhoea following bariatric surgery), low dietary intake (e.g., in alcohol-related liver disease), increased urinary loss of magnesium in distal tubular dysfunction, and drugs (e.g., proton-pump inhibitors).[16][37][38]​​

Pathophysiology

Humans rely on dietary sources of thiamine such as whole grains, meat, fish, legumes, and fortified cereals and bread.[7][39][40]​​​ There is also some biosynthesis of thiamine by intestinal bacteria.[1]

Thiamine is mostly absorbed in the proximal small intestine by passive diffusion at high concentrations, and by various transporters at low concentrations.[39][41]​​​ Thiamine is transported in the bloodstream by erythrocytes.[39]​ Cells take up thiamine via specific transporters such as SLC19A2 and SLC19A3.[39]

Thiamine is converted into thiamine diphosphate (TDP; also known as thiamine pyrophosphate), the active co-factor form of thiamine, by thiamine pyrophosphokinase in the cell cytoplasm in a process that requires magnesium.[18][39][42]​​

Thiamine has a relatively short half-life, so thiamine reserves can become depleted within 20 days of inadequate intake.[1]​ Thiamine deficiency reduces TDP-mediated functioning of enzymes including pyruvate dehydrogenase and a-ketoglutarate dehydrogenase (involved in the tricarboxylic acid cycle), and transketolase enzyme (part of the pentose phosphate pathway).[42][43]​​​ This results in decreased energy generation and increased accumulation of toxic products (such as lactate).[7][43]​​​ As tissues such as the brain and nerve cells rely on glucose for energy, vitamin B1 deficiency can lead to cell damage.[42]​​ Cardiac myocytes are also affected by the disruption to aerobic respiration.[44][45]

​It is likely that overall nutritional status contributes to the spectrum of clinical presentations seen in thiamine deficiency and multiple micronutrient deficiencies may be present.[10]

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