Etiology

Vitamin B1 (thiamine) is an essential micronutrient and is dependent on dietary intake.[1] In countries where diets are low in thiamine, particularly east parts of Asia, where the diet is based around polished rice, vitamin B1 deficiency and outbreaks of beriberi are common.[1][4][5]The germ cells of whole-grains and seeds are rich in thiamine, but polished rice is deficient in thiamine. Rates of beriberi decrease when the food supply is enriched with thiamine or non-polished rice is used.[5]

In the developed world, vitamin B1 deficiency presenting as Wernicke encephalopathy occurs mainly in those who chronically abuse alcohol, particularly in the context of poor nutritional intake.[2] Alcohol blocks the active-transport mechanism for the absorption of thiamine in the gastrointestinal tract.[2][6]

Non-alcoholic causes of vitamin B1 deficiency can be due to inadequate intake (e.g., fasting, starvation, malnutrition, the use of unbalanced diets), malabsorptive conditions (e.g., gastrointestinal surgery, conditions that cause recurrent vomiting and/or diarrhoea), and conditions with increased demand (e.g., cancer, thyrotoxicosis, infection).[7][8]

In women with hyperemesis gravidarum, vitamin B1 deficiency can result in Wernicke’s encephalopathy if not recognized and adequately treated.[9]

Increased caloric intake, as seen in patients with obesity, results in an increased load on metabolic pathways and demand for micronutrients such as vitamin B1 as enzyme cofactors.[10]Vitamin B1 deficiency has been reported in 16%-47% of patients planning to undergo bariatric surgery for obesity.[10][11][12] Bariatric surgery can also result in vitamin B1 deficiency.[13][14][15] Gastrointestinal surgery for any reason can lead to a reduced area of intestinal and gastric mucosa for the absorption of thiamine, as well as recurrent postoperative vomiting and poor appetite, resulting in vitamin B1 deficiency.[16][11][17][18][19]

Cachexia and the catabolic state associated with HIV infection and AIDS place these patients at risk of vitamin B1 deficiency.[20][21]The anorexia, nausea and vomiting, and, in some cases, malabsorption associated with malignancy place patients with cancer at risk of vitamin B1 deficiency.[22] Gastrointestinal malignancies and haematological malignancies are particularly implicated due to the many means by which they induce inadequate supply of the thiamine (e.g., mucositis, gastrointestinal obstruction, gastrointestinal tract resection, total parenteral nutrition) and the increased thiamine consumption of fast-growing cancer cells.[22][23]  Some chemotherapeutic agents also interfere with thiamine function.[22][24][25][26] Thiamine is a co-factor in the metabolism of carbohydrates. Therefore, vitamin B1 deficiency should always be considered and treated before refeeding orally, enterally, or parenterally (including simple intravenous dextrose).[27] Inadequate thiamine supplementation in total parenteral nutrition can cause vitamin B1 deficiency.[28]

Magnesium is a co-factor for thiamine-containing enzymes.[10] Thus, an adequate supply of magnesium is required in order for thiamine to function fully. Magnesium deficiency may be acute secondary to increased loss, such as diarrhoea following bariatric surgery, or chronic, such as in patients with alcohol-related liver disease due to low dietary uptake, greater urinary secretion, and lower plasma albumin concentrations.[10][29]

Thiaminases break down thiamine in food, and thiamine antagonists can interfere with the absorption of thiamine. A diet rich in certain foods, such as fermented fish (source of thiaminase), betel nuts, tea, coffee, and red cabbage (sources of thiamine antagonists), can result in vitamin B1 deficiency.[30][31]

Genetic defects in thiamine transport and metabolism have been described.[32] Mutations in SLC19A2 (thiamine transporter-1), SLC19A3 (thiamine transporter-2), TPK1 (thiamine pyrophosphokinase), and SLC25A19 (mitochondrial thiamine pyrophosphate carrier) exhibit well-defined clinical phenotypes.[32] Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare disease characterized by thiamine-responsive anemia, diabetes and deafness; it is caused by recessively inherited mutations in the SLC19A2 gene.[33] Mutations in SLC19A3, TPK1, and SLC25A19 genes have predominantly neurological involvement.[32][34]

Pathophysiology

Thiamine has a half-life of 9 to 18 days, so tissues with a high thiamine turnover become thiamine depleted after only 2 to 3 weeks of deficiency.[35]Thiamine is obtained from cereals, meat, eggs, legumes, and vegetables and requires specific transporters for the absorption in the small intestine and for cellular and mitochondrial uptake.[32] Within the cellular compartment, the thiamine-dependent enzyme thiamine pyrophosphate is a co-enzyme in intermediate carbohydrate metabolism.[36] As tissues such as the brain and nerve cells rely on glucose for energy, the decrease in carbohydrate metabolism caused by vitamin B1 deficiency leads to cell damage. 

The heart and other muscles can use the beta-oxidation of long-chain fatty acids for energy. It is therefore proposed that cardiac cells are only damaged in vitamin B1 deficiency when there is also a deficiency of long-chain fatty acids reaching the cells.[37] 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.[1]

Classification

Clinical classification

Wernicke encephalopathy

  • Acute neuropsychiatric syndrome classically presenting with the triad of acute confusion, ataxia, and ocular abnormalities (e.g., nystagmus, strabismus). Secondary to acute deficiency.

Dry beriberi

  • A distal peripheral polyneuropathy characterized by paresthesia, reduced knee jerks and other tendon reflexes, and progressive severe weakness with muscle wasting. Secondary to chronic deficiency.

Wet beriberi

  • High-output cardiac failure with peripheral vasodilation, peripheral edema, and orthopnea; or low-output cardiac failure with lactic acidosis and peripheral cyanosis. Secondary to acute or chronic deficiency.

Shoshin beriberi

  • Rapid onset of low-output cardiac failure with lactic acidosis and peripheral cyanosis. Secondary to acute or chronic deficiency.

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