Aetiology

Thiamine (vitamin B1) is an essential micronutrient. Deficiency of thiamine typically occurs in susceptible individuals and is the precipitant cause of Wernicke's encephalopathy.[26]

In the developed world, thiamine deficiency presenting as Wernicke's encephalopathy occurs mainly in alcohol-use disorders, particularly in the context of poor nutritional intake.[4]​ Alcohol blocks the active-transport mechanism for the absorption of thiamine in the gastrointestinal tract, although other mechanisms may also be involved.[4][27]​​​​​

Non-alcoholic causes of thiamine deficiency may be due to inadequate intake (e.g., fasting, starvation, malnutrition, unbalanced diets), malabsorptive conditions (e.g., GI surgery, recurrent vomiting and/or diarrhoea), and conditions associated with increased metabolic demand (e.g., cancer and infection).[23]

Thiaminases break down thiamine in food, and thiamine antagonists can interfere with its absorption. Therefore, 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 thiamine deficiency.[28][29]​​

Increased caloric intake, as seen in patients with obesity, results in an increased load on metabolic pathways and demand for micronutrients.[30][31]​​​​ Thiamine deficiency has been reported in 16% to 47% of patients planning to undergo bariatric surgery for obesity.[30][32]​​ Additionally, bariatric surgery can result in thiamine deficiency. GI surgery of any type can precipitate thiamine deficiency if it results in a reduced mucosal absorptive surface area in the small intestine, as well as sustained post-operative vomiting and reduced dietary intake.[31][33][34][35]​​​​

Thiamine levels have been shown to be low after major surgery, for example, following coronary artery bypass graft surgery.[36]​ Renal replacement therapy also causes loss of most micronutrients, especially water soluble vitamins.[37]​ This mainly occurs due to loss in the dialysate compounded by poor oral intake due to anorexia commonly associated with uraemia.[38]

Cachexia and catabolism associated with HIV infection and AIDS place these patients at risk of thiamine deficiency and subsequent Wernicke's encephalopathy.[39][40][41][42]​​​​​​​​​ Patients with cancer are also at risk as a result of anorexia, nausea and vomiting, and malabsorption associated with malignancy.[43] Gastrointestinal and haematological malignancies are particularly implicated due to means by which they induce inadequate supply of the thiamine (e.g., mucositis, gastrointestinal obstruction, gastrointestinal tract resection) and the increased thiamine consumption of fast-growing cancer cells.[43][44]​​​ Some chemotherapeutic agents also interfere with thiamine function.​[43][45]​​​ Inadequate or absent thiamine supplementation in total parenteral nutrition can also cause thiamine deficiency.[46][47]​​​

Magnesium is a co-factor for enzymes involved in thiamine metabolism.[48]​ Thus, an adequate supply of magnesium is required in order for thiamine to function optimally. 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, urinary losses in distal tubular dysfunction, or medications (e.g., proton pump inhibitors).[48][49]​​

Women with hyperemesis gravidarum are at particular risk of Wernicke's encephalopathy as a result of severe vomiting.​[8][50]

Although rare, several thiamine metabolism dysfunction syndromes, secondary to genetic defects in transport and metabolism, have been described, generally among younger patients.[51][52] Mutations in SLC19A2 (thiamine transporter-1), SLC19A3 (thiamine transporter-2), TPK1 (thiamine pyrophosphokinase), and SLC25A19 (mitochondrial thiamine pyrophosphate carrier) exhibit well-defined clinical phenotypes.[51] 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.[53]​ Mutations in SLC19A3, TPK1, and SLC25A19 genes have predominantly neurological involvement.[54]

See Vitamin B1 deficiency.

Pathophysiology

Thiamine is a precursor for thiamine pyrophosphate, which serves as a co-factor for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase in the Kreb's cycle, and transketolase in the pentose-phosphate pathway.[55] Thiamine is a water-soluble vitamin stored predominantly in the liver. However, body stores last only up to 18 days.[56] Thiamine deficiency leads to decreased activity of thiamine-dependent enzymes. This triggers a sequence of metabolic events resulting in energy compromise and ultimately neuronal death in certain neuronal populations with high metabolic requirements and high thiamine turnover.[57] The areas commonly affected include the medial dorsal thalamic nucleus, mammillary bodies, the periaqueductal grey matter, and the floor of the fourth ventricle, which includes the oculomotor and vestibular nuclei and the cerebellar vermis.[17] Lesions may also involve the fornices, the hippocampus, the area around the third ventricle, the quadrigeminal bodies, and the cortex. The predilection to affect structures involved in encoding and memory recall (e.g., structures within the Papez circuit) is responsible for the most prominent sequela of Wernicke's encephalopathy - Korsakoff's psychosis.[58]

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