Thiamine has long been recognized as an essential nutrient. Its minimal essential requirement is about 0.5 mg/1000 kcal, which is usually obtained through a normal, well-balanced diet (recommended daily thiamine intake ranges from 0.2 mg in neonates to 1–1.2 mg in adults). However, requirements are variable and increase in parallel with carbohydrate intake and during pregnancy, lactation, and hypermetabolic states. Thiamine is physiologically active in its phosphorylated form, thiamine pyrophosphate (TPP), which is a coenzyme for pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase (BCKDH) in the mitochondrion; 2-hydroxyacyl-CoA lyase in the peroxisome; and transketolase (pentose phosphate pathway) in the cytosol. Being placed at these highly regulated enzymatic steps, thiamine plays a crucial role in carbohydrate metabolism and in the metabolic switch from the fed to the fasting state.
Acute acquired thiamine deficiency states (as occurs with total parenteral nutrition without thiamine supplementation or beriberi) are life-threatening emergencies and present with cardiac failure, Gayet-Wernicke encephalopathy, and/or lactic acidosis. Metabolic markers include elevated serum lactate and pyruvate with normal lactate-to-pyruvate ratio, slight elevations of branched-chain amino acids in plasma, the presence of α-keto acids (ketoglutarate, pyruvate, branched-chain keto acids) in urine with a positive dinitrophenylhydrazine (DNPH) reaction, and low transketolase activity in red blood cells. However, these markers are rarely available in an emergency, and the diagnosis relies on the primary care or emergency physician recognizing the disorder and administering the lifesaving therapeutic test of thiamine 5 mg/kg/d. There is no significant risk of adverse effects from supplementation.
Through the diet, thiamine is consumed as phosphate derivatives and converted into free thiamine by phosphatases present in the lumen of the small intestine. The epithelia of the small intestine contain two thiamine transporters, THTR1 and THTR2, which are localized to the basal and apical membranes of the polarized cell, respectively (these transporters are variably expressed in other tissues). Within the cell, free thiamine is converted into TPP in the cytosol by thiamine pyrophosphokinase (TPK). A mitochondrial TPP carrier (TPC) imports TPP from the cytosol into the mitochondrion, allowing TPP to associate with mitochondrial dehydrogenases.
Thiamine-dependent inborn errors of metabolism are rare. They can be caused by: (1) mutations in subunits of PDH or BCKDH that directly or indirectly interfere with the binding of TPP and thus activation of the apoenzyme, (2) a defect of conversion of thiamine into TPP, or (3) defects of specific cellular or mitochondrial transporters of thiamine and TPP, respectively. THTR1 is encoded by SLC19A2 (chromosome 1q24.2; Mendelian Inheritance in Man [MIM] no. 603941). THTR2 is encoded by SLC19A3 (chromosome 2q36.3; MIM no. 606152). TPK is encoded by TPK1 (chromosome 7q35; MIM no. 606370). TPC is encoded by SLC25A19 (chromosome 17q25.1; MIM no. 606152). Pathogenic variants in each of these genes cause autosomal recessive syndromes with predominant neurologic signs and symptoms (deficiency of ...