• Thiamine (vitamin B1) serves as a coenzyme for a number of important enzymes, including transketolase, α-ketoglutarate dehydrogenase, and pyruvate dehydrogenase.
• Function
  • a cofactor for several enzymes such as thiamine pyrophosphate (TPP)
    • pyruvate dehydrogenase (glycolysis)
    • α-ketoglutarate dehydrogenase (TCA cycle)
    • transketolase (HMP shunt)
    • branched-chain AA dehydrogenase (metabolism of Val, Leu, Ile)
• Thiamine deficiency may present as Wernicke encephalopathy (eg, encephalopathy, ataxia, ophthalmoplegia) or beriberi (eg, peripheral neuropathy, dilated cardiomyopathy).

<aside> 🫐 Thiamine deficiency causes beriberi and Wernicke-Korsakoff syndrome.

• Dry beriberi is characterized by symmetrical peripheral neuropathy; wet beriberi includes the addition of high-output congestive heart failure.

Wernicke Encephalopathy & Korsakoff Syndrome

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• Thiamine (vitamin B1) participates in glucose metabolism and is a cofactor for the following enzymes:

  • Pyruvate dehydrogenase, which converts pyruvate (glycolysis end product) into acetyl-CoA, which then enters the citric acid cycle
  • Alpha-ketoglutarate dehydrogenase, an enzyme of the citric acid cycle
  • Branched-chain alpha-ketoacid dehydrogenase, which is essential for the catabolism of branched-chain amino acids (eg, leucine, isoleucine, valine)
  • Transketolase, an enzyme of the pentose phosphate pathway that helps convert ribulose-5-phosphate (derived from glucose) to glycolysis intermediates (eg, glyceraldehyde-3-phosphate)

  

• Therefore, thiamine deficiency impairs glucose utilization, which can have catastrophic effects on the CNS as the brain always requires some glucose.

• Without thiamine, cerebral energy production is impaired, increasing neuronal susceptibility to oxidative stress and causing disruption of the tight junctions that form the blood-brain barrier.  The resulting neuronal injury primarily affects areas of the brain with the highest metabolic demand and leads to the classic triad of WE:

  • Encephalopathy (mammillary bodies): somnolence, confusion, inattention
  • Ataxia (cerebellum): gait and balance disturbances
  • Oculomotor dysfunction: nystagmus, lateral gaze palsy

• Thiamine deficiency leads to wet beriberi (cardiac failure), dry beriberi (peripheral neuropathy), and Wernicke encephalopathy (oculomotor dysfunction, ataxia, and encephalopathy); clinically relevant toxicity does not occur.

• Thiamine deficiency is often diagnosed clinically in patients with a history of heavy alcohol use or malnutrition and signs of Wernicke encephalopathy; the diagnosis can be confirmed with a baseline erythrocyte transketolase activity that is low but increases after the addition of thiamine pyrophosphate.  Treatment involves thiamine supplementation with glucose; glucose administration alone may precipitate or worsen Wernicke encephalopathy due to rapid thiamine consumption.
  • Central nervous system involvement (ie, Wernicke-Korsakoff syndrome) occurs primarily with heavy alcohol use.
• Thiamine deficiency causes infantile and adult beriberi
  • Manifestations of infantile beriberi appear at age 2-3 months and include a fulminant cardiac syndrome with cardiomegaly, tachycardia, cyanosis, dyspnea, and vomiting.
• Adult beriberi is categorized as dry or wet depending on cardiac involvement.
  • Dry beriberi is characterized by symmetrical peripheral neuropathy of the distal extremities, with resulting sensory and motor impairments.
  • Wet beriberi includes the addition of cardiac involvement (cardiomyopathy, high-output congestive heart failure, peripheral edema, and tachycardia).

Infantile Wet Beriberi:

• This patient has decreased activity of erythrocyte transketolase (ETKA), a thiamine-dependent enzyme in the pentose phosphate pathway.  This finding is essentially diagnostic for thiamine (vitamin B1) deficiency.  The primary risk factor for thiamine deficiency is malnutrition; in this case, gastric bypass surgery without appropriate micronutrient supplementation likely led to maternal thiamine deficiency and, in turn, to deficiency in this exclusively breastfed infant.
• In addition to involvement in transketolase activity, thiamine is a cofactor for other enzymes involved in glucose metabolism (eg, 2-carbon transfer, decarboxylation), including alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase (converts pyruvate to acetyl-CoA).  Impaired pyruvate dehydrogenase activity diverts pyruvate to the anaerobic glycolysis pathway, which produces lactate.  Lactic acidosis leads to decreased peripheral vascular resistance, which contributes to the classic finding of high-output heart failure.  However, over time, direct impairment of myocyte energy production leads to reduced cardiac contractility and a low-output state.
• Myocardial dysfunction due to thiamine deficiency is referred to as wet beriberi.  Infantile beriberi is rare but often fulminant, with symptoms related to pulmonary/systemic fluid overload, including feeding intolerance and respiratory distress, as well as cardiomegaly and hepatomegaly, as seen in this patient.  Wet beriberi can be fatal without prompt thiamine supplementation.