From the Guidelines
Thiamine pyrophosphate (TPP) deficiency primarily affects four key enzymes in the body: pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase, branched-chain alpha-keto acid dehydrogenase complex, and transketolase, as highlighted in the espen micronutrient guideline 1. These enzymes are crucial for various metabolic processes, including energy production, neurotransmitter synthesis, and nucleic acid synthesis. Pyruvate dehydrogenase complex, for instance, is essential for converting pyruvate to acetyl-CoA, a critical step in linking glycolysis to the citric acid cycle. Alpha-ketoglutarate dehydrogenase plays a vital role in the citric acid cycle, while branched-chain alpha-keto acid dehydrogenase complex is involved in the metabolism of branched-chain amino acids. Transketolase, on the other hand, is important in the pentose phosphate pathway, which generates NADPH and pentoses.
The deficiency of these enzymes can lead to severe metabolic disruptions, resulting in conditions such as Wernicke-Korsakoff syndrome, beriberi, and lactic acidosis. According to the espghan/espen/espr/cspen guidelines on pediatric parenteral nutrition: vitamins 1, thiamine deficiency can have severe consequences, particularly in infants and children on parenteral nutrition, including severe lactic acidosis, Wernicke's encephalopathy, and even death.
Key points to consider:
- Thiamine pyrophosphate (TPP) is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and for pyruvate dehydrogenase activity, as noted in the espen micronutrient guideline 1.
- The main enzymes affected by TPP deficiency include pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase, branched-chain alpha-keto acid dehydrogenase complex, and transketolase.
- Treatment of TPP deficiency involves thiamine supplementation, with recommended doses varying depending on the severity of deficiency and underlying conditions, as discussed in the guidelines 1.
- Parenteral thiamine intake recommendations for preterm infants and children on parenteral nutrition are provided in the guidelines, emphasizing the importance of adequate thiamine supply to prevent severe metabolic complications 1.
From the FDA Drug Label
CLINICAL PHARMACOLOGY: ... Thiamine combines with adenosine triphosphate (ATP) to form thiamine pyrophosphate, also known as cocarboxylase, a coenzyme Its role in carbohydrate metabolism is the decarboxylation of pyruvic acid in the blood and α-ketoacids to acetaldehyde and carbon dioxide. The enzymes deficient in TPP (Thiamine Pyrophosphate) deficiency are those involved in the decarboxylation of:
- pyruvic acid
- α-ketoacids These enzymes are coenzymes for the decarboxylation reactions, which are crucial for carbohydrate metabolism 2.
From the Research
Enzymes Deficient in TPP Deficiency
- Pyruvate dehydrogenase complex (PDHC) is an enzyme that is deficient in thiamine pyrophosphate (TPP) deficiency, as it requires TPP as a cofactor for its activity 3
- Alpha-ketoglutarate dehydrogenase (alpha KGDH) is another enzyme that is affected by TPP deficiency, with decreased activity leading to impaired cerebral glucose and energy metabolism 4
- Transketolase (TK) is also a TPP-dependent enzyme, with its activity being more sensitive to thiamin deprivation in blood than in liver 5
- 2-hydroxyacyl-CoA lyase (HACL1) is a peroxisomal enzyme that is dependent on TPP and is involved in alpha oxidation, with its deficiency potentially leading to critical effects on normal brain metabolism 6
Effects of TPP Deficiency on Enzyme Activity
- TPP deficiency can lead to decreased affinity of PDHC for TPP, resulting in low PDHC activity in the presence of low TPP concentrations 3
- Decreased alpha KGDH activity can lead to decreased aspartate, glutamate, and GABA, and increased alanine in the brain 4
- TPP deficiency can also lead to impaired transketolase activity, with a more pronounced TPP-stimulatory effect in blood than in liver 5
Clinical Implications of TPP Deficiency
- TPP deficiency can lead to thiamine deficiency disorders (TDDs), which can affect various systems, including metabolic, neurologic, cardiovascular, respiratory, gastrointestinal, and musculoskeletal systems 7
- Early diagnosis and treatment of TDDs are crucial to prevent fatal consequences or permanent neurologic sequelae 7
- Thiamine supplementation can lead to rapid clinical improvement in patients with thiamine-responsive PDHC deficiency 3