Rudolph's Pediatrics, 22nd Ed.

CHAPTER 149. Vitamin B₆ and Vitamin B₁ Responsive Disorders

Jean-Marie Saudubray

VITAMIN B₁: THIAMINE

Thiamine has long been recognized as an essential component. Its minimal essential requirement is about 0.5 mg/1000 Kcal, which is usually covered by a normal, well-balanced diet. However, requirements are variable and increase in parallel with carbohydrate intake, during pregnancy, lactation, hypermetabolic states, and in infants. Thiamine acts under its phosphorylated form, thiamine pyrophosphate (TPP), which is the coenzyme of pyruvate decarboxylase in the pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, and oxidative decarboxylation of the three-branched chain alpha-keto acids. It is also the coenzyme of the transketolase in the pentose phosphate pathway. 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 thiamine deficiency states (as in total parenteral nutrition without thiamine supplement) are life-threatening emergencies and present as cardiac failure, Gayet-Wernicke encephalopathy, or lactic acidosis.^1,2

Metabolic markers are hyperlactatemia with hyperpyruvicemia and normal lactate-to-pyruvate ratio, slight elevation of branched-chain amino acids in plasma, presence of alpha-keto acids (ketoglutarate, pyruvate, branched-chain keto acids) in urines with a positive dinitrophenylhydrazine (DNPH) reaction, and low transketolase activity in red blood cells. However, these markers are rarely available in an emergency, and diagnosis relies on the primary care or emergency physician recognizing the disorder and administering the lifesaving therapeutic test of thiamine 5 mg/kg per day. There is no risk of adverse effects. Thiamine-dependent inborn errors of metabolism are very rare. They involve the binding of the coenzyme to the enzyme or specific cellular or mitochondrial transporters of thiamine and TPP, respectively (Table 149-1).

Table 149-1 Vitamin B₆ and B₁ Disorders

VITAMIN B₆: PYRIDOXINE

Vitamin B₆ is present in the human body as six vitamers that all share a 2-methyl-3-hydroxypyridine structure but differ in the nature of the C4 and C5 substituents. The C4 carbon bears a CH₂OH group in pyridoxine, a CHO group in pyridoxal, and a CH₂NH₂ group in pyridoxamine. All three of these C4 variants can exist with the C5 substituent esterified to phosphate: the pyridoxal-5′ -phosphate (PLP) is a highly reactive chemical. Requirement for B₆ is primarily related to the fact that PLP is the cofactor for over 100 enzyme-catalyzed reactions that occur in humans. PLP is involved in the metabolism of many amino acids and neurotransmitters including decarboxylation of aromatic amino acid, glutamate, and histi-dine; transamination of branched-chain amino acid, tyrosine and GABA; the glycine cleavage system; threonine and serine dehydratase; cystathionine β–synthase; and aminolevulinate synthase. Consequently, there are many biochemical markers for B₆ deficiency or dependency states.

The phosphorylated B₆ vitamers in the diet are thought to be hydrolyzed by intestinal phosphatases before absorption. The absorbed vitamers are rapidly cleared by uptake into the liver, where they are phosphorylated by pyridoxal kinase. Pyridoxine phosphate and pyridoxamine phosphate are then converted to pyridoxal phosphate (PLP) by pyridox(am)-5′-phosphate oxidase (PNPO). PLP reenters the circulation bound to the lysine-190 residue of albumin. Delivery of PLP to the tissues requires hydrolysis of circulating PLP to pyridoxal by the ectoenzyme tissue nonspecific alkaline phosphatase. Only pyridoxal is able to cross the blood-brain barrier and enter other tissues, but it then needs to be rephosphorylated by pyridoxal kinase to produce active cofactor PLP.

There are several mechanisms that lead to an increased requirement for pyridoxine or PLP³ (Table 149-1): (1) inborn errors affecting the pathways of B₆ vitamer metabolism: PNPO and alkaline phosphatase defects; (2) inborn errors that lead to accumulation of small molecules that react with PLP and inactivate it, hyperprolinemia type II, and pyridoxine-responsive epilepsy; (3) drugs that affect the metabolism of B₆ vitamers or that react with PLP; (4) celiac disease, which is thought to lead to malabsorption of B₆ vitamers or renal dialysis, which leads to increased losses of B₆ vitamers from the circulation; (5) inborn errors affecting specific PLP-dependent enzymes: X-linked sideroblastic anemia, classical homocystinuria, and gyrate atrophy of the choroids.^1-16