The B Vitamins

The B vitamins are a collection of eight water-soluble, chemically very heterogeneous organic compounds. They function as coenzymes for enzymatic reactions in different biological systems. Their collective effects include energy production, synthesis and repair of DNA/RNA, genomic and non-genomic methylation, and synthesis of numerous neurochemicals and signalling molecules^{1, 2}. However, as Prof. Wong stated, human epidemiological and controlled trial investigations have focused almost exclusively on a trio of B vitamins – folate B₉, cobalamin B₁₂ and pyridoxine B₆, all of which are involved in the metabolism of the potentially toxic amino acid homocysteine².

 
Biochemistry and Function of Folate, Cobalamin and Pyridoxine

Folate and cobalamin play complementary roles in the folate and methionine cycles, regenerating methionine from homocysteine (Figure 1)². When methionine is in excess, it can be converted into cysteine, via series of intermediate steps requiring pyridoxine as a cofactor, ultimately leading to the synthesis of the potent endogenous antioxidant glutathione^1-3.

 

Figure 1. The folate and methionine cycles.^{1- 3}
SAH: S-adenosylhomocysteine;
SAM: S-adenosylmethionine; THF: tetrahydrofolate

 

Also, cobalamin plays a role in conversion into succinyl CoA from methylmalonyl CoA (Figure 2)¹. The conversion is necessary for myelin synthesis⁴. Pyridoxine, on the other hand, functions as a coenzyme in the synthesis of neurotransmitters needed for synaptic transmission^{1, 2}.

 

Figure 2. Conversion from methylmalonyl CoA into succinyl CoA – an important intermediate of the Krebs cycle

(a series of chemical reactions that generate energy, in the form of ATP, in the mitochondria) – with cobalamin^{1, 2}.
MCM: methylmalonyl CoA mutase

Neurological Manifestations of Folate, Cobalamin and Pyridoxine Deficiencies

Generally, sufficient folate, cobalamin and pyridoxine can reduce levels of homocysteine, while deficiencies in these B vitamins can cause increased homocysteine levels^{1, 3}. Hyperhomocysteinaemia is associated with an increased risk of stroke, cognitive decline and mood disorders^{1, 3, 5}.

 

As pointed out by Prof. Wong, a deficiency in cobalamin alone can result in a functional folate deficiency. A functional folate deficiency not only hamper neuronal differentiation and repair, and promote hippocampal atrophy and demyelination, but also compromise the integrity of membrane phospholipids, impairing the propagation of action potentials². Also, lack of cobalamin can lead to a decrease in normal myelin synthesis and incorporation of abnormal fatty acids into neuronal lipids. Common neurological manifestations associated with cobalamin deficiency include neuropathy, myelopathy, neuropsychiatric abnormalities, dementia, optic nerve atrophy, and subacute combined degeneration (SCD) of the spinal cord⁴.

 

Since the synthesis of neurotransmitters is differentially affected by the levels of pyridoxine, greater depletion of some neurotransmitters would occur even with mild deficiency, thereby resulting in imbalances between the levels of different neurotransmitters^{1, 2}. Neurological manifestations of pyridoxine deficiency include impaired cognitive function, convulsive seizures, depression, carpal tunnel syndrome and peripheral neuropathy¹.

 

Table 1. Specific risk factors for deficiencies in B vitamins^{1, 6-9}

Management of Deficiencies in B Vitamins

Owing to widespread food fortification with folate, cobalamin deficiency is a much more com­mon cause of hyperhomocysteinaemia than folate deficiency in developed countries⁸. To avoid causing SCD of the spinal cord, cobalamin deficiency must be treated first if cobalamin deficiency coexists with folate deficiency¹⁰.

 

Most patients with clinical cobalamin deficiency have malabsorption and will require parenteral or high-dose 1,000 to 2,000 µg oral replacement. Adequate supplementation can achieve resolution or improvement in myelopathy and megaloblastic anaemia¹¹. However, as told by Prof. Wong, cobalamin must be converted into active forms before it is used by the body. “Methylcobalamin is the active form of cobalamin that acts as a coenzyme for methionine synthase involved in the conversion of methionine from homocysteine and may therefore be a better treatment for cobalamin deficiency than inactive forms such as cyanocobalamin,” added Prof. Wong. In fact, a meta-analysis of individual patient data from trials of cobalamin therapy has indicated that patients with impaired renal function exposed to high-dose cyanocobalamin do not benefit from therapy with B vitamins for preventing stroke⁵.

 

In general, patients with a reversible cause should be treated until the deficiency is corrected and symptoms resolve, while treatment for those with an irreversible cause should be continued for life^{8, 10}. As advised by Prof. Wong, for patients on long-term metformin or acid-suppressing medications, increased screening and vigilance of cobalamin deficiency and the use of oral cobalamin could be consid­ered. In fact, cobalamin supplementation has been advocated as a prophylactic measure in vegetarians, gastrectomised patients, patients undergoing high-flux haemodialysis, and infants born to mothers with pernicious anaemia⁴.

 

Pyridoxine deficiency always coexists with deficiencies of other B vitamins such as folate and cobalamin. The vitamin is available therapeutically in both oral and parenteral formulations in illnesses linked to pyridoxine deficiency. However, the formulation and dosage used both depend on the severity of symptoms¹².

 

References

1. Calderón-Ospina CA and Nava-Mesa MO. CNS Neurosci Ther. 2020;26:(1)5-13. 2. Kennedy DO. Nutrients 2016;8:(2)68. 3. Mitchell ES, et al. Neurosci Biobehav Rev 2014;47:307-320. 4. Briani C, et al. Nutrients 2013;5(11):4521-4539. 5. Spence JD, et al. Lancet Neurol 2017;16(9): 750-760.6. Scaglione F and Panzavolta G. Xenobiotica 2014; 44(5):480-488. 7. Kumar N. Handb Clin Neurol 2014;120:915-926. 8. Langan RC and Goodbred AJ. Am Fam Physician. 2017;96(6):384-389. 9. Morris MS, et al. Am J Clin Nutr 2008;87(5):1446–1454. 10. Hunt A, et al. BMJ. 2014;349:g5226. 11. Stabler SP. N Engl J Med 2013;368(21):149-160. 12. Brown MJ and Beier K. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019-.