Vitamin B12 Deficiency: What are the consequences?

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Symptoms of vitamin B12 deficiency and hypothyroidism

Many of the symptoms of hypothyroidism are similar to the symptoms of vitamin B12 deficiency. Thus, fatigue, weakness, depression, irritability, memory loss, abnormal menstrual cycles, decreased libido and poor mental growth are similar. to both conditions.  Confounding the situation is that  there is a high (approx 40%) prevalence of vitamin B12 deficiency in hypothyroid patients. Traditional symptoms are not a good guide to determining presence of B12 deficiency. Screening for vitamin B12 levels should be undertaken in all hypothyroid patients, irrespective of their thyroid antibody status.

Hypothyroidism leads to vitamin B12 deficiency.

Normal cycling of folate results in the formation of an irreversible reaction in which 5, 10 methylenetetrahydrofolate is converted to 5-methyltetrahydrydrofolate (5-MTHF) by the enzyme 5,10 methyltetrahydrofolate reductase (MTHFR). Of note in this reaction is that MTHFR uses FAD (derived from riboflavin, vitamin B2) as an essential cofactor. In addition, the reduction that occurs requires input from NADH + H+ (derived from nicotinamide, vitamin B3). In the absence of these two vitamins (B2/B3) the enzyme is not functional. In this situation, folate is not able to recycle via the conversion of 5,10-methenyltetrahydrofolate to 5-methyltetrahydrofolate. This leads to an intracellular deficiency of folate, MeCbl, methionine and SAM. Furthermore, the regeneration of reduced *Co(I)VB12) that often becomes oxidized to inactive Co(II)VB12 requires the FAD dependent methionine synthase reductase (MTRR), and lack of FAD due to hypothyroidism decreases the activity of this enzyme and hence VB12 used by methionine synthase cannot be recycled.

In addition, often in hypothyroidism there is inefficient stimulation of gastric acid production and release of intrinsic factor from the parietal cells in the intestine. This lack of gastric acid reduces the activity of pepsin in the stomach leading to incomplete digestion/extraction of vitamin B12, iron and riboflavin from food. This in itself can lead to vitamin B12 deficiency.

 

Role of the Thyroid in FAD synthesis

Synthesis of Flavin Mononucleotide (FMN) from riboflavin requires the addition of phosphate from ATP, via riboflavin kinase, with the input of triiodothryonine (T3) and thyroxine (T4). Both T3 and T4 are produced in the thyroid following stimulation by thyroid stimulating hormone (TSH). The subsequent synthesis of FAD from FMN also involves contribution of thyroxin in the presence of FAD plus AMP. Deficiency in thyroxine, due to hypothyroidism can result in reduced levels of FAD in the body. Similarly dietary deficiency in either iodine (required for synthesis of T4), selenium (required for the conversion of T4 to T3), molybdenum (for the conversion of FMN to FAD) and/or riboflavin can result in reduced FAD, subsequently resulting in vitamin B12 deficiency..

Vitamin B12 supplementation and role of FAD

Several studies on vitamin B12 supplementation have used either cyanocoblamin (CN-B12) or hydroxylcobalamin (OH-B12) and up to 50% of the patients were found not to respond to the B12 supplements either in reduction of symptoms or in the lowering of homocysteine and/or MMA. Whilst FAD levels were not tested in these individuals, low FAD (from vitamin B2, or hypothyroidism) would lead to an inability to reduce OH-B12 or CN-B12 to adenosyl and/or methyl B12.

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