B12 Serum and MTHFR

B12 Serum and MTHFR

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Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - BSN, RN

Medical Reviewer:

Kari Asadorian - BSN, RN
Jamie Hope - Methyl-Life® Founder

Edited By:

Jamie Hope - Methyl-Life® Founder

Updated On:

December 05, 2025

What is B12 serum?

Serum B12 refers to the concentration of cobalamin (vitamin B12) circulating in the liquid portion of your blood. 

A serum B12 test is a biochemical measurement of that amount, usually expressed in picograms per millilitre (pg/mL) or picomoles per litre (pmol/L).

Connection between B12 serum level and B12 in the body

Clinically, a serum B12 test is used to assess whether a person has adequate, deficient or excessive levels of vitamin B12. However, serum B12 is only the total amount of vitamin B12 circulating in the blood, not the amount that cells may be able to use. 

This is because around 70-90% of vitamin B12 in the blood is bound to the protein haptocorrin, which acts as a carrier in circulation but cannot deliver it to cells for metabolic use. This portion of B12 is technically inactive.

The remaining 10–30% is bound to transcobalamin (TC), a complex referred to as holotranscobalamin (holoTC). Only the holoTC complex can be taken up by cells and used for biological processes such as methylation. This portion is therefore considered the active or ‘usable’ form of B12.1

However, total serum B12 concentrations may not always reflect intracellular B12 levels,  because a serum B12 test will only show the total B12 in the bloodstream (including B12 bound to haptocorrin (HC) and transcobalamin (TC) rather than the amount that can be used by the body.2

A test result may show that someone has normal or high serum B12 levels even when they are lacking in holotranscobalamin (usable B12). 

For this reason, tests for functional markers are recommended. When intracellular B12 is insufficient, methylmalonic acid (MMA) and homocysteine levels rise. Testing for MMA and homocysteine levels is considered a more accurate reflection of metabolic B12 activity (or B12 that’s available for your body to actually use).3

B12 serum levels: What is considered a normal level? What is elevated?

While there is no exact definition for B12 levels, ‘normal’ is considered around 300-900pg/mL, while deficiency is less than 200 pg/mL.4

Elevated serum B12 is generally defined as around 1000 ± 100 ng/L (738 ± 73.8 pmol/L).5

However, it’s important to note that  serum levels do not accurately reflect B12 cellular sufficiency.

Symptoms of elevated B12 serum level

Elevated B12 does not usually produce noticeable symptoms. However, one study reported that children and adults with normal to elevated levels of serum vitamin B1 had many symptoms normally associated with vitamin B12 deficiency, including fatigue, depression, anxiety, lack of motivation, poor memory, fuzzy thinking, peripheral neuropathy and difficulty sleeping.6

Causes of elevated B12 serum level

High vitamin B12 concentrations may be caused by:

  • Underlying disorders such as liver diseases. Vitamin B12 is stored primarily in the liver and an increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases (including acute hepatitis, cirrhosis, hepatocellular carcinoma and metastatic liver disease) can cause cobalamin to be released during liver cell breakdown and/or reduce the ability of the liver to take up and store cobalamin from the blood.7
  • Immune complexes (ICs) can cause an abnormally high total vitamin B12 by binding to the B12 transport proteins in the plasma. This creates a large macromolecule referred to as ‘macro-B12’, which cannot be efficiently filtered and removed by the kidneys, and instead accumulates in the blood.8
  • Hematological disorders, including neutrophilia, secondary eosinophilia, myeloproliferative neoplasms can cause high B12 by creating a larger pool of white blood cells and binding proteins that hold vitamin B12. This may result in enhanced release of transcobalamin I (TCI) from proliferating white blood cells, which leads to higher serum levels of B12.9
  • Although uncommon, oversupplementation with high-dose B12 supplements or injections may lead to elevated serum B12.

What happens if B12 serum is elevated?

Elevated B12 can be a problem for several reasons. The most common issue is that someone with high serum B12 may actually be deficient in intracellular B12, but they don’t receive treatment for the deficiency.

Elevated B12 may also be a sign of an underlying disorder affecting normal B12 metabolism, including liver disease, a blood disorder or an immune complex. People who are tested as having high B12 should undergo further testing for functional markers of MMA and homocysteine. When intracellular B12 is insufficient, methylmalonic acid (MMA) and homocysteine levels rise. Testing for MMA and homocysteine levels is considered a more accurate reflection of usable B12.10

Serum B12 and folate levels

B12 and folate (vitamin B9) are both involved in one-carbon metabolism and are essential for DNA biosynthesis, homocysteine metabolism, neurotransmitter production and many other processes. 

High serum B12 levels themselves are not typically linked to folate deficiency, but low B12 may affect how folate is used in the body. In severe B12 deficiency, methylfolate is trapped in one form and can't be converted to the other folate forms cells need for DNA synthesis and cell division. Instead, it accumulates in the blood, raising serum folate levels. This is called the 'folate trap'.11

Recent research suggests that excess folic acid intake may lead to insufficient B12, but the biochemical mechanism for this is not yet certain. One study has hypothesized that excess folic acid causes the body to redirect holoTC (the active form of B12) from the bloodstream to bone marrow, where it supports the rapid growth of new red blood cells. Folic acid can then interfere with the kidney's reabsorption of holoTC, causing holoTC to be passed out in urine rather than returned to the bloodstream.12

B12 serum levels and MTHFR

Studies show a link between low serum B12 levels and the MTHFR C677T variant.13

In B12 deficiency, methionine synthase cannot function properly, causing methylfolate to accumulate while other folate forms needed for DNA synthesis (5,10‑methylene‑THF / THF) become depleted.14

Low B12 and/or low folate are both risk factors for high homocysteine, which is common in people with MTHFR mutations.15

People with MTHFR are advised to monitor their folate and B12 levels and supplement when necessary. The most effective supplements are those with the active forms of the nutrients (i.e. methylfolate and methylcobalamin), as these do not require metabolism by the MTHFR enzyme. 

B12 Serum and MTHFR

Key takeaways

  • Icon Serum B12 is the concentration of B12 circulating in the liquid portion of your blood.
  • Icon High serum B12 doesn’t necessarily reflect the ‘usable’ amount in the tissues.
  • Icon High serum B12 may indicate an underlying condition such as liver disease, blood disorders or immune complexes.

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Frequently Asked Questions about B12 serum levels

What is a serum B12 test for?

A serum B12 test measures the concentration of cobalamin (vitamin B12) circulating in the blood. It is the most commonly used B12 test, though it does not provide an accurate picture of intracellular B12 sufficiency.

What is a normal serum B12 level?

While there is no exact definition for B12 levels, a ‘normal’ B12 serum test level is considered around 300-900pg/mL, while deficiency is less than 200 pg/mL.16 Elevated serum B12 is around 1000 ± 100 ng/L (738 ± 73.8 pmol/L).17 However, MMA and homocysteine tests may provide a more accurate depiction of B12 intracellular sufficiency.

What if serum B12 is high?

High serum B12 is not necessarily a condition in itself, but rather an indication of an underlying condition that is affecting the transport and distribution system of B12 for cellular use. This could be a liver disease, an autoimmune disorder or a hematological condition. The causes of high B12 should be investigated by a healthcare professional in addition to the individual’s actual cellular B12 sufficiency levels (possibly through testing for MMA and homocysteine levels.

What happens if serum B12 is low?

B12 serum includes both active and inactive forms of the vitamin, so a test result showing low serum B12 doesn’t necessarily mean that you are deficient in the active form (holotranscobalamin).
Low serum B12 typically means less holoTC is circulating, which can slow down the delivery of B12 to cells.
Low serum B12 can mean that tissues are competing for limited holoTC in the bloodstream, and areas with high B12 turnover (including the bone marrow) may get priority, while the brain, liver and peripheral nerves do not receive enough. In addition, the kidneys may excrete more holoTC (usable B12) in urine if reabsorption is impaired, reducing availability further.
In such cases, supplementation with sublingual B12 may be recommended as a means of restoring B12 levels.

References

  1. Ebba Nexo, Elke Hoffmann-Lücke; "Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility"; The American journal of clinical nutrition; 2011 Jul

    https://pmc.ncbi.nlm.nih.gov/articles/PMC3127504

  2. C Vollbracht, G P McGregor, K Kraft; "Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation"; QJM: Monthly Journal of the Association of Physicians; 2019 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7550708/

  3. London: National Institute for Health and Care Excellence (NICE); "Vitamin B12 deficiency in over 16s: diagnosis and management"; Vitamin B12 deficiency in over 16s: diagnosis and management; 2024 Mar

    https://www.ncbi.nlm.nih.gov/books/NBK603364/

  4. Hernando Vargas-Uricoechea, Juan Patricio Nogueira, María V Pinzón-Fernández, Valentina Agredo-Delgado, Hernando David Vargas-Sierra; "Population Status of Vitamin B12 Values in the General Population and in Individuals with Type 2 Diabetes, in Southwestern Colombia"; Nutrients; 2023 May

    https://pubmed.ncbi.nlm.nih.gov/37242240/

  5. Valentin Lacombe, Floris Chabrun, Carole Lacout, Alaa Ghali, Olivier Capitain, Anne Patsouris, Christian Lavigne, Geoffrey Urbanski; "Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer"; Scientific Reports; 2021 Jun

    https://www.nature.com/articles/s41598-021-92945-y

  6. Gregory Russell-Jones; "Paradoxical Vitamin B12 Deficiency: Normal to Elevated Serum B12, With Metabolic Vitamin B12 Deficiency"; Journal of Biology and Today's World; 2022

    https://www.iomcworld.org/articles/paradoxical-vitamin-b12-deficiency-normal-to-elevated-serum-b12-with-metabolic-vitamin-b12-deficiency-91903.html

  7. A A M Ermens, L T Vlasveld, J Lindemans; "Significance of elevated cobalamin (vitamin B12) levels in blood"; Clinical biochemistry; 2003 Nov

    https://pubmed.ncbi.nlm.nih.gov/14636871/

  8. Bruce H R Wolffenbuttel, Anneke C Muller Kobold, Agata Sobczyńska‐Malefora, Dominic J Harrington; "Macro-B12 masking B12 deficiency"; BMJ case reports; 2022 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8762123

  9. Abdalla Fadul, Elmustafa Abdalla, Anas Mohamed, Bashir Ali, Nusiba Elamin, Ahmed Abdelghafar Alsayed, Abdulrahman F Al-Mashdali, Kalpana Singh, Shehab F Mohamed; "Elevated Vitamin B12 Levels in Myeloproliferative Neoplasm (MPN) Patients: A Potential Diagnostic and Prognostic Marker"; Journal of blood medicine; 2024 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11687131

  10. London: National Institute for Health and Care Excellence (NICE); "Vitamin B12 deficiency in over 16s: diagnosis and management"; Vitamin B12 deficiency in over 16s: diagnosis and management; 2024 Mar

    https://www.ncbi.nlm.nih.gov/books/NBK603364/

  11. K E Elizabeth; "Folate: Its Biological Interactions and Strategies to Achieve Sufficiency Without Causing Excess"; American journal of public health; 2021 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7893371/

  12. Jacob Selhub, Joshua W Miller, Aron M Troen, Joel B Mason, Paul F Jacques; "Perspective: The High-Folate–Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology—A Hypothesis"; Advances in nutrition; 2021 Oct

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8803489/

  13. Khalid M Al-Batayneh, Mazhar Salim Al Zoubi, Murad Shehab, Bahaa Al-Trad, Khaldon Bodoor, Wesam Al Khateeb, Alaa A A Aljabali, Mohammad Al Hamad, Greg Eaton; "Association between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-control Study"; Journal of medical biochemistry; 2018 Apr

    https://pubmed.ncbi.nlm.nih.gov/30581350/

  14. Sabrina Giammarco, Patrizia Chiusolo, Roberto Maggi, Monica Rossi, Gessica Minnella, Elisabetta Metafuni, Francesco D’Alò, Simona Sica; "MTHFR polymorphisms and vitamin B12 deficiency: correlation between mthfr polymorphisms and clinical and laboratory findings"; Annals of hematology; 2024 Aug

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11512882

  15. Shanel Raghubeer, Tandi E Matsha; "Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks"; Nutrients; 2021 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8703276

  16. Hernando Vargas-Uricoechea, Juan Patricio Nogueira, María V Pinzón-Fernández, Valentina Agredo-Delgado, Hernando David Vargas-Sierra; "Population Status of Vitamin B12 Values in the General Population and in Individuals with Type 2 Diabetes, in Southwestern Colombia"; Nutrients; 2023 May

    https://pubmed.ncbi.nlm.nih.gov/37242240/

  17. Valentin Lacombe, Floris Chabrun, Carole Lacout, Alaa Ghali, Olivier Capitain, Anne Patsouris, Christian Lavigne, Geoffrey Urbanski; "Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer"; Open access; 2021 Jun

    https://www.nature.com/articles/s41598-021-92945-y

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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