top of page

What Is With High Serum B12 - In Chronic Illness - Even For Folks Who Don't Take B12 ? Plus...Neurodegeneration and Blue Zone diets

This is not medical advice, before starting any health related regimen seek the advice of your Primary Care Physician or an M.D.

Well, there are certainly oodles of folks in various chronic illness facebook groups who report high serum b12. And are incapacitated.

And there is of course, Greg R Jones, and his well known paradoxical b12 deficiency work - high serum b12 is actually a deficiency.

Not sure fast. It could be. And it could be other things too - that do result in a deficiency, but its important to resolve whats causing the deficiency rather than just more B12 - which as we will see - can cause big potential problems.

"Recent findings in diseases associated with oxidative stress have revealed that intracellular oxidative stress results in local functional B12 deficiency. Insufficient intracellular processing of B12 due to oxidative stress has been reported in diabetes mellitus or in Alzheimer’s disease, where it has been postulated to be a significant pathophysiological factor. Intracellular reduction of the central cobalt atom is essential for the formation of the metabolically active forms of B12. This process requires reduced glutathione and the hydroquinone form of flavin adenine dinucleotide (FADH2), it is therefore compromised by oxidative stress. In such conditions treatment with glutathione and/or vitamin C, a key physiological regenerator of intracellular glutathione, may provide therapeutic benefit. This warrants further investigation."[1]

"Pathways for tailoring and processing vitamins into active cofactor forms exist in mammals that are unable to synthesize these cofactors de novo. A prerequisite for intracellular tailoring of alkylcobalamins entering from the circulation is removal of the alkyl group to generate an intermediate that can subsequently be converted into the active cofactor forms. MMACHC, a cytosolic cobalamin trafficking chaperone, has been shown recently to catalyze a reductive decyanation reaction when it encounters cyanocobalamin. In this study, we demonstrate that this versatile protein catalyzes an entirely different chemical reaction with alkylcobalamins using the thiolate of glutathione for nucleophilic displacement to generate cob(I)alamin and the corresponding glutathione thioether. Biologically relevant thiols, e.g. cysteine and homocysteine, cannot substitute for glutathione. The catalytic turnover numbers for the dealkylation of methylcobalamin and 5′-deoxyadenosylcobalamin by MMACHC are 11.7 ± 0.2 and 0.174 ± 0.006 h−1 at 20 °C, respectively. This glutathione transferase activity of MMACHC is reminiscent of the methyltransferase chemistry catalyzed by the vitamin B12-dependent methionine synthase and is impaired in the cblC group of inborn errors of cobalamin disorders."[2]

"Human CblC has been shown to interact with CblD, a protein involved in B12 trafficking, albeit its function is not understood. Stable interaction between CblC and CblD required the presence of alkylcobalamins and GSH (Glutathione)."[3]

"Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q (rs rs121918243 ), R161G (rs ), R206P (rs ), R206W (rs ), and R206Q (rs ), have been reported to cause Cbl diseases. The impact of these variations on MMACHC’s structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking."[4]. In case you are wondering, its : rs371753672.

"Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake."[9] 271dupA on MMACHC, rs398124292 [8].

There it is folks - low b2, glutathione and or excess oxidative stress that depletes glutathione - renders B12 useless. Bam. What does this ? - blocked recycling of glutathione (b2 is needed), excess hydrogen peroxide (GPX4, GPX1 mutations), and peroxynitrite from excess nitric oxide and super oxide (NOS Uncoupling). High serum B12 is a sign of low b2, low glutathione, high oxidative stress (hydrogen peroxide, peroxynitrite) and will result in a blocked heme pathway - see below. MMACHC is the gene that requires glutathione in processing b12.

It Gets Better...

"The causes of cobalamin (B12, Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B12 deficiency in a cblC-disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level."[5]

"Ethanol, arsenic, lead, mercury, aluminum and the vaccine preservative thimerosal are suspected to be etiological factors for neurodegenerative and neurodevelopmental disorders. Autism is a neurodevelopmental disorder characterized by oxidative stress and impaired methylation status, including decreased activity of the folate and vitamin B12-dependent enzyme methionine synthase (MS, known as the MTR gene). MS-mediated conversion of homocysteine to methionine is crucial for neurons and all mammalian cells to sustain normal methylation status, involving more than 100 different reactions. Glutathione (GSH) protects MS from oxidative inactivation by reactive oxygen species, while MS inactivation increases GSH (glutathione) synthesis by augmenting transsulfuration. Utilizing SH-SY5Y cultured human neural cells, we found that a 1 hour pre-incubation of cells with arsenic, lead, mercury, aluminum and thimerosal potently decreased both hydroxocobalamin (OHCbl) and methylcobalamin (MeCbl)-based MS activity, although OHCbl exhibited greater sensitivity than MeCbl. At a concentration of 100 nmol, each of these neurodevelopmental toxins caused a 60–70% reduction of intracellular GSH levels. 22 mM (0.1%) ethanol caused a similar inhibition of OHCbl- and MeCbl-based MS activity and a similar decrease in GSH levels. Our findings suggest that heavy metals and ethanol may contribute to the occurrence of neurodevelopmental disorders such as autism via a mechanism that involves oxidative stress and inhibition of MS activity."[6]

What does high cobalt block ? The heme pathway, thats what, at the ALAD gene. What does that do:

  • Lowers heme, and results in unbound iron.

  • What does unbound iron do ?

    • Inserts itself into SOD2 (in place of manganese) turning it into a pro oxidant. So now, SOD2 creates free radicals inside the mitochondria and stops removing super oxide.

    • It also creates hydroxyl radicals - very caustic

  • What do we find in Autism?

    • When we inhibit SOD 2 - they improve (Suramin inhibits SIRT 1 which is needed by SOD2). Which at first seems bizarre.

    • Low heme - the following interfere with heme production

      • Aluminum (high levels in Cali)

      • Mercury, Lead, Arsenic

      • Glyphosate - blocks glycine (Cali)

      • Anti fungals sprayed on non organic crops (Cali)

      • High manganese

      • High cobalt

      • VOC's

      • DDT

      • Dioxins

      • Low b2, b6, copper, iron, zinc

      • genetics

  • What do we find in Alzheimer's:

    • Aluminum in the brain

    • Excess iron legions

  • What helps Alzheimer's

    • Percepta (Cats Claw, and Ooolong Tea)

      • Cats Claw - anti viral, calcium channel blocker to protect against high glutamate / NMDA receptor activation

      • Oolong tea - metals binder, including iron binder

  • Blue zone diets - very little dementia / alzheimers - what is going on ?

    • High serine in diet, which we convert to glycine (heme cofactor)

      • Serine is a cofactor for........thyroid....maybe its more than just iodine in the Japanese diet

      • Phosphatidyl serine is also an anti oxidant that gets transported into the inner membrane of the mitochondria to protect the cardio lipin.

    • Low animal protein - lower iron

    • High legumes / beans - binders for toxins

    • Brown Seaweed - source of silica - which helps remove aluminum, and is a good source of fucoidan which lowers glutamate and protects against neuronal death from NMDA receptor activation

    • Soy / Tofu - which is high in amino acids Phenylalinine and Tyrosine needed for dopamine, and Tryptophan need for serotonin.

    • Tea drinkers - many teas bind metals and especially iron

Food for thought:)


  1. Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation C Vollbracht, G P McGregor, and K Kraft. QJM. 2020 Sep; 113(9): 619–620. Published online 2019 June 28.  doi: 10.1093/qjmed/hcz164. PMCID: PMC7550708 PMID: 3125136

  2. A Human Vitamin B12 Trafficking Protein Uses Glutathione Transferase Activity for Processing Alkylcobalamins By Jihoe Kim. J Biol Chem. 2009 Nov 27; 284(48): 33418–33424.  doi: 10.1074/jbc.M109.057877. PMCID: PMC2785186. PMID: 19801555

  3. Glutathione-dependent One-electron Transfer Reactions Catalyzed by a B12 Trafficking Protein. By Li, et. al. Received for publication, March 20, 2014, and in revised form, April 16, 2014 Published, JBC Papers in Press, April 17, 2014, DOI 10.1074/jbc.M114.567339

  4. Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling. by Priya Antony. Biomedicines 2023, 11(12), 3217;

  5. Proteomics of vitamin B12 processing. By Hannibal, et. al. Published by De Gruyter December 12, 2012. From the journal Clinical Chemistry and Laboratory Medicine.

  6. Neurodevelopmental Toxins Deplete Glutathione and Inhibit Folate and Vitamin B12-Dependent Methionine Synthase Activity: A Link between Oxidative Stress and Autism. By MOSTAFA IBRAHIM-AHMED WALY, RICHARD DETH. The FASEB Journal First published: 01 March 2008

  7. VCV000848845.21 - ClinVar - NCBI (

  8. NM_015506.3(MMACHC):c.271dup (p.Arg91fs) AND Cobalamin C disease - ClinVar - NCBI (

  9. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. By Lerner-Ellis, et. al. February 2006. Nature Genetics 38(1):93-100 DOI:10.1038/ng1683

  10. Distinct clinical, neuroimaging and genetic profiles of late-onset cobalamin C defects (cb1C): a report of 16 Chinese cases. By Wang et. al. Orphanet J Rare Dis. 2019; 14: 109. Published online 2019 May 15. doi: 10.1186/s13023-019-1058-9 PMCID: PMC6521494 PMID: 31092259.

38 views0 comments

Recent Posts

See All


bottom of page