Hidden Intracellular/Functional Vitamin B12 Deficiency with normal or high blood markers

[Keyhole]

I am opening this thread to share some information on vitamin B12 deficiency which can go unnoticed or misdiagnosed because of inferior testing methods. It is a pattern that I have noticed in many individuals who present with neurological symptoms and chronic fatigue/fibromyalgia type symptoms, yet have normal or high serum vitamin B12 on an ordinary blood panel.

This may lead a clinician to assume that B12 levels are optimal. However, the high serum B12 can actually be indicative of a functional problem with transporting it into the cells and then utilizing it properly. Hence, the B12 deficiency is masked by the "unremarkable" blood testing results. This is the main reason why I find urinary/blood methylmalonic acid as the best marker for B12 deficiency, along with homocysteine as a supporting marker. I have consulted with numerous people who had high serum B12, but markers of severe functional deficiency. So maybe there will be some people on the forum who might find this information helpful.

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency
Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.


Vitamin B12 Deficiency
Vitamin B12 (B12 = Cbl, “cobalamin,” the chemical name) is an essential water-soluble micronutrient required by all cells in the body. Humans are unable to synthesize B12 and thus rely on dietary intakes and a complex intracellular route for vitamin processing and delivery to its target destinations (Figure 1) (Hannibal et al., 2009). Vitamin B12 deficiency due to malabsorption and inadequate intake is a public health issue worldwide. It is estimated that 15–20% of the elderly in the United States are B12 deficient (Allen, 2009). In Germany, about 10% of the male elderly population and 26% of the female elderly population present with insufficient levels of vitamin B12 (Hartmann, 2008; Grober et al., 2013). In India, ~75% of the population, i.e., over 650 million people, have B12 deficiency (Antony, 2001; Refsum et al., 2001), which can only be partly ascribed to a vegetarian diet in a substantial portion of the population.


Vitamin B12 deficiency is a multifactorial condition caused by insufficient intake (nutritional deficiency) as well as acquired or inherited defects that disrupt B12 absorption, processing and trafficking pathways (functional deficiency). Methylcobalamin (MeCbl) serves as a coenzyme for the biosynthesis of methionine from homocysteine catalyzed by the cytosolic enzyme methionine synthase (MS). This reaction regenerates tetrahydrofolate (THF) from N5-methyl-tetrahydrofolate (N5-CH3-THF), which is essential for the de novo biosynthesis of nucleic acids. Adenosylcobalamin (AdoCbl) is required for the conversion of methylmalonyl-CoA to succinyl-CoA catalyzed by mitochondrial methylmalonyl-CoA synthase (MCM), an anaplerotic reaction that furnishes increased demands for the Krebs cycle and heme biosynthesis precursor succinyl-CoA.

Insufficient supply of B12 and genetic defects impairing its cellular processing and trafficking lead to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), which enter circulation and give rise to hyperhomocystinemia and methylmalonic acidemia.

[My note: What this basically means is that you need B12 to be functioning inside the cells to recycle homocysteine and methylmalonic acid. Hence, if either of these markers test as high, then this demonstrates a functional deficiency. In this context, you can have perfectly normal B12 levels in serum, but it is not being used inside the cells properly. The end result is a deficiency on the intracellular level]

Vitamin B12 deficiency is frequently under-diagnosed in pregnancy and in infants from mothers having insufficient levels of the micronutrient (Wheeler, 2008; Sarafoglou et al., 2011). Ensuring sufficient intake of vitamin B12 during pre-conception, pregnancy, and post-partum is strongly recommended (Bjørke Monsen et al., 2001; Rasmussen et al., 2001; Bjørke-Monsen et al., 2008; Hinton et al., 2010; Dayaldasani et al., 2014). Other populations at risk of developing vitamin B12 deficiency include the elderly, vegetarians and vegans, recipients of bariatric surgery (Majumder et al., 2013; Kwon et al., 2014) as well as those suffering from gastrointestinal diseases featuring ileal resections >20 cm (Battat et al., 2014). Certain medications such as metformin (Greibe et al., 2013b; Aroda et al., 2016) and proton-pump inhibitors (Howden, 2000; Wilhelm et al., 2013) may also transiently induce a status of cobalamin deficiency, which may be reversible upon completion of treatment and/or with oral vitamin B12 supplementation.

Herein, we discuss three aspects of the assessment of B12 status: (1) The utility of metabolites used as biomarkers of vitamin B12 deficiency in neonates and adults, (2) The algorithms employed to predict subclinical and clinical B12 deficiency, and (3) Major challenges and diagnosis of vitamin B12 deficiency in special populations.

Serum Biomarkers of Vitamin B12 Deficiency: Strengths and Limitations
Total Serum Vitamin B12
The most direct assessment and perhaps preferred first-assay to determine vitamin B12 status is the measurement of total serum vitamin B12. This assay is widely available in clinical chemistry laboratories. Ranges for normal (>250 pmol/L), low (150–249 pmol/L), and acute deficiency (<149 pmol/L) vitamin B12 have been defined and are used in most clinical chemistry laboratories worldwide (Clarke et al., 2003; Selhub et al., 2008; Mirkazemi et al., 2012). One limitation of this biomarker is that it assesses total circulating vitamin B12, of which ~80% is bound to haptocorrin, and therefore, not bioavailable for cellular uptake. Another limitation of this assay lies in its unreliability to reflect cellular vitamin B12 status. Results from studies assessing serum and cellular vitamin B12 have shown that the levels of serum B12 do not always represent cellular B12 status (Carmel, 2000; Solomon, 2005; Devalia et al., 2014; Lysne et al., 2016). In particular, patients with inborn errors of vitamin B12 metabolism can present with normal or low serum values of the vitamin, while being deficient at the cellular level. Furthermore, functional vitamin B12 deficiency due to oxidative stress has been identified in elders exhibiting normal values of serum vitamin B12 (Solomon, 2015). Functional deficiency of vitamin B12 was corrected upon supplementation with cyanocobalamin (CNCbl), as judged by reduction in the serum levels of tHcy and MMA (Solomon, 2015). Thus, total serum B12 is not a reliable biomarker of vitamin B12 status when used alone. Nonetheless, this marker should not be considered obsolete as a number of studies show that total serum vitamin B12 may be helpful to predict prognosis and status of diseases featuring abnormally high vitamin B12 levels in serum (>650 pmol/L), such as cancer (Arendt et al., 2016) and autoimmune lymphoproliferative syndrome (ALPS) (Bowen et al., 2012).

Homocysteine
Homocysteine is a metabolite of one-carbon metabolism that is remethylated by MeCbl-dependent MS or betaine-homocysteine methyltransferase as part of the methionine cycle (Finkelstein and Martin, 1984) and degraded by cystathionine β-synthase (CBS) in the transsulfuration pathway (Figure 2). Conversion of Hcy to Met by MS depends on the availability of both vitamin B12 and folate (as N5-CH3-THF), and therefore, nutritional deficiencies in either one of these micronutrients lead to the accumulation of Hcy in serum and urine. Likewise, inborn errors of metabolism that impair the upstream processing and trafficking of B12 or folate lead to elevation of this metabolite, a condition collectively known as hyperhomocystinemia. The normal range of total plasma Hcy (tHcy) in human plasma is 5–15 μmol/L (Ueland et al., 1993) and values >13 μmol/L may be considered elevated in adults (Jacques et al., 1999). Homocysteine levels are always higher in serum compared to plasma due to the release of Hcy bound to cellular components (Jacobsen et al., 1994). Hence, plasma and not serum should be used to determine the levels of tHcy. Although gender and age reference intervals have been established in some studies (Jacobsen et al., 1994; Rasmussen et al., 1996; van Beynum et al., 2005), they are usually ignored in the reporting of tHcy levels. Because of the dual biochemical origin of elevated Hcy, this biomarker is of limited value to assess vitamin B12 status as a stand-alone measurement. This is also true for the newborn screening of inborn errors of vitamin B12 metabolism found in the cblD, cblF, and cblJ (Huemer et al., 2015) disorders.




Figure 2. Pathways for Hcy and MMA metabolism in humans. (A) Homocysteine is a branch-point metabolite at the intersection of either the remethylation or the transsulfuration pathways. Thus, Hcy homeostasis relies on three different biochemical reactions [MS, cystathionine β-synthase (CBS) and S-adenosylhomocysteine hydrolase (SAHH)], two of which (CBS and SAHH) are independent of vitamin B12. In addition to nutritional deficiency of vitamin B12, elevation of Hcy in plasma may arise from reduced function of CBS and MTHFR, as well as nutritional deficiencies of folate. (B) MMA is produced during catabolism of odd-chain fatty acids and amino acids in the mitochondrion. Propionyl-CoA is the precursor of MMA in a reaction catalyzed by propionyl-CoA carboxylase (PCC). Inborn errors of PCC lead to propionic acidemia. Likewise, mutations in AdoCbl-dependent MCM lead to a buildup of MMA-CoA and inhibition of PCC that manifests as increased propionyl-CoA and so of propionic acid the circulation. Propionylcarnitine can also be transported out of the cell to reach systemic circulation. Propionylcarnitine is a first-line test in newborn screening.

Methylmalonic Acid
MMA increases upon inactivation of AdoCbl-dependent MCM in the mitochondrion. Nutritional and functional deficiencies of vitamin B12 result in the inactivation of MCM leading to buildup of its substrate methylmalonyl-CoA, which enters circulation as free MMA. The reaction catalyzed by MCM (Figure 2) is not affected by other vitamins of one-carbon metabolism, and therefore, MMA is considered a more specific marker of vitamin B12 deficiency (Clarke et al., 2003). Serum values of MMA, ranging from >260 to 350 nmol/L indicate elevation of this metabolite (Clarke et al., 2003). Nonetheless, there are few pathologies such as renal insufficiency that lead to an increase in MMA (Iqbal et al., 2013). For example, one study showed that 15–30% of individuals with high vitamin B12 concentrations in serum also had elevated MMA concentrations, which may reflect renal dysfunction instead of authentic vitamin B12 deficiency (Clarke et al., 2003). Thus, the utility of this marker should be considered carefully in older patients and patients with suspected or established renal disease. Assessment of a second marker of vitamin B12 status, such as holo-transcobalamin (holo-TC) (Iqbal et al., 2013) should be considered. Another study showed that the clearance of both Hcy and MMA may be compromised in patients with reduced kidney function (Lewerin et al., 2007).

Total Serum Holo-Transcobalamin
Dietary B12 is transported in the digestive system via the use of three protein transporters that bind the micronutrient in a sequential fashion, following the order haptocorrin (HC), intrinsic factor (IF), and transcobalamin (TC) (Fedosov et al., 2007; Fedosov, 2012). After absorption in the intestine, vitamin B12 bound to TC (holo-TC) reaches circulation and it is distributed to every cell in the body. Cells take up holo-TC via receptor-mediated endocytosis, aided by the transcobalamin receptor (TCblR; CD320) (Quadros et al., 2009). Because the only fraction of dietary vitamin B12 that is bioavailable for systemic distribution is in the form of holo-TC (Valente et al., 2011), the level of holo-TC in serum has been successfully utilized as a marker of bioactive vitamin B12 (Nexo et al., 2000, 2002; Valente et al., 2011; Yetley et al., 2011). Holo-TC represents 6–20% of the total vitamin B12 present in serum (Nexo et al., 2000, 2002; Valente et al., 2011; Yetley et al., 2011). This marker is more accurate in assessing the biologically active fraction of vitamin B12 in circulation than serum B12 itself, and its level correlates well with the concentration of vitamin B12 in erythrocytes (Valente et al., 2011). The diagnostic value of holo-TC has proven superior to Hcy and MMA for the assessment of vitamin B12 status in the elderly (Valente et al., 2011). The normal range of holo-TC in healthy subjects is 20–125 pmol/L (Valente et al., 2011). Additional research is needed to elucidate the mechanisms that control holo-TC homeostasis in the normal population and in pathologies that alter vitamin B12 transport and utilization. For example, abnormally low levels of holo-TC have been documented in patients receiving chemotherapy, macrocytosis and in individuals carrying the TC polymporphism 67A>G, without vitamin B12 deficiency (Vu et al., 1993; Wickramasinghe and Ratnayaka, 1996; Riedel et al., 2005, 2011). Insufficient sensitivity (44%) of holo-TC as a marker of vitamin B12 status was noted in a cohort of 218 institutionalized elderly patients (Palacios et al., 2013). At present time, it is unknown whether and how holo-TC levels vary in patients harboring inborn errors affecting intracellular vitamin B12 metabolism (cblA-cblJ). Thus, the diagnostic value of holo-TC as a first line test awaits further investigation.

 

[Laura]

So, what to do about it?

 

[Keyhole]

Here is some information from PhD biochemist who specializes in B12 chemistry. His name is Gregory Russel-Jones, and he has several websites with information on functional B12 deficiency.

He has mapped out several interactions between the B vitamins. His work highlights the complex relationships these vitamins have with one another, and how when one is low, it can produce functional deficiencies in others. The below article highlights the importance of riboflavin and some of the minerals in the activation and utilization of vitamin B12 inside the cells.

In short - You need enough molybdenum and active thyroid hormone (selenium & iodine) to activate vitamin B2 (riboflavin) into the active forms called FAD and FMN. FAD and FMN are needed to utilize vitamin B12 at the cellular level. This means that even if you have enough B12 in the diet, if you are unable to perform any of the steps involving the above nutrients, then you can still be "functionally deficient" in B12 and show all of the symptoms.

Link to the website here: https://b12oils.com/b12info.htm

Paradoxical Vitamin B12 Deficiency
Many people experience symptoms of vitamin B12 deficiency yet their serum levels of vitamin B12 may be normal or much higher than normal. Subsequent examination of biochemical markers such as MMA or homocysteine may show that these markers are moderate to highly elevated. As such the symptoms and biochemical markers are indicative of vitamin B12 deficiency, yet the serum vitamin B12 levels are paradoxically high. Such persons are deemed to have "Paradoxical Vitamin B12 Deficiency".

Causes of Paradoxical B12 Deficiency

The major cause of Paradoxical Vitamin B12 Deficiency appears to lack of functional vitamin B2, which may occur due to overt vitamin B2 deficiency in a person's diet, or due to lack of adequate intake of Iodine, Selenium and/or Molybdenum, which in turn leads to insufficient production of the two active forms of vitamin B2, namely FMN and FAD. FMN and FAD both have critical roles in cycling and maintenance of activity of vitamin B12, particularly methyl B12.

Methyl-Co(III)B12 has a major role in the body in the removal of homocysteine, and in the regeneration of methionine in the methylation cycling using the enzyme methionine synthase reductase (MTR). In the reaction, homocysteine + Methyl-Co(III)B12[MTR] => Methionine + Co(I)B12[MTR]. The problem with this reaction is that the methyl group is lost from MethylCo(III)B12, which is reduced to Co(I)B12 and so cannot perform further methylation reactions. Theoretically if the reaction only happened once you would need approximately 13.7 gm of MethylCo(III)B12 to remethylate the 1.35 gm of homocysteine formed per day, and around 1.37 kg of the enzyme methionine synthase. Since the daily requirement for vitamin B12 is only around 5 ug, of which around 1.37 ug is MethylCo(III)B12, then clearly this does not happen.

Regeneration of MethylCo(III)B12 is performed by methionine synthase which transfers the methyl group from 5-methyl-tetrahydrofolate (5MTHF) to Co(I)B12. Thus, 5MTHF + Co(I)B12[methionine synthase] => THF + MethylCo(III)B12[methionine synthase]. If the 5MTHF was only used once, then the body would require around 459 mg of 5MTHF per day, however, the daily requirement for folate is around 1000th of this at 400-500 ug/day, so clearly some other source, apart from diet is required to supply this amount of 5MTHF.

The solution comes from within the folate cycle. Here the THF, formed above is converted to the folate derivative 5,10-methylene-THF by the enzyme serine hydroxymethyl transferase (SHMT). The enzyme methylene-tetrahydrofolate reducate (MTHFR), then converts the 5,10-methylene group to 5-methyl-THFwhich it transports of the folate cycle into the methylation cycle, in this way a single folate molecule can be recycled over 1000 times into and out of the folate cycle providing the many 5MTHF groups for regeneration of MethylCo(III)B12.

The reaction 5,10-methylene-THF [MTHFR] => 5-methyl-THF [MTHFR]

The enzyme, MTHFR, though is critically dependent for FAD and NADPH for enzymatic activity and as levels of FAD drop, the enzyme rapidly loses activity, leading to insufficient 5MTHF for remethylation of Co(I)B12 to MethylCo(III)B12. In this instance the Co(I)B12 is rapidly oxidized to the biologically inactive Co(II)B12. The body does though have a "way around this" and it uses the enzyme methionine synthase reductase plus S-Adenosylmethionine (SAM) to remethylate Co(II)B12.

Thus, Co(II)B12[MTR] + SAM[MTRR] => MethylCo(III)B12 + SAH + MTRR.

MTRR, like MTHFR is also a "Flavoprotein" and uses both of the active forms of vitamin B2, FMN and FAD for activity. Once again the activity of the enzyme is critically dependent upon the concentration of FMN and FAD. The activity of the enzyme MTRR is so critical for regeneration of MethylCo(III)B12, that certain mutations in the gene have been found to be conditionally lethal in the womb, or are associated with much higher rates of Down Syndrome, Neural Tube Defects, and increased cancer risks.

Vitamin B2 deficiency and Paradoxical B12 Deficiency

From the above it can readily be seen that if levels of the two functional analogues of vitamin B2, namely FMN and FAD are reduced the following will happen.

1. The activity of MTHFR will decrease proportionally with the decrease in FAD, thus resulting in reduced production of 5MTHF.

2. The reduced 5MTHF will result in a build-up in Co(I)B12, which over time will oxidize to Co(II)B12.

3. The reduced FMN and FAD will in turn reduce the activity of the enzyme MTRR and so the levels of inactive Co(II)B12 will build up inside the cell and will eventually be discarded from the cell resulting in a build up of Co(II)B12 in serum. A condition of Paradoxical B12 Deficiency will result.

The major cause of Paradoxical Vitamin B12 Deficiency appears to lack of functional vitamin B2, which may occur due to over vitamin B2 deficiency in a person's diet, or deficiency of Iodine, Selenium and/or Molybdenum. Such deficiencies are very common, and our studies have shown that 50% of people with CFS or ASD being deficient in Iodine, 80% in Selenium and/or 50% in Molybdenum.

See Hypothyroidism for further information.

Conditions associated with Paradoxical B12 Deficiency

Conditions known to be associated with Paradoxical B12 deficiency include:

• Chronic Fatigue Syndrome​
• Fibromyalgia​
• Myalgic Encephalitis​
• Autism​
• Down Syndrome​
• Insufficient intake of vitamin B2, Iodine, Selenium and/or Molybdenum​
• Hypothyroidism​

Conditions where Paradoxical B12 deficiency should be suspected

• Gestational diabetes​
• Obesity​
• Diabetes​
• Conditions of elevated serum vitamin B12 levels above the norm.​
• Solid neoplasms​
• Myeloproliferative blood disorders​
• Liver diseases​
• Dementia​
• Depression​
• ADHD​
• Schizophrenia​
• Psychosis​
• Refractory treatment of vitamin B12 deficiency, particularly with hydroxocobalamin and cyanocobalamin​
• Chronic Viral Diseases​
• Lyme disease​
• Prolonged antibiotic treatment​
• Parkinson's Disease​
• Peripheral Neuropathy​
• Paresthesia​
• Pain and numbness in fingers or toes​
• Fatigue​
• Insomnia​
• Dizziness​
• Pain in joints​
• Stomach complaints​
• Difficulty focusing​
• Mood changes​
• Elevated homocysteine​
• Elevated MMA​
• Prolonged oral treatment with vitamin B12 in which serum B12 levels rise but there is no change in symptoms​

Treatment of Paradoxical B12 Deficiency

It is essential that for successful treatment of Paradoxical B12 deficiency that the cause of the functional vitamin B2 deficiency be addressed including supplementation with sufficient vitamin B2, Iodine, Selenium and Molybdenum. Such treatment, though, is generally not performed, but it has immense consequences as far as treatment results, and explains why literature on treatment of vitamin B12 deficiency is rife with examples in which supplementation studies using inactive forms of vitamin B12 (cyanocobalamin or hydroxocobalamin) without the co-administration of the necessary B2/I/Se and Mo have been ineffective in treatment. (see Langan and Goodbred, 2017;

 

[Keyhole]

Some more information from his other website, B12Info

Link here: vitamin B12 deficiency

Vitamin B12 Deficiency, a much under-diagnosed condition


The prevalence of vitamin B12 deficiency in the population appears to be increasing. Originally vitamin B12 deficiency was quite a rare condition, mainly associated with anaemia caused by antibodies to intrinsic factor or parietal cells (pernicious anaemia),. The condition is now much more common and can be the result of a wide range on conditions such as those caused by malabsorption due to atrophic gastritis, the use of PPIs, GORD medication, certain drugs, low dietary intake such as occurs in veganism and vegetarianism, intestinal parasites such as Giardia lmblia, Blastocystis hominilis, fish tapeworms, Ascaris lumbricoides, Entomoeba histolytica, roundworms, hookworms, certain religions, such as 7th Day Adventists, Rastafarians, and excessive smoking. More recently vitamin B12 deficiency has been shown to also occur as a result in functional vitamin B2 deficiency as occurs in hypothyroidism and lack of dietary intake of vitamin B2, Iodine, Selenium and/or Molybdenum. As such the condition has become much more common and conservatively may affect up to 20% of the population.

Vitamin B12 deficiency is arguably the most under-diagnosed condition in the community. "In general, doctors are trained to recognize only the blood abnormalities associated with B12 deficiency - macrocytosis. B12 deficiency, however, mimics many other diseases and often physicians fail to confirm B12 deficiency and therefore fail to test for it. The development of vitamin B12 deficiency is a slow and insidious process, which may take several years to manifest itself. During this time there can be progressive loss of vitamin B12 in the cerebrospinal fluid (CSF), which precedes overt deficiency as measured in serum, and without anaemia or macrocytosis.

Vitamin B12 Deficiency and drug use.
Vitamin B12 deficiency has been associated with the use of the following drugs: Prilose, Yosprala, Prevacid, Dexilent, Aciphex, Protonix, Nexium, Vimovo, Zegerid, cholestyramine, cymetidine, clofibrate, colchicine, Isotretinoin (Accutane), methotrexate, methyldopa, neomycin, omeprazole, some oral contraceptives, phenobarbital, ranitidine, tetracyclines, valproic acid, anti-epileptic drugs (carbamazipine and others) and zidovudine (AZT).


Consequences of Vitamin B12 Deficiency.

Deficiency of vitamin B12 in the cerebro-spinal fluid can lead to brain atrophy (shrinkage), subacute combined degeneration of the spinal cord, cerebrovasular disease, dementia, Alzheimer's disease and has been postulated as being causative for Parkinson's disease, and multiple sclerosis.

Vitamin B12 deficiency in the elderly has been associated with a slow and unstable gait, numbness and tingling in the hands and feet, urinary and fetal incontinence, hearing loss and an increased incidence of bone fracture.


Vitamin B12 deficiency in pregnant mothers is associated with an increased incidence of neural tube defects in the young and the development of Autism in the new born.

Apart from the conditions mentioned above deficiency in either vitamin B12 or folate often leads to hyperhomocystinaemia, which has been associated with MS, AD, dementia, cardiovascular disease, an increased risk of thrombosis, reduced glomerular filtration rate, stroke, ischemic heart disease, mental retardation and seizures, ectopia lentis, secondary glaucoma, optic atrophy, retinal detachment, skeletal abnormalities, osteoporosis, neurological dysfunction, epilepsy, psychiatric symptoms, dementia, Parkinson's disease, neoplasia, cognitive impairment, autism, cretinism, allergy, depression, fatigue, low CoQ10, low creatine, and many other conditions.



Once a person is deficient in vitamin B12, it is almost impossible to overcome this deficient through dietary supplementation, particularly if the underlying cause is not removed/cured. Thus persons who are deficient normally require regular injections of vitamin B12, Recently it has been found that it is possible to obtain vitamin B12 through application to the skin using specialized topical technology described in this site. Vitamin B12 deficiency can be further exacerbated in the presence of MTHFR genetic mutations.



Vitamin B12 deficiency (<250 ρmol/L) is associated with cognitive impairment. Low vitamin B12 levels have also been associated with multiple sclerosis,.

Pregnant women with vitamin B12 levels below 250 pmol/L have twice the incidence of children with neural tube defects than those with higher levels.

Post menopausal women with low levels of vitamin B12 have been shown to have a higher risk of breast cancer (see Vitamin B12 )



Causes of Vitamin B12 Deficiency
Vitamin B12 deficiency can occur after bowel resection, or gastric by-pass surgery. Vitamin B12 deficiency can occur due to atrophic gastritis, a condition that effects 10-30% of the elderly. Other causes of vitamin B12 deficiency include achlorhydria, ageing, use of PPIs, use of Nitrous Oxide anaesthetics, excessive antibiotics or anti-convulsants (often used in persons with epilepsy), gastrectomy, especially of the cardiac or fundus, liver disease or cancer, megadoses of vitamin C and/or copper, pregnancy, intestinal parasites such as Giardia, fish tapeworms, anorexia nervosa, certain religions, such as 7th Day Adventists, Rastafarians, and excessive smoking. Vitamin B12 deficiency can be a serious complication of Metformin use in people with diabetes. Recently it has been shown that vitamin B12 deficiency can be a serious complication of cancer chemotherapy using methotrexate following treatment of psoriasis and rheumatoid arthritis.



Hypothyroidism is often also associated with vitamin B12 deficiency Individuals with hypothyroidism have a reduced capacity to convert riboflavin (vitamin B2) to flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD). This then results in the reduced capacity to recycle folate leading to "sacrificial" use of methyl cobalamin for the methylation cycle, ultimately leading to vitamin B12 deficiency (see the section on VB12 and MTHFR and VB12 and MTRR).



Dietary insufficiency of folate can reduce the ability to regenerate methyl B12, thereby causing vitamin B12 deficiency. Dietary insufficiency of iodine, selenium and/or molybdenum can lead to functional vitamin B2 deficiency, due to their role in converting dietary vitamin B2 (riboflavin), into the two active forms of the vitamin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). The result is very similar to the effect of hypothyroidism, and supplementation with one or all of these metals is required to overcome the deficiency, even in the presence of adequate vitamin B2 (riboflavin) intake.



Mutations in the genes for several enzymes involved in the folate cycle and methylation can also lead to vitamin B12 deficiency (vzi MTHFR, MTR, MTRR, amongst others) and also in inherited genes involved in the proteins involved in vitamin B12 processing within the cell (cblA, B, C, D, E, F).



Vitamin B12 - Definition of Deficiency - levels in serum
In the USA and Australia, normal levels of vitamin B12 have been determined to be in the range 180-750 pmol/L (244-1017 pg/ml), with vegans normally much lower at around 110 pmol/L, being regarded as deficient. The definition of deficiency is very random and appears to vary from country to country. Recently, many studies looking at biological markers of vitamin B12 deficiency (MMA and Hcy) as well as neurological markers of deficiency, have suggested that deficiency may start at 300 pmol/L or higher (406 pg/ml)(Ulak etal, 2016), which is also regarded as the lower level of the normal range by the Japanese health authority. In South Korea, vitamin B12 deficiency is defined as vitamin B12 <300 pg/ml. It is estimated that as many as two thirds of the people who are in the lower range of serum vitamin B12 levels (190-300 pmol/L) may have functional vitamin B12 deficiency, thus the true level of vitamin B12 deficiency may be as high as 14-40%, depending upon the population.

Subclinical deficiency in vitamin B12 (<250 pmol/L) can be monitored by rises in the level of homocysteine (Hcy) (>10 umol/L) and methylmalonic acid (>200 nmoll/L). Increased levels of Hcy is associated with vascular inflammatory disease and increases in cardiovascular disease, as well as reduction in eGFR (Ahmed etal, 2019), whilst increases in MMA can result in destruction of the myelin sheath around neurones.



One of the problems with the measurement of vitamin B12 in serum is that current methods do not determine which analogue(s) is(are) present. Thus, if a subject has been injected with cyanocobalamin and then serum vitamin B12 is measured, the subsequent measurement, which shows increased vitamin B12 really only establishes that the injection has been successful. It does not "tell" you if the cyanocobalamin (CN-B12) has been converted to methyl or adenosyl B12.

More recently a new test, called the Active B12 test, has been added to the list of tests, pertaining to measure levels of vitamin B12 in serum. This test is poorly named, as the test measures the amount of vitamin B12 (of unknown identity) that is bound to transcobalamin II (the vitamin B12 carrier responsible for uptake into the cell). Many years ago, it was shown that measurement of Holo-TC was not predictive of B12 status as defined by macrocytosis (Wickramasinghe and Ratnayaka, 1996), however this information appears to have been ignored by those purveying the test. Once again it does not determine if in fact the subject has the active forms of vitamin B12 (adenosyl and methyl B12), and as such has very questionable utility. Unfortunately this aspect of the test is not stated on the general Information Sheets for the test.



Paradoxical Vitamin B12 Deficiency
Measurement of serum vitamin B12 can lead to paradoxical results, thus a person may have many symptoms of vitamin B12 deficiency, but measurement of serum vitamin B12 does not show deficiency, a condition called "Paradoxical B12 Deficiency". Thus, whilst the serum may have elevated levels of vitamin B12, the vitamin B12 is an inactive analogue such as Co(II)B12, or more likely cyanocobalamin or hydroxycobalamin. Determination of active vitamin B12 is therefore better achieved through the measurement of MMA, Homocysteine, or elevations in Homovanillic acid, Vanillylmandelic acid, Quinolinic Acid, Kynurenic Acid, or 5-Hydroxyindoleacetic acid. Such determinations are readily obtained using a simple urinary Organic Acids Test.

Paradoxical vitamin B12 deficiency is arguably the most common form of vitamin B12 deficiency, its origin is very poorly understood and poses many problems for patients and clinicians, and often leads to rather erroneous conclusions regarding the utility, or not, of supplementing with vitamin B12. It should though be an "alert" warning for both as it indicates that the measured, or injected or orally administered vitamin B12 is not being properly processed to the two active forms Adenosylcobalamin or Methylcobalamin, thereby suggesting that potentially a functional B2 deficiency should be addressed prior to treatment. Numerous examples of publications where paradoxical vitamin B12 deficiency have been observed occur (Ahmed etal, 2019; Andres etal, 2013; Chiche etal, 2008; Arendt and Nexo, 2012; Deneuville etal, 2009; Corbetta eta; 2015), and have been associated with a wide range of conditions including hypothyroidism, Lyme disease, Chronic Fatigue Syndrome, functional B2 deficiency, anorexia nervosa, autism, solid neoplasms, myeloproliferative blood disorders and liver diseases.

 

[Keyhole]

I originally came across his work because some of the people I have worked with went on his protocol and saw immense improvements in a very short time using his B12 oils and vitamin protocol. Here is some further information on the implementation of B12 therapy with cofactors and other supporting information:

Treatment of Vitamin B12 Deficiency

By far the best method of treating Vitamin B12 deficiency with all its undesirable consequences, is to avoid becoming deficient in the first place. Whilst generally this can be achieved through adequate dietary uptake in many instances the genetic make-up of an individual, infections, or the use of various drugs may lead either to reduced uptake of vitamin B12 from the gut, or may lead to excessive use or depletion of vitamin B12 stores in the liver, brain and other tissues. Once this has occurred the individual must make every effort to restore and maintain adequate vitamin B12 levels in the serum, liver and in particular the central nervous system including the brain.


Measurement of vitamin B12
Measurement of vitamin B12 is normally performed by analysis of circulating vitamin B12 levels in the blood. The standard test, however, measures not only the active forms of vitamin B12 (methylcobalamin and adenosylcobalamin) but also inactive forms of vitamin B12, such as CN-cobalamin and nitrosylcobalamin. This can lead to spuriously high levels of vitamin B12 being measured, despite the patient showing overt signs of clinical insufficiency. Compounding this is the insistence of Pathology labs around the world to quote vitamin B12 in reference to the range of data that they measure, and hence to determine levels as being "normal" if they fit within their standard "range" of measurement. As such the quoted levels include many individuals who have sub-clinical deficiency. Thus, in the USA and Australia, normal levels of vitamin B12 have been determined by Pathology Labs to be in the range 180-750 pmol/L (244-1017 pg/ml), with normally much lower at around 110 pmol/L, being regarded as deficient. Recently, many studies looking at biological markers of vitamin B12 deficiency (MMA and Hcy) as well as neurological markers of deficiency, have suggested that deficiency may start at 300 pmol/L (406 pg/ml). When this level of vitamin B12 is used to define the lower level of normal, it is estimated that functional vitamin B12 deficiency may be as high as 14-40% of the population even in omnivorous populations, and even higher in communities which are predominantly of vegetarian or vegan persuasion (see PDF),.

Vitamin B12 deficiency in the brain

Vitamin B12 loading of the brain occurs primarily during foetal development. Shortened foetal development, such as occurs in premature babies results in lower amounts of B12 in the brain. Brain levels stay reasonably constant through youth until the mid-twenties, from then on there is a gradual decline in levels of all forms of B12 in the brain, but particularly of methylcobalamin in the frontal region of the brain. To date there has been no animal or human study that has ever demonstrated effective replenishment of brain vitamin B12 through oral administration of small or large doses of vitamin B12. Even in enterally administered vitamin B12, very, very little material can be seen to enter the brain.

Prevention of Vitamin B12 Deficiency

Vitamin B12 insufficiency can be prevented either by adherence to a diet that is sufficient in vitamin B12 (see link), by the use of supplements, by injection of vitamin B12 or via topical administration of vitamin B12. Persons who are deficient due to poor absorption, or through conditions affecting absorption require regular vitamin B12 supplementation either via vitamin B12 injections or by regular application of topical vitamin B12.

Overcoming Vitamin B12 Deficiency

Unfortunately it is almost impossible to to overcome deficiency once it occurs, through either a change in diet or by the use of standard supplements. The normal uptake system in the gut for vitamin B12 is not sufficient to deliver enough vitamin B12 to overcome deficiency, a situation made even worse in those who have compromised intestinal uptake, are on various drugs or take metformin. Prompt treatment of B12 deficient patients is required to prevent progressive, irreversible neurological and cognitive impairment. In situations where there has been prolonged deficiency, which has resulted in extensive peripheral neuropathy due to demyelination of the nerves, it can take months to years to regenerate the myelin sheath on the nerves. During this time it is essential that vitamin B12 is administered with essential support from vitamin B2, Iodine, Selenium, Molybdenum, iron, biotin and vitamin D, all of which are by Schwann cells in the peripheral nervous system and Oligodendrocytes in the brain. In addition, the process of myelin repair is very slow, even in a nutritionally normal person.



Vitamin B12 in Supplements
The use of vitamin B12 in supplements for treatment of deficiency is controversial with many studies showing no benefit being obtained from standard supplements as the amount of vitamin B12 that is absorbed from the standard supplements is too low, even in high dose supplements. In addition many supplements contain cyanocobalamin (a synthetic pro-vitamin) rather than adenosylcobalamin or methylcobalamin, the two natural forms of the vitamin. Furthermore, studies with high dose oral supplements with cyanocobalamin were not effective in restoring normal levels of homocysteine or methylmalonic acid, in reversing clinical signs of deficiency, or in maintaining normal levels of serum vitamin B12 once supplements were ceased. In addition, countless studies using high dose oral supplements have NOT been shown to be able to increase the concentration of vitamin B12 in the cerebral spinal fluid, or the brain. Furthermore, in inflammatory conditions where there increased production of nitric oxide, vitamin B12 introduced by supplements is quickly inactivated to form nitrosylvitamin B12. In addition, despite it being known for over 50 years, that functional vitamin B2 is essential for maintenance of vitamin B12 function and for conversion of cyanocobalamin to adenosyl and methyl cobalamin, NO supplementation study has been performed to date combining B12/folate/B2 and Iodine, Selenium and Molybdenum. There is a more extensive discussion on this at preventingdementia.org


Vitamin B12 Injections
Vitamin B12 injections can be administered in cases of insufficiency, however these are generally expensive, must be given by a medical practitioner, are painful and like oral supplements, invariably contain cyanocobalamin (a synthetic pro-vitamin) rather than adenosylcobalamin or methylcobalamin, the two natural forms of the vitamin. In some countries such as Europe and South America both the methyl and adenosyl-vitamin B12 forms of the vitamin are available for injection. Injections must be given every 4 to 6 weeks, as they do not seem to overcome deficiency, but merely provide a temporarily boost in circulating levels of the injected form of vitamin B12, often with little change from provitamin forms (OHCbl or CNCbl) to the active forms (MeCbl and AdoCbl). Evidence suggests that persons with mutations in the methionine synthase reductase enzyme (MTRR) have trouble converting CN-Cbl and OH-Cbl to adenosyl and methylcobalamin. This mutation is relatively common and may explain why many individuals who have symptoms of vitamin B12 deficiency do not respond to treatment with either CN-Cbl or OH-Cbl. It may also explain why many supplementation trials using CN-Cbl have not been effective in treating conditions that are apparently linked to vitamin B12 deficiency (ie, dementia, AD, PD, MS). Thus, even with injections, it is essential to ensure sufficient vitamin B2/Iodine/Selenium/Molybdenum/iron and vitamin D, in order for supplementation to reverse peripheral neuropathy.



Topical Vitamin B12
A topical form of vitamin B12 has recently been developed. This preparation is easy to administer, contains the natural forms of the vitamin (adenosyl and methylcobalamin), is able to deliver therapeutic amount of vitamin B12 and has the added advantage of providing a prolonged release of the vitamin over several hours. This prolonged release potentially allows for continuous loading of the various organs including the liver and more importantly the CNS and brain. Moreover, the high dose of vitamin B12 that is deliverable by this method is sufficient to act as a powerful anti-oxidant and also to neutralize circulating levels of homocysteine, thus reducing the incidence and severity of conditions associated with hyperhomocysteinemia. This is not possible with the much lower dose of vitamin B12 that is delivered via supplements See b12oils.com .


Therapeutic use of Vitamin B12
Vitamin B12 has been used in therapy for many conditions including AIDS/HIV support, anaemia, anaemia of pregnancy, pernicious anaemia, asthma, atherosclerosis, allergies, atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, bursitis, sciatica, canker sores, chronic fatigue syndrome, Alzheimer’s disease, dementia, depression, Crohn’s disease, diabetes mellitus, diabetic neuropathies, neuralgias, post-herpetic neuralgia, diabetic retinopathy, fatigue, herpes zoster, high cholesterol, high blood homocysteine levels, insomnia, male infertility, tinnitus, viral hepatitis, and vitiligo. Recent studies have shown that high dose vitamin B12 treatment can slow or prevent brain shrinkage and loss of cognitive impairment. High dose formulations have also been shown to reverse bowel and bladder incontinence. Continued high dose injection of methylcobalamin has been shown to reverse the clinical signs of dementia.



Further Information on Treatment of Vitamin B12 deficiency
Further information on vitamin B12 and deficiency states, as well as potential use of vitamin B12 can found by following the links.

Vitamin B12 supplementation and ageing

Office of Dietary Supplements - Vitamin B12 NIHPDF

Vitamin B12

Could Vitamin B12 Help Your Anxiety, Depression?

http://www.nrv.gov.au/nutrients/vitamin b12.htm

Vitamin B12

http://www.abc.net.au/radionational...itamin-b12-supplementation/3823160#transcript PDF

References about Treatment with vitamin B12


Hill et al, 2013 A vitamin B12 supplement of 500 ug/d for eight weeks does not normalize urinary Methylmalonic acid or other biomarkers of vitamin B12 status in elderly people with moderately poor vitamin B12 status. J. Nutrition 143, 142-147

Harris etal, 2015 Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients 7:3796-3812

Harris etal, 2012 Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: Hum Phychopharmacol. 27: 370-377

Cathou and Buchanan 1963 Enzymatic synthesis of the methyl group of Methionine JBC 238, 1746-1751

Katzen and Buchanan, 1965 Enzymatic synthesis of the methyl group of Methionine.. JBC 240, 825-835

Hyland, et al, 1988 Demyelination and decreased S-adenosylmethionine in 5,10-methylenetetrahydrofolate reductase deficiency. Neurol, 39,459-62

Leclerc et al, 1998 Cloning and mapping of a cDNA for methionine synthase reductase, flavoprotein defective in patients with homocystinuria PNAS, 95 2059-64.

Greibe et al, 2017 Effect of 8-week oral supplementation with 3 ug cyano-B12 or hydroxo-B12 in a vitamin B12-deficient population. Eur J Nut

Serapinas et al 2017 The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Reprod Tox 72: 159-163

 

[Keyhole]

Some more information:

Vitamin B12 levels in serum may be misleading
The methods used for measurement of vitamin B12 levels in serum do not determine what form of vitamin B12 is present in the serum, nor what the vitamin B12 is bound to. Thus, in individuals supplementing with high doses of vitamin B12, the subsequent measurement of vitamin B12 is generally a reflection of the analogue of vitamin B12 used in the supplements. Thus, if cyanocobalamin (the inactive vitamer) has been used in supplementation, this is the form measured, Similarly for hydroxycobalamin Similarly the generally used detection methods do not distinguish if the vitamin B12 (of whatever form) is free, or bound to transcobalamin II (the form required for uptake into the cell) or to haptocorrin (the form that is unavailable to the cell). Care must therefore be taken in assuming that just because vitamin B12 levels have been increased or are high in serum the vitamin B12 may either not be bound to transcobalamin II, or it is not the active forms, adenosyl or methylcobalamin.

Therapeutic use of Vitamin B12
Vitamin B12 has been used in therapy for many conditions including AIDS/HIV support, anaemia, anaemia of pregnancy, pernicious anaemia, asthma, atherosclerosis, allergies, atopic dermatitis, contact dermatitis, psoriasis, seborrheic dermatitis, bursitis, sciatica, canker sores, chronic fatigue syndrome, Alzheimer’s disease, dementia, depression, Crohn’s disease, diabetes mellitus, diabetic neuropathies, neuralgias, post-herpetic neuralgia, diabetic retinopathy, fatigue, herpes zoster, high cholesterol, high blood homocysteine levels, insomnia, male infertility, tinnitus, viral hepatitis, and vitiligo. Recent studies have shown that high dose vitamin B12 treatment can slow or prevent brain shrinkage and loss of cognitive impairment. High dose formulations have also been shown to reverse bowel and bladder incontinence.

Prevention of Vitamin B12 Deficiency
Vitamin B12 insufficiency can be prevented either by adherence to a diet that is sufficient in vitamin B12 (see link), by the use of supplements, by injection of vitamin B12 or via topical administration of vitamin B12. Persons who are deficient due to poor absorption, or through conditions affecting absorption require regular vitamin B12 supplementation either via vitamin B12 injections or by regular application of topical vitamin B12

Overcoming Vitamin B12 Deficiency
Unfortunately it is almost impossible to to overcome deficiency once it occurs, through either a change in diet or by the use of standard supplements. The normal uptake system in the gut for vitamin B12 is not sufficient to deliver enough vitamin B12 to overcome deficiency, a situation made even worse in those who have compromised intestinal uptake, are on various drugs or take metformin. Prompt treatment of B12 deficient patients is required to prevent progressive, irreversible neurological and cognitive impairment. In addition, measurement of serum vitamin B12 levels may not be indicative of deficiency in the central nervous system (CNS), particularly during periods of vitamin B12 supplementation, where it may be possible to significantly boost serum levels of vitamin B12, however, levels in the CNS may be relatively unchanged, or only slightly increased.


Vitamin B12 in Supplements
The use of vitamin B12 in supplements for treatment of deficiency is controversial with many studies showing no benefit being obtained from standard supplements as the amount of vitamin B12 in the standard supplements is too low, and because almost invariably the supplement contains cyanocobalamin (a synthetic pro-vitamin) rather than adenosylcobalamin or methylcobalamin, the two natural forms of the vitamin. Furthermore, studies with high dose oral supplements with cyanocobalamin were not effective in restoring normal levels of homocysteine or methylmalonic acid, in reversing clinical signs of deficiency, or in maintaining normal levels of serum vitamin B12 once supplements were ceased. In addition, high dose oral supplements have NOT been shown to be able to increase the concentration of vitamin B12 in the cerebral spinal fluid, or the brain, nor to improve mini mental score estimations in dementia. Furthermore, in inflammatory conditions where there are high circulating levels of homocysteine, vitamin B12 introduced by supplements is quickly inactivated to form Co(II)-cobalamin (Co(II)B12), which must be activated by the B2-dependent enzyme MTRR before it can be effective..


The main powerhouses for energy production within the cell are the mitochondria. Within the mitochondria, fatty acids, sugars and amino acids can be converted to energy in the form of ATP via the glycolysis, Krebs cycle and the Electron Transport Chain. . Whilst is it is generally accepted that the B group vitamins play an essential role in energy production, vitamin B12 has several unique roles to play. Through its interaction with the folate and methylation cycles, methylcobalamin contributes the methyl group that is essential for the production of creatine (2-(Methylguanidino)ethanoic acid). In the muscles creatine and creatine phosphate supply "instant" energy through the conversion of creatine phosphate to ATP. Carnitine, formed from the break-down of N-methyl-lysine is essential for transport of free fatty acids into the mitochondria for use in energy production. In addition, methylcobalamin, through its role in the production of S-AdenosylMethionine (SAM), also is essential for the production of the electron-shuffle molecule ubiquinone (CoQ10), and in methyl B12 deficiency CoQ10 levels decrease. Elevated levels of SAM are also required in order to turn on the enzyme cystathionine beta synthase, and to pull the sulphur, originally resident in methionine, through CBS to generate iron-sulphur complexes, and in reduced B12 levels the activity of Fe-S proteins can be observed to decrease. The activity of one of these, aconitase, is critical for energy movement around Krebs cycle and in reduced B12, aconitase activity is reduces. Reduced aconitase activity has been associated with reduced mini mental score estimations, and dementia. In the mitochondria, adenosylcobalamin serves as an essential co-factor in the enzyme methylmalonyl-Co mutase, which utilizes odd chain fatty acids and odd chain amino acids for energy production. A deficiency of adenosylcobalamin can in itself lead to alterations in mitochondrial morphology and function.

Deficiency in adenosylcobalamin leads to the accumulation of methylmalonic acid, which disrupts normal glucose and glutamic acid metabolism in the cell due to its inhibitory activity on the Krebs cycle and by inhibition of ATP synthase. Continued deficiency of adenosylcobalamin, with resultant reduction in energy output can lead to anorexia, lacrimation, alopecia, and eventual emaciation. In addition there is a build up of lesions in the liver and the development of optic neuropathies.

Elevated MMA also results in the formation of faulty lipids for incorporation into the myelin sheath of nerves.

Several studies have also shown that mitochondrial function can be affected by the generation of reactive oxygen species (ROS), which can result from decreased levels of glutathione within the cells due to VB12 deficiency and also because vitamin B12 is known to be a scavenger of nitric oxide.

In summary vitamin B12 deficiency has a dramatic effect on energy levels within the cell due to decreased creatine phosphate, reduced fatty acid uptake into the mitochondria, the toxicity of methylmalonic acid and increased levels of ROS. .

 

[Keyhole]

I am amazed at how many individuals with CFS or other neurological symptoms test positive for markers related to B2 defiency in conjunction with B12.

Here is an example of a patient of mine who has POTS, dysautonomia, Vertigo/dizziness, and chronic fatigue syndrome:



The lactic acid is caused by mitochondrial dysfunction (inability to properly make energy, which needs B vitamins)

The Fumaric and Malic acid elevations are likely due to the same defect, but are also transformed by enzymes which require activated B vitamins (specifically B2 in its active form).


Notice the Suberic Acid marker (no. 48) is elevated, and that is a marker for B2 deficiency. At the same time, Methylmalonic acid (for B12) is way out of range and has built up quite significantly. Finally, the "Glutaric Acid" is a direct marker for B2, which is just on the cusp of reference range but is still quite elevated.

The picture we see here is basically the same as the scenario laid out by Dr Gregory Russel Jones. You need B2 and other cofactors to utilize B12 inside the cells.


Here is another elderly client I have been working with who has been complaining of severe fatigue as of late. We see the same pattern - Functional vitamin B2 and B12 deficiency, when she had HIGH serum B12. In fact, when she showed her doctor the organic acids test that showed her low levels of B12, the doctor poo-pooed the idea because her serum levels were high :

 

[Keyhole]

For those who want the technical details of B12 function in the body (I will summarize at various points):

Function of Vitamin B12

Vitamin B12 (cobalamin), the only cobalt containing vitamin, is also the vitamin that is present in least amount in the body. Despite this, a deficiency in vitamin B12 can have huge consequences both in obtaining energy from food and for processing energy within the energy chain, as well as through its involvement in over 200 methylation reactions in the body..



Intracellular Activity of Vitamin B12
Intracellular vitamin B12 functions as a co-factor for only two enzymes in the body.

AdenosylCo(III)B12 (adenosylcobalamin) is a co-factor for methylmalonylCoA mutase in the mitochondria and the other co-enzyme form is methylCo(III)B12 (methylcobalamin, which acts as a co-factor for methionine synthase in the cytoplasm (Matthews et al, 2007; Evans et al, 2000). During the binding to the two enzymes both AdenosylCo(III)B12 and MethylCo(III)B12 assume an extended shape, wherein the imidazole ring dissociates from the central cobalt atom, thus allowing greater reactivity of the central cobalt atom.

AdenosylCo(III)B12 and methylmalonylCoA-mutase
Approximately 50%-70% of intracellular Cbl is Adenosyl B12 with only 5% to 15% present as methyl B12, with the rest either inactive Co(II)B12 or hydroxyB12 (Collins et al, 1999). MMACoA-mutase is involved in obtaining energy from branched chain amino acids such as Isoleucine, valine, threonine, thymine and also from odd-chain fatty acids. Lack of activity of the enzymes results in an increase in levels of MMA. MMA is neurotoxic, which is a problem in the brain as this dicarboxylic acid is poorly transported across the blood-brain barrier, leading to trapping within the CNS, which in turn leads to neurological debilities.

MethylCo(III)B12 and methionine synthase
Methionine synthase (MTR/MS) with its co-factor MethylCo(III)B12 plays an essential role in recycling methionine to enable the ultimate synthesis of the methylating agent, s-Adenosylmethionine (SAM, or SAMe). In this reaction, MS transfers the methyl group from MethylCo(III)B12 to homocysteine, yielding Co(I)B12 and methionine. Subsequently the cofactor is remethylated using the methyl group from 5-methyltetrahydrofolate. Thus, cycling of the enzyme is critically dependent upon the presence of incoming 5MTHF. In the absence of 5MTHF, the Co(I)B12 is oxidized to inactive Co(II)B12.

Cycling of MethylCo(III)B12 is essential for the generation of more and more SAM from dietary methionine. In methylCo(III)B12 deficiency homocysteine becomes elevated and SAM levels drop, with an accompanying drop in methylation. In this case there is also an accompanying decrease in the movement of homocysteine through to cystathionine, which is the precursor for the production of hydrogen sulphide and also for the production of free sulfur for synthesis of iron-sulphur complexes, which are essential several enzymes including lipoate synthase, aconitase, succinate dehydrogenase (complex II), Complex I, and GABA-aminotransferase. Potentially deficiency in methylCo(III)B12 would effect around 200 methylation reactions in the body.

[My note for the basics: The methylation cycle is essentially how we process certain amino acids (methionine) to remove a "methyl group", so that we can use that methyl group to produce a wide variety of molecules including neurotransmitters, hormones, and other important substances. The methylation process is involved in turning genes ON or OFF, and detoxifying toxic agents and hormones like estrogen.

The methylation cycle also connects with other cyclical processes like the "transulfuration cycle", which is needed for us to process the amino acid cysteine to make an antioxidant called glutathione. It is needed for us to make sulfate, which is essential for detoxification,joint/connective tissue health, and a variety of other things. We can also make taurine from the transulfuration cycle.

In short: this process is VERY IMPORTANT to perform hundreds of cellular functions. If it is not working correctly, a LOT of different things can go downhill very quickly]




Methylation reactions affected by Methyl B12 deficiency


There are approximately 200 methylation reactions that are potentially affected by a deficiency in methyl B12, including the production of adrenalin and melatonin, inactivation of histamine and the neuroamines, dopamine, nor-adrenalin, adrenalin and melatonin, production of CoQ10, carnitine, creatine, methylation of DNA and histones, structural modifications of lysine, histidine and arginine, Methylation of myelin basic protein, inactivation of metals, such as arsenic, and many others. Lack of methylation has been implicated in the development of autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, systemic sclerosis, and Sjogren's syndrome. Lack of methylation has been implicated in conditions such as adrenal fatigue.

[Note: As you can see, methylation is essential for balance of brain chemicals, in our ability to tolerate chemical substances found in foods like histamines, salicylates, and glutamates etc, and the synthesis of the basic building blocks which are needed to maintain healthy cells.]

Vitamin B12 and Production of Melatonin

Melatonin has often been considered the sleep hormone. Production of melatonin depends upon a methylation reaction, and so in methylB12 deficiency, there can be a lack of production of melatonin in the pineal gland, and can result in an alteration in sleep patterns with characteristic insomnia, with around 30% of people over the age of 50 yr exhibiting sleep problems. Melatonin, though has a much greater role in the body than just controlling the circadian rhythm and melatonin has been shown to act as an analgesic, an anxiolytic agent, and has been used in the treatment of fibromylagia and neuropathic pain. Melatonin has also been shown to have a role in the management of depression, epilepsy, Alzheimer's disease, diabetes, obesity, alopecia, migraine, some cancers and in immune and cardiac disorders. A deficiency in production of melatonin has been linked to CNS disorders such as stroke, OCD and shizophrenia (Karu and Shyu, 2018).

Melatonin has also been shown to stimulate neurogenesis and is involved in the differentiation of neuronal stem cells to form oligodendrocytes and Schwann cells, and as such is essential for myelination of nerves.

Melatonin was originally thought to only be synthesized in the brain, but a considerable amount of melatonin is produced in the gut, where it is essential for maturation of the gut. Lack of synthesis of gut melatonin, due to vitamin B12 deficiency, has been associated with IBS.

Vitamin B12, Adrenalin and Orthostatic Hypotension

Production of Adrenalin depends upon a methylation reaction in which nor-adrenalin is methylated by the enzyme Phenylethanolamine-N-methyltransferase. One of the earliest signs of vitamin B12 deficiency is orthostatic hypotension, initially described in 1962 (Kalbfliesch and Woods, 1962), and infrequently thereafter (White etal, 1981; Eisenhofer etal, 1982; Johnson 1987; Lossos and Argov, 1991; Girard etal, 1998; Beitzke etal 2002; Moore etal, 2004; Ganjehei etal, 2012), however, the association between methyl B12 and the formation of adrenalin does not seem to have been commonly known until much later, despite the existence of the enzyme PNMT in the adrenals being known as early as 1968 (Laduron and Belpaire, 1968; Kitabche and Williams, 1969).


Mitochondrial Disease and B12 deficiency

Deficiency of vitamin B12 has been shown to cause mitochondrial disease, and as such potentially is implicated in the known mitochondrial diseases, including autism, cerebral palsy, Parkinson's disease, epilepsy, dementia, Alzheimer's disease, Huntington's disease, developmental delay, Chronic Fatigue, Fibromyalgia, Lou Gehrig's, Atypical Learning disorder, muscular dystrophy and diabetes.


References
Evans et al Protection of radical intermediates at the active site of adenosylcobalamin-dependent methylmalonyl-CoA mutase Biochem 2000 39: 9213-21PMID 10924114

Collins et al Tumor imaging via Indium 111-labeled DTPA-adenosylcobalamin. Mayo Clin Proc 1999 74: 687-691

Mancia et al. Methylmalonyl-CoA mutase. Structure 1996 4: 339-350

Zhang et al Decreased brain levels of vitamin B12 in aging, autism and schizophrenia Plos One 2016

Kaur T and Shyu B-C Melatonin: a new-generation therapy for reducing chronic pain and improving sleep disorder-related pain. Adv Exp Med Biol 2018 1099:229-251

Kalbfliesch and Woods Orthostatic hypotension associated with pernicious anemia.... JAMA 1962 182:198-200

White etal Pernicious anemia seen initially as orthostatic hypotension. Arch Intern Med 1981 141:1543-4

Eisenhofer etal Deficient catecholamine release as the basis of orthostatic hypotension in pernicious anemia. J Neurol Neurosurg Psychiatry 1982 45:1053-5

Johnson GE Reversible orthostatic hypotension of pernicious anemia. JAMA 1987 257:1084-6

Lossos and Argov Orthostatic hypotension induced by vitamin B12 deficiency. J Am Geriatr Soc 1991 38:601-2

Girard etal Orthostatic hypotension revealing vitamin B12 deficiency. Rev Neurol 1998 154:324-4

Laduron and Belpaire Biochem Pharmacol 1968 17:1127-40

Kitabchi and Williams BBA 1969 178:181-4

Beitzke etal Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Auton Neurosci. 2002 97:45-54

Moore etal Orthostatic tolerance in older patients with vitamin B12 deficiency before and after vitamin B12 replacement. Clin Auton Res 2004 14:67-71

Ganjehei etal Orthostatic hypotension as a manifestation of vitamin B12 deficiency. Tex Heart Inst. J 2012 39:722-3

 

[nature]

Thank you Keyhole for this thread!
What do you think about hydroxy-cobalamin? It's a natural form too. Do you know if it's less or as effective as methyl-cobalamine?

 

[Keyhole]

Thank you Keyhole for this thread!
What do you think about hydroxy-cobalamin? It's a natural form too. Do you know if it's less or as effective as methyl-cobalamine?

Based on my fairly limited understanding at this point, I would say that in THIS context (chronic B12 deficiency accompanied by other cofactor deficiencies) - hydroxycobalamin would be inferior to adenosyl or methylcobalamin.
The reason is that hydroxy is in an "inactive" form which needs to be activated in vivo to be put to use.

The problem with taking high dose methyl/adenosyl transdermally is that it can be used, but not recycled unless the groundwork is in place.

So as I understand it, building up cofactors first is an essential part of this protocol, BEFORE adding in active B12 emulsion. This includes a month or two of working on the cofactors (B2, potentially B1, Selenium, Molybdenum, and Iodine). Then starting at very small doses of the B12 per day and gradually working up to the full dose.

 

[Laura]

So, is the bottom line that there is a supplement designed exactly for this issue?

 

[Keyhole]

So, is the bottom line that there is a supplement designed exactly for this issue?

From what I have read, Dr Greg Jones formulated a B12 emulsion designed to bypass the issues he came up against in the research. The topical forms of B12 is are the ones which are used in his protocol, and people seem to get good results.

The oils are sold here: https://b12oils.com/products.htm

The Adenosyl/Methyl version is theoretically going to be the most appropriate for those people who have this issue of functional deficiency.

 

[Laura]

Rather pricey.

 

[Ant22]

From what I have read, Dr Greg Jones formulated a B12 emulsion designed to bypass the issues he came up against in the research. The topical forms of B12 is are the ones which are used in his protocol, and people seem to get good results.

Rather pricey.

Don't sublingual lozenges absorb through skin too? Is there a difference between absorption through the skin in the mouth and elsewhere? They're definitely much cheaper than the B12 oils.

The Adenosyl/Methyl version is theoretically going to be the most appropriate for those people who have this issue of functional deficiency.

If I take B12 I opt for sublingual methylcobalamin and it seems to do the job pretty well. It didn't solve all of my problems but when I started taking it around 6-7 years ago it did help with persistent fatigue to a small but noticeable extent. Adenosyl gave me pretty bad depression so I guess it may not be optimal for everyone. The hydroxy version is said to help with cognitive abilities but I didn't notice much difference despite taking it for 2 months until the supply ran out.

 

[jhonny]

Thanks for bringing this up, Keyhole!
My mother-in-law is suffering from diabetes, and she is taking metformin. She was complaining of extreme tiredness. ringing in the ears and headache, so I told her this symptoms were associated with a lack of vitamin B12 when taking metformin. She told this to her physician, and he said that her B12 level was ok in her blood test. I was like .