Common CFS symptoms from a vitamin deficiency despite supplements

[Chocolove]

Also:
Nutrients. 2013 Dec 12;5(12):5031-45. doi: 10.3390/nu5125031.
Neuroenhancement with vitamin B12-underestimated neurological significance.
Gröber U1, Kisters K, Schmidt J.
Author information
Abstract
Vitamin B12 is a cofactor of methionine synthase in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAMe), which is involved in different epigenomic regulatory mechanisms and especially in brain development. A Vitamin B12 deficiency expresses itself by a wide variety of neurological manifestations such as paraesthesias, skin numbness, coordination disorders and reduced nerve conduction velocity. In elderly people, a latent Vitamin B12 deficiency can be associated with a progressive brain atrophy. Moderately elevated concentrations of homocysteine (>10 µmol/L) have been associated with an increased risk of dementia, notably Alzheimer's disease, in many cross-sectional and prospective studies. Raised plasma concentrations of homocysteine is also associated with both regional and whole brain atrophy, not only in Alzheimer's disease but also in healthy elderly people. Clinician awareness should be raised to accurately diagnose and treat early Vitamin B12 deficiency to prevent irreversible structural brain damage.

PMID: 24352086
PMCID: PMC3875920
DOI:1 0.3390/nu5125031
Free PMC Article

 

[Chocolove]

And excerpts from this PubMed article:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691896/

Conclusion:
Vitamin B12 deficiency may be more common than generally thought and is most likely under-diagnosed due to varied and unusual presentations.


Vitamin B12 is a water soluble vitamin, present in various forms: cyanocobalamin (vitamin B12), hydroxocobalamin (vitamin B12a), aquacobalamin (vitamin B12b), nitritocobalamin (vitamin B12c), 59-deoxyadenosylcobalamin (coenzyme B12), and methylcobalamin (methyl B12). Vitamin B12 deficiency is a major health issue and a major diagnostic challenge; its presentation varies from being asymptomatic to affecting multiple organ systems. Some of the better studied and better known manifestations are hematologic such as macrocytic anemia, pancytopenia and neurological, such as orthostatic hypotension, paraesthesias, and abnormal gait [1, 2]. Some of the lesser known manifestations are cutaneous such as skin hyperpigmentation, stomatitis, and hair and nail changes. These may be important to recognize as early may prevent potentially irreversible complications.

Vitamin B12 deficiency results in neuropsychiatric, hematologic, gynecologic, cardiovascular, and cutaneous manifestations. Manifestations of pernicious anemia may be similar to Addison disease and may lead to a misdiagnosis. Herein, we report two cases of vitamin B12 deficiency in which clinical features shared many similarities with Addison disease.

The effects of vitamin B12 deficiency on the hematologic, nervous, and gastrointestinal systems are well studied. It has been implicated as a cause of orthostatic hypotension [8], mood disorders [9], dementia, psychosis, depression, myocardial infarction, stroke [10], and retinal hemorrhages [11]. Orthostatic hypotension is considered a neurological manifestation of vitamin B12 deficiency and clearly relates to the underlying autonomic neuropathy [12].

An understanding of the enzymatic reactions dependent on vitamin B12 helps appreciate the mechanisms involved in the development of neurological complications. Two principal enzymatic reactions require vitamin B12 as a key cofactor: the mitochondrial conversion of methylmalonyl-CoA to succinyl-CoA and the cytoplasmic methyl transfer reaction that converts homocysteine to methionine. The latter reaction is accompanied by the conversion of methyltetrahydrofolate to tetrahydrofolate, a precursor for purine and pyrimidine synthesis. The interruption of this step due to vitamin B12 deficiency leads to impaired synthesis of DNA and a megaloblastic maturation pattern of hematopoietic cells [20].

Methionine is converted to S-adenosylmethionine (SAM) which methylates neurotransmitters and phospholipids [21]. Vitamin B12 deficiency interferes with production of choline and choline-containing phospholipids, oligodendrocyte function, and myelin basic protein methylation. The neurological damage usually begins with demyelination, followed by axonal degeneration and eventually irreversible axonal death. The neurological damage is reversible when replacement therapy is initiated early.

 

[Hip]

It appears to be stating that these B vitamins are not being used properly as part of normal metabolic functioning in persons with ME/CFS, and it would not be huge stretch to posit that the same is true of B12 - that we have a defect in utilizing these vitamins.

Yes, I agree, it's not infeasible that some ME/CFS patients may have some defect in utilizing B12.

High serum B12 coupled with elevated MMA (either serum or urine), which is indicative of functional B12 deficiency, would suggest this.

I found this study which says that raised levels of either serum methylmalonic acid (MMA) or homocysteine may indicate a functional B12 deficiency.

The study claims failure of transcobalamin II to transport B12 into cells can lead to functional B12 deficiency.

Looking at the full paper on Sci-Hub, they speculate transcobalamin II gene polymorphisms might be behind this functional B12 deficiency. They refer to the 776C-->G polymorphism in the transcobalamin II gene being problematic.



But it is not clear how that fits in to the picture in ME/CFS, because presumably prior to developing ME/CFS, patients did not have B12 issues.

I am just thinking that if there is some problem of B12 transport into cells due to transcobalamin II abnormalities in ME/CFS, those abnormalities would probably have been primarily induced by the disease pathophysiology, rather than by a genetic predisposition (although of course a genetic weakness in transcobalamin II might exacerbate the issue).

For example, I am thinking perhaps some factors present in ME/CFS pathophysiology (eg, increased oxidative stress, autoimmunity, etc) might degrade or inhibit the transcobalamin II protein.



This study is very interesting: it found that a case of functional B12 deficiency which did not respond to B12 injections was rapidly rectified by steroids.

In the full paper, they say that this patient with functional B12 deficiency had auto-antibodies to intrinsic factor, and they speculate that these antibodies may have cross-reacted with the patient's transcobalamin II, thereby deactivating the transcobalamin II. But once steroids were administered (intravenous methylprednisolone 1 gram daily for 3 days), they speculate that this reduced the auto-antibodies, thus allowing transcobalamin II to function properly, and resume transporting B12 into cells.

It might be interesting to try taking some hydrocortisone for a few days, along with high doses of B12, to see if that improves ME/CFS symptoms.



@Valentijn, would you know what this transcobalamin II gene 776C-->G risk allele corresponds to in terms of 23andme results? The transcobalamin II gene data is found here on 23andme.

This study on this transcobalamin II polymorphism concluded:

We conclude that the TCII 775G>C genotype significantly influences tissue B12 delivery and functional B12 status. Because none of the subjects in the study sample exhibited evidence of hematologic abnormalities, the differences among the genotypes in methylmalonic acid and holoTCII may represent preclinical alterations in B12 status and function. It remains to be determined whether TCII genotype ultimately influences the susceptibility of persons to develop the overt clinical manifestations of B12 deficiency, including hematologic and neurologic sequelae.

 

[Valentijn]

@Valentijn, would you know what this transcobalamin II gene 776C-->G risk allele corresponds to in terms of 23andme results? The transcobalamin II gene data is found here on 23andme.

It's rs1801198. Both alleles are extremely common, near 50% prevalence with a bit of variation in different ethnic groups. The gene is called TCN2 now, instead of TCII.

The holo-TC2 concentration was 50% higher in people with the "GG" genotype, versus CG or CC. Methylmalonic acid (MMA) was higher in people with "CC", suggesting less cellular uptake of B12. Homocysteine was pretty much the same for all groups.

It isn't considered pathogenic. The research is summarized and linked at http://omim.org/entry/613441#0002

 

[Hip]

Methylmalonic acid (MMA) was higher in people with "CC", suggesting less cellular uptake of B12. Homocysteine was pretty much the same for all groups.

It isn't considered pathogenic.

So on 23andme, if you are "CC" for rs1801198, your cellular B12 uptake might be slightly less, but not a degree that it causes any pathology or dysfunction in healthy people.

 

[Chocolove]

Undiagnosed B12 deficiency may be fairly common. Check this out:

Opportunistic Screening of Vitamin B12 Deficiency in IT Professionals Presenting for Routine Health Check-up.
Ingole JR1, Patel RD1, Ingole SJ2, Pandave HT3.
Author information
Abstract
INTRODUCTION:
Vitamin B12 deficiency is mainly diagnosed in symptomatic patients. However, the deficiency may also be prevalent in asymptomatic patients. Our aim was to study the prevalence of Vit B12 deficiency in IT professionals (Information Technology Professionals from Software industry) who presented for routine health screening and to correlate the deficiency to various parameters.

MATERIALS AND METHODS:
This was single centre, observational study comprising of 84 IT professionals. The data was collected in structured format. The study was designed to identify prevalence of Vit B12 deficiency and correlate to other factors such as type of diet, income level & regular use of medication (such as Antacid & Metformin).

RESULTS:
Total 28 individuals were found to be deficient (33.34%). Prevalence of Vit B12 deficiency amongst Vegetarian and non vegetarian diet adhering subjects was 47.5% and 20.45% respectively. B12 deficiency was also prevalent in high income age group. Further chronic intake of PPI (Proton pump inhibitor) and Metformin was associated with prevalence of 37.5% and 33.34% in the present study.

CONCLUSION:
During health screening of IT Professionals, significant prevalence of Vit B12 deficiency was noted across all income groups & non vegetarian diet consuming subjects also. There is significant correlation between Vit B12 deficiency with chronic use of PPI and Metformin.

KEYWORDS:
Asymptomatic patients; Proton pump inhibitor; Serum Vitamin

PMID: 26816929
PMCID: PMC4717757
DOI: 10.7860/JCDR/2015/16191.6866
Free PMC Article

 

[Chocolove]

Isr Med Assoc J. 2015 May;17(5):288-92.
Association of Vitamin B12 Deficiency with Homozygosity of the TT MTHFR C677T Genotype, Hyperhomocysteinemia, and Endothelial Cell Dysfunction.
Shiran A, Remer E, Asmer I, Karkabi B, Zittan E, Cassel A, Barak M, Rozenberg O, Karkabi K, Flugelman MY.
Abstract
BACKGROUND:
Hyperhomocysteinemia is associated with increased cardiovascular risk, but treatment with folic acid has no effect on outcome in unselected patient populations.

OBJECTIVES:
To confirm previous observations on the association of homozygosity for the TT MTHFR genotype with B12 deficiency and endothelial dysfunction, and to investigate whether patients with B12 deficiency should be tested for 677MTHFR genotype.

METHODS:
We enrolled 100 individuals with B12 deficiency, tested them for the MTHFR C677T polymorphism and measured their homocysteine levels. Forearm endothelial function was checked in 23 B12-deficient individuals (13 with TT MTHFR genotype and 10 with CT or CC genotypes). Flow-mediated dilatation (FMD) was tested after short-term treatment with B12 and folic acid in 12 TT MTHFR homozygotes.

RESULTS:
Frequency of the TT MTHFR genotype was 28/100 (28%), compared with 47/313 (15%) in a previously published cohort of individuals with normal B12 levels (P = 0.005). Mean homocysteine level was 21.2 ± 16 μM among TT homozygotes as compared to 12.3 ± 5.6 μM in individuals with the CC or CT genotype (P = 0.008). FMD was abnormal ( 6%) in 9/13 TT individuals with B12 deficiency (69%), and was still abnormal in 7/12 of those tested 6 weeks after B12 and folic treatment (58%).

CONCLUSIONS:
Among individuals with B12 deficiency, the frequency of the TT MTHFR genotype was particularly high. The TT polymorphism was associated with endothelial dysfunction even after 6 weeks of treatment with B12 and folic acid. Based on our findings we suggest that B12 deficiency be tested for MTHFR polymorphism in order to identify potential vascular abnormalities and increased cardiovascular risk.

PMID: 26137654
Free full text

 

[Chocolove]

Hip, you may be interested in this one:

J Investig Med. 2015 Apr;63(4):636-40. doi: 10.1097/JIM.0000000000000187.

Diagnosis of vitamin B12 deficiency in patients with myeloproliferative disorders.
Cinemre H1, Serinkan Cinemre BF, Çekdemir D, Aydemir B, Tamer A, Yazar H.
Author information
Abstract
BACKGROUND:
Myeloproliferative disorders are characterized by proliferation of 1 or more lineage of hematologic cells. Rapid proliferation of cells may lead to depletion of vitamin B12, which may be falsely elevated by conventional assays in these disorders. We evaluated vitamin B12 status with conventional vitamin B12 assay and levels of serum methylmalonic acid (MMA), serum holotranscobalamin (holoTC), and plasma homocysteine in myeloproliferative disorders.

METHODS:
In 58 patients who had myeloproliferative disorders and normal serum creatinine levels, we measured levels of vitamin B12, MMA, holoTC, and homocysteine. Correlations were evaluated between these tests, with MMA as the reference standard for vitamin B12 deficiency.

RESULTS:
Prevalence of vitamin B12 deficiency was 69%, despite high serum vitamin B12 levels. Levels of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L were the best cutoff levels with sensitivity values of 75% and 70%, specificity values of 80% and 68%, and positive predictive values of 88% and 80%. Logistic regression showed that cutoff values of holoTC of 40.6 pmol/L or less and homocysteine of greater than 14 mol/L resulted in odds ratio 15.5 for low versus high holoTC, and odds ratio 5.4 for high versus low homocysteine, to confirm vitamin B12 deficiency.

CONCLUSIONS:
Patients who had myeloproliferative disorders had a high prevalence of vitamin B12 deficiency, despite high serum vitamin B12 levels. Therefore, vitamin B12 status should be evaluated in patients with myeloproliferative disorders.

Holotranscobalamin level may be the best initial test and may replace vitamin B12 assay to accompany MMA and homocysteine levels.

PMID: 25730455
DOI: 10.1097/JIM.0000000000000187

 

[CFS_for_19_years]

A quick Google reveals that elevated MCV can indicate B12 deficiency, but this study suggests it is not that accurate, though a useful guide.

You made an incorrect interpretation of that study. It reads:

This systematic review shows that a considerable number of B12-deficient patients will remain unnoticed when the MCV is used to rule in patients for further evaluation. Depending on the population studied, up to 84% of cases will than be missed.

What they are saying is that when doctors rely on a normal MCV value to indicate adequate B12 status, a lot of B12 deficient cases will be MISSED, i.e., it's possible to have a normal MCV with B12 deficiency.

They're NOT saying that a high MCV has poor predictive value. What they are saying is that doctors shouldn't be lulled into a false sense of security when seeing a normal MCV.

 

[alicec]

This is speculation on my part.

I am struck by the number of people on PR who are helped by B12 supplementation (including myself).

I don't think all these people have primary B12 deficiencies, though some might.

I suspect that some aspect of the disease process impacts B12 and related pathways (such as folate) leading to inefficient use and/or uptake of the vitamin. A functional B12 deficiency results.

In essence the disease causes the B12 problems.

However there will be variations on the theme depending on individual circumstances. Some peoples SNPs combinations may mean they start out with inefficient B12 pathways. These have little impact when the person is healthy and eating well, but add CFS/ME and they are seriously affected. There may be the rare individual such as Freddd whose genetics are a major driving factor.

As the various papers above show, B12 deficiency has very wide impacts, so bypassing the functional deficiency with supplements might have noticeable benefits. They won't cure the disease but they certainly help at least some people.

I haven't researched in any detail to see how this might work, but I'll give an example of an analogous situation that I have also experienced.

People may have heard of oxalate accumulation leading to kidney stones and possibly be aware that a rare genetic condition (primary hyperoxaluria - PH) can cause this.

They may be less aware that in various chronic illnesses, the same enzymes which are defective in PH can become less functional and lead to oxalate accumulation (so called endogenous oxalate production) even though no genetic defect exists.

The driving force behind this seems to be chronic oxidative stress. This leads to conformational change in vitamin B6 dependant enzymes which are dimeric proteins held together by B6. The change in protein shape means it can no longer bind B6 well and the enzymes tend to fall apart - ie they can no longer function well. Giving high doses of B6 can at least in part overcome the problem.

B6 dependant enzymes have widespread roles so many metabolic functions could be adversely affected. In the case of oxalates, the enzyme which normally turns precursors into harmless glycine becomes slower, precursors accumulate and can be converted into oxalate.

Oxalate itself is a metabolic poison so once it starts to accumulate, many metabolic systems are affected, long before kidney stones emerge. For some people (I include myself here), kidney stones are never the problem, it is the deranged metabolic pathways. These include biotin dependant pathways (ie all the major energy pathways, including ATP production), B1 and B5 dependant pathways, sulfation and glutathione transport and turnover.

So for the case of CFS/ME and B12 problems, I don't know what would be equivalent to the effect of oxidative stress on B6 dependant enzymes. However I envisage an analogous fundamental change that would lead to widespread consequences as in the oxalate example.

 

[Chocolove]

Hip, this study provides clarification:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827408/

Blood Transfus. 2013 Oct; 11(4): 627–629.
doi: 10.2450/2012.0183-12
PMCID: PMC3827408

Undetected vitamin B12 deficiency due to false normal assay results
Elisabetta Scarpa, Laura Candiotto, Roberto Sartori, Paolo Radossi, Nilla Maschio, and Giuseppe Tagariello
Author information ► Article notes ► Copyright and License information ►

Until the 1990s serum vitamin B12 levels were measured using radioisotope assays, which were replaced more recently by competitive-binding luminescence assays. Few studies have compared the different methods4,7,12.

Salomon reported normal plasma cobalamin levels in patients with clinical signs of vitamin B12 deficiency who later improved after treatment with the vitamin2.

Others have documented assays being repeated using kits from different manufacturers the results of which substantiated the diagnosis of vitamin B12 deficiency making evident the false normal results originally obtained4–8.

The assay carried out in our laboratory (Siemens Centaur, Beckman Access, Siemens Immulite 2000/2500, San Diego, CA, USA) was equally open to error and it is possible that a false normal vitamin B12 level may have been caused by interference from a high-titre of intrinsic factor antibody4. However, abnormal haemoglobin and erythrocyte mean cell volume values support suspected pernicious anaemia, but normal levels do not rule out the presence of vitamin B12 deficiency, leading to a high risk of clinical error.

In conclusion, our experience further supports the fact that when the diagnosis of B12 deficiency is suspected on the basis of clinical findings and additional tests, supplementation treatment should be administered even if the assayed level of the vitamin is not low and, if possible, an assay from another manufacturer is recommended.

Case report
A 59-year old woman with severe anaemia (haemoglobin 58 g/L) who had been suffering from progressively increasing palpitations, profound fatigue and exertional dyspnoea for about one month was admitted to our hospital in May 2011. She had a good, well-balanced diet and was not taking any medication apart from thyroxine....

Vitamin B12 and folate deficiency were considered immediately, but on analysis their values were in the normal range (NR), >1,000 pg/mL (NR 193–982 pg/mL) and 4.5 ng/mL (NR 3.0–17,0 ng/mL), respectively...

Repeated analyses showed the vitamin B12 concentration close to the upper limit at 910 pg/mL and folate at 10.3 ng/mL; intrinsic factor and parietal cell antibodies were strongly positive. In the interim the patient received two red cell units and was discharged from hospital but, 2 weeks later, was admitted again with anaemia (Hb 67 g/L) and the same symptoms as previously....

A diagnosis of vitamin B12 deficiency was still suspected despite the initial normal B12 values and with four repeated measurements being 331, 357, 380, and 297 pg/mL it was decided to treat this patient with a pharmacological dose of subcutaneous vitamin B12 (1,000 mg/day for 1 week followed by once a week 4 times). After 2 weeks the patient’s condition improved and complete clinical and haematological recovery occurred within the next month (Figure 2).

 

[Hip]

You made an incorrect interpretation of that study.

I am at the moment a bit too foggy to understand it properly. I just want to be simply told the sensitivity and specificity of MCV as a test for B12 deficiency.

 

[Chocolove]

And for those who suffer from tinnitus:

Noise Health. 2016 Mar-Apr;18(81):93-7. doi: 10.4103/1463-1741.178485.
Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study.
Singh C1, Kawatra R, Gupta J, Awasthi V, Dungana H.
Author information
Abstract
True tinnitus is a phantom auditory perception arising from a source or trigger in the cochlea, brainstem, or at higher centers and has no detectable acoustic generator. The most accepted is the famous neurophysiologic model of Jastreboff, which stresses that tinnitus, is a subcortical perception and results from the processing of weak neural activity in the periphery. The aim of this study is to determine the role of Vitamin B12 in treatment of chronic tinnitus. In this randomized, double-blind pilot study, total 40 patients were enrolled, of which 20 in Group A (cases) received intramuscular therapy of 1 ml Vitamin B12 (2500 mcg) weekly for a period of 6 weeks and Group B (20) patients received placebo isotonic saline 01 ml intramuscular. The patients were subjected to Vitamin B12 assay and audiometry pre- and post-therapy.

Of the total patients of tinnitus, 17 were Vitamin B12 deficient that is 42.5% showed deficiency when the normal levels were considered to be 250 pg/ml.

A paired t-test showed that in Group A, patients with Vitamin B12 deficiency showed significant improvement in mean tinnitus severity index score and visual analog scale (VAS) after Vitamin B12 therapy.

This pilot study highlights the significant prevalence of Vitamin B12 deficiency in North Indian population and improvement in tinnitus severity scores and VAS in cobalamin-deficient patients receiving intramuscular Vitamin B12 weekly for 6 weeks further provides a link between cobalamin deficiency and tinnitus thereby suggestive of a therapeutic role of B12 in cobalamin-deficient patients of tinnitus.

PMID: 26960786
PMCID: PMC4918681
DOI: 10.4103/1463-1741.178485
Free PMC Article

 

[Hip]

So for the case of CFS/ME and B12 problems, I don't know what would be equivalent to the effect of oxidative stress on B6 dependant enzymes. However I envisage an analogous fundamental change that would lead to widespread consequences as in the oxalate example.

There are some details of the metabolic pathways that B12 is involved with here, and it mentions two main B12-dependent enzymes:

• Methylmalonyl-CoA mutase (MCM), a mitochondrial enzyme. When the functionality of this MCM enzyme is under par, it results in increased methylmalonic acid (MMA) levels. Details of what MCM does found here:
Methylmalonyl-CoA mutase - Wikipedia
Methylmalonyl-CoA mutase deficiency - Wikipedia

• Methionine synthase (MS), responsible for the regeneration of methionine from homocysteine. Encoded by the MTR gene.

Methionine synthase's main purpose is to regenerate Met in the S-Adenosyl Methionine cycle, which in a single turnover consumes Met and ATP and generates Hcy. This cycle is critical because S-adenosyl methionine is used extensively in biology as a source of an active methyl group, and so methionine synthase serves an essential function by allowing the SAM cycle to perpetuate without a constant influx of Met.

Source: Methionine synthase - Wikipedia

 

[alicec]

There are some details of the metabolic pathways that B12 is involved with

Yes I know about those pathways but the something that goes wrong starts before that and impacts those pathways. I haven't had the energy to dig enough to propose what that something might be.

 

[Hip]

Looks like the B12-dependent enzyme methionine synthase (MS) is sensitive to, and inactivated by, oxidative stress (at least in Escherichia coli bacteria):

Oxidative stress inactivates cobalamin-independent methionine synthase (MetE) in Escherichia coli

Although in this dissertation, it says that it is the oxidation of the vitamin B12 cofactor of MS that actually halts MS activity.



Methionine synthase is also inhibited by nitrosative stress:

Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway

 

[Chocolove]

Eur J Clin Nutr. 2015 Jan;69(1):1-2. doi: 10.1038/ejcn.2014.165. Epub 2014 Aug 13.
Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.
Thakkar K1, Billa G2.
Author information
Abstract

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl).

There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and promoted.

This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl is primarily involved along with folate in hematopiesis and development of the brain during childhood.

Whereas deficiency of AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin.

Thereby, it is important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl

or hydroxocobalamin or Cbl.

Regarding the route, it has been proved that the oral route is comparable to the intramuscular route for rectifying vitamin B12 deficiency.

PMID: 25117994
DOI:[URL='http://dx.doi.org/10.1038/ejcn.2014.165'] 10.1038/ejcn.2014.165[/URL]

 

[CFS_for_19_years]

I am at the moment a bit too foggy to understand it properly. I just want to be simply told the sensitivity and specificity of MCV as a test for B12 deficiency.

You commented on the sensitivity and specificity of an elevated MCV to predict a B12 deficiency, while the study you mentioned discussed the sensitivity of using a normal MCV to rule out a B12 deficiency. The study you cited showed that the presence of a normal MCV does not rule out the presence of a B12 deficiency.

An elevated MCV can be due to many different things. The usual clinical algorithms should be followed to make a determination of the cause of the elevated MCV or elevated MCV combined with anemia.
Evaluation of Macrocytosis
http://www.aafp.org/afp/2009/0201/p203.html

The most common etiologies are alcoholism, vitamin B12 and folate deficiencies, and medications. History and physical examination, vitamin B12 level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of macrocytosis. When the peripheral smear indicates megaloblastic anemia (demonstrated by macroovalocytes and hypersegmented neutrophils), vitamin B12 or folate deficiency is the most likely cause. When the peripheral smear is nonmegaloblastic, the reticulocyte count helps differentiate between drug or alcohol toxicity and hemolysis or hemorrhage. Of other possible etiologies, hypothyroidism, liver disease, and primary bone marrow dysplasias (including myelodysplasia and myeloproliferative disorders) are some of the more common causes.

Megaloblastic Anemia and Other Causes of Macrocytosis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570488/

Macrocytosis Without Anemia
Large circulating erythrocytes are not always associated with a pathologic process or condition. In fact, RBCs of newborns and infants tend to be larger (mean MCV = 108 fl) than normal adult RBCs,10,11 and large erythrocytes can be seen during pregnancy in the absence of an obvious etiology. Macrocytosis without anemia may be a normal variant and is only noted as a result of repeated peripheral RBC indices in the absence of any known or existing clinical problems. In some instances this variation from normal can be found in other family members, which suggests a genetic predisposition, and requires no therapeutic intervention or further investigation.12,13

I've had a consistently elevated MCV (98 - 103) for as long as I've lived. I first became aware of it in 1975 as a medical technology student, and have had many CBCs since then. I've never been anemic or benefited from B12 shots or had low serum B12 or folate levels.

 

[CFS_for_19_years]

@Chocolove, you might be interested in this website:
http://www.b12deficiency.info/signs-and-symptoms/

"Common CFS symptoms from a vitamin deficiency despite supplements" was your topic title. There could a zillion topics discussing "common CFS symptoms from ........" because fatigue is such a common symptom, although in the case you mentioned, there were also some neurological symptoms.

The usual screening tests for fatigue (and CFS) include a CBC, which would show anemia and/or macrocytosis. That is how a B12 deficiency would normally be picked up before the patient is given a diagnosis of CFS. I don't think these problems fly "under medical radar" as much as you might imagine. It is basic first-line screening.

B12 deficiency is just one of a number of vitamin deficiencies that fly under medical radar. I hope all will think to ask their doctors to test their vitamin and mineral levels for such deficiencies.

I do, I do. I ask them to check for many things, all day long, which I'm sure many others do too.

 

[Valentijn]

So on 23andme, if you are "CC" for rs1801198, your cellular B12 uptake might be slightly less, but not a degree that it causes any pathology or dysfunction in healthy people.

Yes. As you and others have speculated, that might have the potential to cause problems in people who aren't healthy, though I'm not aware of any evidence showing that to actually happen in this case. Additionally, other SNPs having a large but otherwise non-pathogenic effect upon B12 uptake and utilization might have a cumulative impact.