Like so many others. I am finding it nearly impossible to get past my GP with regards to B12 deficiency because my serum levels are OK.
I understand how it can be difficult for some of us to get B12 from our blood. But how does the B12 get from the blood into the cells? If there is a problem with that latter stage, it would explain why many of us with PA symptoms have higher B12 serum levels.
All I know is that when I've had B12 injections (twice) I've felt better than at any other time in my life. That apparently is not a good enough reason to prescribe injection.
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Hypopotamus
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re: "how does the B12 get from the blood into the cells?", that is very complicated, I will direct you to a link that gives you some info, and also you will read that still very little is known about certain aspects , enzymes, genetics etc that are needed in B12 metabolisme.
After ingestion, the low stomach pH cleaves cobalamin from other dietary protein.[11] The free cobalamin binds to gastric R binder, a glycoprotein in saliva, and the complex travels to the duodenum and jejunum, where pancreatic peptidases digest the complex and release cobalamin. Free cobalamin can then bind with gastric intrinsic factor (IF), a 50-kd glycoprotein produced by the gastric parietal cells, the secretion of which parallels that of hydrochloric acid. Hence, in states of achlorhydria, IF secretion is reduced, leading to cobalamin deficiency. Importantly, only 99% of ingested cobalamin requires IF for absorption. Up to 1% of free cobalamin is absorbed passively in the terminal ileum. This why oral replacement with large vitamin B-12 doses is appropriate for PA.
Once bound with IF, vitamin B-12 is resistant to further digestion. The complex travels to the distal ileum and binds to a specific mucosal brush border receptor, cublin, which facilitates the internalization of cobalamin-IF complex in an energy-dependent process. Once internalized, IF is removed and cobalamin is transferred to other transport proteins, transcobalamin I, II, and III (TCI, TCII, TCIII). Eighty percent of cobalamin is bound to TCI/III, whose role in cobalamin metabolism is unknown. The other 20% binds with TCII, the physiologic transport protein produced by endothelial cells. Its half-life is 6-9 min, thus delivery to target tissues is rapid.
The cobalamin-TCII complex is secreted into the portal blood where it is taken up mainly in the liver and bone marrow as well as other tissues. Once in the cytoplasm, cobalamin is liberated from the complex by lysosomal degradation. An enzyme-mediated reduction of the cobalt occurs by cytoplasmic methylation to form methylcobalamin or by mitochondrial adenosylation to form adenosylcobalamin, the 2 metabolically active forms of cobalamin.
Vitamin B-12 role in bone marrow function
In the cytoplasm, methylcobalamin (see image below) serves as cofactor for methionine synthesis by allowing transfer of a methyl group from 5-methyl-tetrahydrofolate (5-methyl-THF) to homocysteine (HC), forming methionine and demethylated tetrahydrofolate (THF). This results in reduction in serum homocysteine, which appears to be toxic to endothelial cells. Methionine is further metabolized to S-adenosylmethionine (SAM).
THF is used for DNA synthesis. After conversion to its polyglutamate form, THF participates in purine synthesis and the conversion of deoxyuridylate (dUTP) to deoxythymidine monophosphate (dTMP), which is then phosphorylated to deoxythymidine triphosphate (dTTP). dTTP is required for DNA synthesis; therefore, in vitamin B-12 deficiency, formation of dTTP and accumulation of 5-methyl-THF is inadequate, trapping folate in its unusable form and leading to retarded DNA synthesis. RNA contains dUTP (deoxyuracil triphosphate) instead of dTTP, allowing for protein synthesis to proceed uninterrupted and resulting in macrocytosis and cytonuclear dissociation.
Because folate deficiency causes macrocytosis and cytonuclear dissociation via the same mechanisms, both deficiencies lead to megaloblastic anemia and disordered maturation in granulocytic lineages; therefore, folate supplementation can reverse the hematologic abnormalities of vitamin B-12 deficiency but has no impact on the neurologic abnormalities of vitamin B-12 deficiency, indicating both result from different mechanisms.
Vitamin B-12 role in the peripheral and central nervous systems
The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.
SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.
Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see image below), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.
Vitamin B-12–associated neurological diseases. Cobalamin deficiency leads to reduced adenosylcobalamin, which is required for production of succinyl-CoA. D-methylmalonyl-CoA is converted to methylmalonic acid.
More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.
In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.
In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.[12]
N2 O pathomechanisms in vitamin B-12 deficiency
N2 O can oxidize the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM. Patients with sufficient vitamin B-12 body stores can maintain cellular functions after N2 O exposure, but in patients with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations
Inadequate vitamin B-12 absorption is the major pathomechanism and may result from several factors.
•Intrinsic factor deficiency ◦PA accounts for 75% of cases of vitamin B-12 deficiency. It is an autoimmune attack on gastric IF. Antibodies are present in 70% of patients. They may block the formation of the cobalamin-IF complex or block its binding with cublin. Other antibodies are directed at parietal cell hydrogen-potassium adenosine triphosphatase (ATPase).
◦Juvenile PA results from inability to secrete IF. Secretion of hydrogen ions and the gastric mucosa are normal. Transmittance is autosomal recessive inheritance of abnormal GIF on chromosome arm 11q13.
◦Destruction of gastric mucosa can occur from gastrectomy or Helicobacter pylori infection. A Turkish study found endoscopic evidence of H pylori infection in more than 50% of vitamin B-12–deficient patients. Antibiotics alone eradicated H pylori in 31 patients, with resolution of vitamin B-12 deficiency.
•Deficient vitamin B-12 intake: Intake may be inadequate because of strict vegetarianism (rare), breastfeeding of infants by vegan mothers, alcoholism, or following dietary fads.
•Disorders of terminal ileum: Tropical sprue, celiac disease, enteritis, exudative enteropathy, intestinal resection, Whipple disease, ileal tuberculosis, and cublin gene mutation on chromosome arm 10p12.1 in the region designated MGA 1, which affects binding of the cobalamin-IF complex to intestinal mucosa (Imerslünd-Grasbeck syndrome), are disorders that affect the terminal ileum.
•Competition for cobalamin: Competition for cobalamin may occur in blind loop syndrome or with fish tapeworm (Diphyllobothrium latum).
•Abnormalities related to protein digestion related to achlorhydria: Abnormalities include atrophic gastritis, pancreatic deficiency, proton pump inhibitor use, and Zollinger-Ellison syndrome, in which the acidic pH of the distal small intestine does not allow the cobalamin-IF complex to bind with cublin.
•Medications: Medications include colchicine, neomycin, and p -aminosalicylic acid.
•Transport protein abnormality: Abnormalities include transcobalamin II deficiency (autosomal recessive inheritance of an abnormal TCN2 gene on chromosome arm 22q11.2-qter resulting in failure to absorb and transport cobalamin) and deficiency of R-binder cobalamin enzyme.
•Disorders of intracellular cobalamin metabolism: These disorders result in methylmalonic aciduria and homocystinuria in infants. ◦Isolated methylmalonic aciduria ◾Cbl A is due to deficiency of mitochondrial cobalamin reductase resulting in deficiency of adenosylcobalamin.
◾Cbl B is due to deficiency of adenosylcobalamin transferase resulting in deficiency of adenosylcobalamin.
◦Methylmalonic aciduria and homocystinuria ◾Cbl C is a combined deficiency of methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase. Patients have prominent neurologic features and megaloblastic anemia.
◾Cbl D is a deficiency of cobalamin reductase. Patients have prominent neurologic features.
◾Cbl F is a defect in lysosomal release of cobalamin.
◦Isolated homocystinuria ◾Cbl E is due to a defect in methionine synthase reductase located on chromosome arm 5p15.3-p15.2.
◾Cbl G is due to a defect in methyltetrahydrofolate homocysteine methyltransferase located on chromosome arm 1q43.
•Increased vitamin B-12 requirement: Requirement is increased in hyperthyroidism and alpha thalassemia.
•Other causes ◦In AIDS, vitamin B-12 deficiency is not infrequent. Although the exact etiology remains obscure, it is likely a multimodal process involving poor nutrition, chronic diarrhea, ileal dysfunction, and exudative enteropathy. Low vitamin B-12 levels may be more common in late than in early HIV disease.
◦N 2 O exposure can occur iatrogenically (ie, anesthesia) or through abuse ("whippets").
Well its given you an idea of what can go wrong and where, but there still is a lot not known, and no I can not give a simple version of the above..
Thanks you for a comprehensive reply Marre. I will do some serious studying.
There must be a reason why so many of us have normal or raised levels serum B12 and yet are clearly B12 deficient. In my own case, injections in 1981 and earlier this year made such a positive improvement to my health that I will not be convinced that isn't the answer to my life-long health problems.
My GP however will not prescribe them on the grounds that I don't need them. In the same consultation he offered me anti-depressants although he said he didn't think that I was depressed.
If your serum B12 test is just OK (and in the so called grey area) it is very worth while to have active B12 tested and or MMA, as serum B12 is what is in blood, but active B12 (holotranscobalamin) is what is taken up in tissue say and what your body uses.
You can have those tests done privately, or at ST Thomas , where active B12 test costs something like £18,- (MMA much more), but you need a written request from your GP.
For info on where the active B12 test is done see:
I hope this helps you further, many of us learn to self inject or get supplements such as lozenges, patches, sprays etc, but if you want further testing, then its best not to supplement until all investigations are done,
I've just about come to the end of my patience with the GP. He's kept me waiting about for 6 months for an appointment with a haematologist before saying that he has spoken to one and decided that I don't need referring. All that time I have been off my supplements feeling even worse. Complaining to NHS England seems to do nothing either.
I did send my GP a lot of information on B12 deficiency, including the stuff from the links that you posted. I think he's convinced that if you have ME, there can't possibly be a reason for it, and you can't have any other condition.
So I'm about ready to give in and start treating myself. I have thought about private tests but as my current income is just £30 a week, I think that the money would be better spent on B12, either in the form of a spray, or injections.
I am puzzled though that the spray seems to work well for some people but sub lingual tablets don't do a lot for me. I've taken sub lingual methylcobalamin for years, either 1 or 2 grams daily, but the effect is nowhere as positive as when I had the injections. But it isn't expensive to try the spray first, so that will be my first line of attack.
It does read rather hopeless for you, and 30 pounds a week is not enough to pay privately for tests etc, I do agree.
Lozenges seem to help some not others (did nothing for me, nor did high doses B12 tabs). Try the pray, but injections are by far the cheapest option.
Its getting some one to teach you that can be hard, I found the nurses at my surgery very supportive, but then I was B12 def with all the blood markers of high MCV etc, far more difficult for you.
I think the tablets work for some people and not others because of the way they are absorbed through cell walls. I'm too tired to go into the details of it (I can't remember words when I'm tired!) but it does depend on how easy it is for the b12 to transfer in each individual. Which, would, in my case be a reasonable answer as to why b12 oral worked (wonderfully) in the first place (there was no b12 there so no resistance) but when I came to try it a couple of years later, after having injections, they had no effect.
Did you send your GP the link to the BMJ article? If you didn't, do and ask him to put it in your records.
Ooh, and do you know, I'm sick of hearing about ME - not from you - but from doctors. ME is a diagnosis based on a collection of variable symptoms. They don't know the cause! Yet they 'diagnose' it all the time.
Until NICE get their heads out of their behinds and find out if b12 deficiency is an underlying cause of ME, or completely rule it out, personally I wish GPs would shut up about ME - because they don't know what they are talking about on that subject either!
Thanks for that Poppet. I know what you mean about the tiredness, and trying to remember stuff, more so when it is technical.
And, yes, I'm also tired of the ME debacle. Just when I thought that I had found a diagnosis of my life-long health issues, I discovered that it was nothing more than a cop out for the GPs.
Do you believe in karma, and think that we must have been GPs in a previous life? LOL
Oh, I actually cracked out laughing when I got to your last paragraph.
I do wonder sometimes what I've done to deserve all this - I was pootling along quite nicely for 50 years and wasn't any trouble - before the b12 nightmare hit!
But you're right, ME is a cop-out. Somebody 'told' them, if X,Y and sometimes Z happens then it is 'this.' And they went, Okay.
So, if you've got ME you are ill, if you're being treated for B12 deficiency, you're not.
The GP will have written requesting "advice and guidance" from a haematologist. If your referral was rejected by the Consultant who responded the G.P can not do anything for you.
They can't prescribe [anything] without clear evidence of clinical need in case anything went wrong.
You don't have anywhere to go with this I think within the NHS.
For me, someone told me to google "methionine loop". This diagram shows the interaction between the folate loop and the methionine loop. B12 and TMG sit at the intersection of these two metabolic loops.
I'm not certain if this metabolism takes place in the blood or in the cell. I would think it has to be in the cell. The end result is that the DNA get methylated and divides for cell reproduction.
Thanks, I couldn't find the article with the diagram, and most of the stuff I found was hard to comprehend.
What is obvious though is that simply getting B12 into the blood doesn't mean that we will be well. There is so much more to it than that, and probably why so many GP's won't even try and understand what out problem is. It's a case of "I've done my six years training, got the job, got the salary, and don't see why I should do any more learning".
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GP says 'B12 blood test unmeasurable >2000' therefore reducing injections frequency from 4 weeks to three monthly.
How to take B12 injections....
How long for B12 treatment to create healthy blood?
Monitoring and Folate replacement after treatment
