The B12 Deficiency Epidemic: Flawed Diagnostic Criteria
On the problematic philosophy behind using Vitamin B12 serum tests to diagnose deficiency
The first (and often only) marker a physician will use to assess a patient's Vitamin B12 status is B12 in blood serum.1 It is consensus to follow this up with measuring B12-related metabolites, especially Homocysteine and Methylmalonic acid (MMA), in case the serum test is inconclusive, but this is rarely done when the B12 serum test comes back normal, or at all. The diagnostic method of relying primarily on the B12 serum test leads to untold suffering worldwide. Based on the available data, around 80% of cases go undiagnosed, and this number only includes patients where B12 deficiency is suspected in the first place.
There are different reference ranges for what constitutes a "sufficient" level. Levels below 200 pg/ml are usually considered insufficient and between 200 and 350 pg/ml low-normal, but anecdotically many physicians only treat when levels fall below 100 pg/ml. Such a low level of B12 in the serum (<200 pg/mL) is a definitive sign that something is not right. Unfortunately, the converse is not true. A "normal" or "high" level does not rule out a deficiency. This means that in practice, a blood test has no significance for most affected people. The body keeps blood levels stable as long as possible - only in extreme deficiency and rare cases will the blood levels drop significantly. Liver problems can falsely elevate B12 levels.23 There is no causal relationship between serum levels and intracellular B12 content.45 Even in some extreme deficiency cases, blood levels were found to be normal.6
The MMA blood test is the most sensitive test, and MMA measurements show that only 20% of patients are correctly diagnosed with B12 serum tests:7
34 of 42 (81%) elevated MMAs were associated with a serum cobalamin level within our laboratory's reference range, and six (14%) of these were actually greater than the upper limit of normal. Acknowledging the limited size of our data set, this translates to a 19% sensitivity of serum cobalamin for detecting elevations in MMA and, by extrapolation, detecting clinical B12 deficiency. This sensitivity is far lower than that commonly reported in the literature. (...) The mass of accumulated data shows that serum cobalamin is an insensitive assay for B12 deficiency and should be abandoned. MMA is superior for detecting diminished functional B12 stores; increased utilization of this test will result in more accurate and cost-efficient diagnosis of true B12 deficiency.
Getting a larger picture with additionally also testing homocysteine and Methylmalonic Acid (MMA) gives a more accurate understanding of the situation. The medical system does not proactively look for these markers.
But even a low MMA level did not rule out a deficiency in every fourth person tested in one study:8
In patients [responsive to pharmacologic doses of B12], pretherapy B12, MMA, and homocysteine values were normal in 54%, 23%, and 50%, respectively. If therapy had been restricted to symptomatic patients with both low or intermediate B12 levels and increased metabolite values, 63% of responders would not have been treated. (...) It is concluded that B12, MMA, and homocysteine levels fluctuate with time and neither predict nor preclude the presence of B12-responsive hematologic or neurologic disorders.
And also the other way round, some patients with significantly reduced serum B12 or elevated metabolites did not respond to B12 injections - calling into question the validity of the entire framework of primarily relying on blood tests, which modern medical practice rests on.
The clinical picture is the most important factor, as there is no testing available that can rule out deficiency with 100% certainty.91011
Many people recovering from B12 deficiency often ask "Is my B12 level good now?" Behind this question is a false understanding about what B12 really is. Everyone seems to think B12 behaves similar to a fat-soluble vitamin that can be stored, and that blood levels reflect stores.12
In contrast to the other B-vitamins, B12 has to be injected to work reliably.13 While oral B12 can normalize serum B12, homocysteine and MMA levels, and induce short-term neurological responses14, injections induce neurological and cellular repair more reliably15 and so cover a larger percentage of cases. Most of the clinical experience including by Dr. Joseph Chandy and Dr. James Neubrander shows that only injections work in complex cases. As injections are in the domain of Medical Doctors and hospitals, it was the medical system that defined when and how to treat B12 deficiency. And instead of focusing primarily on symptoms, physicians have been instructed to only judge by B12 serum levels.
There's a persistent myth in B12 research and perpetuated by doctors that you can basically fill your B12 stores for weeks, months or even years when treating a deficiency. Together with the false belief that blood levels are the primary marker of deficiency this creates many problems.
B12 that is in the blood is not doing anything. B12 only works when it's in the cells. B12 in the blood is not helping you recover. Even the 20% of B12 that are bound to HoloTC16 ("Active B12") are not reflective of sufficiency. B12 bound to HoloTC may get taken up by a cell, but this is reserved for fundamental processes to keep you alive, not for repair. For repair, you need new B12 to change the "set point" and shift from illness to health.
There is definitely a certain level of tissue saturation that happens with frequently injecting large doses of B12 over time, which keeps intracellular levels stable for a couple days or weeks. But this is not a storage mechanism and it also quickly runs out.
Ridiculously high doses of hydroxocobalamin (4-5 grams!) have been used since 1996 as an antidote in acute cyanide poisoning.17 People who receive these intravenous injections usually have their skin turn red for a couple weeks as it takes a while for the mega-doses of B12 to get cleared out. These are probably the only people in the world who can be said to have actual B12 stores.
Due to the observation that one injection per month or low-dose oral supplements are often sufficient in case of preventing or curing marginal dietary induced B12-deficiency in vegans18 (coupled with the B12-recycling mechanism in the gut that conserves blood levels for months even with no dietary intake), the idea has been introduced that you can somehow "load up" on B12. Unfortunately, this is not the case. In diet-induced marginal deficiency, the requirement for B12 is often just in the range of micrograms per day and irregular injections are sufficient to offset low dietary intake. In deficiency related to metabolic blocks, bad genes and chronic nervous system injury, the requirement becomes supraphysiological, as is the case with all other B-vitamins. For example, no one thinks about measuring riboflavin (B2) levels when taking 200 or 400 mg therapeutically.
Here is what really matters: B12 is water-soluble and any excess is excreted from the body within days. It behaves exactly like any other B-vitamin - the kidneys simply filter it out. The only difference between B12 and the other B-vitamins is that B12 has a recycling mechanism due to it's importance and scarcity and that it's an extremely large molecule.
Actually, it's the largest vitamin and one of the most complex molecules ever synthesized.19 And that's why only a tiny fraction is absorbed (1-2%). For this reason, injections are usually required when supraphysiological doses are needed for healing.
It is true that the levels after an injection often stay a bit elevated for a month or two,20 but this elevation does not imply a sufficient "storage" or tell us anything about intracellular concentrations. After several injections, the B12 serum level may stabilize at 1500 pg/ml for 1-2 months. This is merely 3 times higher than the baseline of 500 pg/ml. A therapeutic level hours after a 1 mg injection is 30,000 or 50,000 pg/ml though and increases linearly with larger doses, so injecting 10 mg can increase the serum level to 300,000 pg/ml easily. The kidneys filter B12 above a certain threshold (1000-2000 pg/ml) quickly and a low amount remains above baseline, but this amount is not being actively used for repair processes, as the cells begin to expect a large influx of new B12 for regenerative and healing purposes. The therapeutic process in many people seems to depend on a concentration gradient high enough for B12 to diffuse into cells, which injections temporarily provide.21 A level above 136,000 pg/ml (comparable to injecting >4 mg) is neuroprotective and even regenerative:22
Here we show that methylcobalamin at concentrations above 100 nM promotes neurite outgrowth and neuronal survival and that these effects are mediated by the methylation cycle, a metabolic pathway involving methylation reactions. (…) Therefore, methylcobalamin may provide the basis for better treatments of nervous disorders through effective systemic or local delivery of high doses of methylcobalamin to target organs.
Dr. Chandy,23 who treated thousands of patients with B12 injections, noted that most of his patients had to repeat their injections every 1-4 weeks to feel well, which supports the data that even “high” serum levels of 1000-2000 pg/ml are not an indicator of sufficiency by themselves.
When one injects large amounts of B12 at once (10 mg/ml), the urine turns red within the first hours, as the kidneys filter out any excess quickly. Up to 99% of the B12 never makes it into a cell but simply gets filtered out.24 When injecting a single dose of 1 mg, 30% of the hydroxocobalamin is retained in the body, while only 10% of cyanocobalamin is retained. Note that with repeated injections or higher doses, the percentage retained goes down.25
One example can be seen in the following image.26 Serum levels peak between 20,000 and 70,000 and then quickly approach the baseline level again. After 2 days, most serum levels are down to around 5-7,000 and it probably takes 3-4 days to see levels of 1000-2000 pg/ml, which are not very active therapeutically.
B12 is a water-soluble vitamin just like B1 or B2. There are no stores, any excess is immediately excreted from the blood, within 2 days 80% is gone. There is probably a window of 1-4 days in which the injection works. For example, if recovering from thiamine deficiency, the vitamin has to be taken daily or injected weekly.27 That's why blood levels are meaningless beyond confirming extreme and acutely life-threatening deficiency, they never reveal the turnover rate and how much is being used by the cells. Injections push such a large amount of B12 into the blood that up to once a week is ok (also depending on dose), but anecdotically many people who only inject 1 mg notice returning symptoms already after 3-4 days.
In people who don’t suffer from pernicious anemia, the recycling mechanism releasing B12 into bile and then re-absorbing it back from the ileum (enterohepatic circulation) via intrinsic factor can keep blood levels stable when no new B12 is ingested for a couple months.2829 This is a mechanism by which B12 is recycled effectively, which includes a complicated process involving intrinsic factor.30 But B12 is not stored. The 3-4 mg of B12 found in the liver of a healthy person are often cited as proof that there are B12 stores.31 But the B12 in the liver is there to keep the liver functioning normally, these are not stores to use in the future:32
To view the liver simply as a “B12 store” is to be profoundly misled. (...) If the liver “stored” B12 in the way that we store surplus energy as adipose tissue, then – logically – there would be a mechanism for “drawing” on it in lean times. However, the only mechanism anyone seems to have found - configured to move B12 from the liver into the rest of the body – is the enterohepatic circulation. Its operation is akin to the circulation of lubricating oil within an engine, with B12 an integral component of the system. The system “pumps” B12 throughout the body to support hundreds of processes, then scavenges it for re-use.
And this recycling mechanism (which is broken in around 1-2% of the population that has Pernicious Anemia)33 has absolutely no relevance for treating deficiency, which involves many things like broken metabolic pathways, blocked B12-dependent co-enzymes, and cells incapable of efficiently converting B12 into the active forms.34 There are likely many genetic impairments that partially reduce the ability of the body to metabolize effectively beyond the known genetic diseases of B12 metabolism. The mere 2-3 mcg of daily recycled B12 (if it gets recycled at all) can not be used to induce repair and healing in people with nervous system dysfunction and injury. The recycling merely cements the status quo, as it is part of the B12 homeostasis. Only a marginal B12-deficiency due to lack of B12 in the food can be cured or prevented with irregular doses of B12.
So until the symptoms are gone, the cells need regular influx of large amounts of B12 in order to stabilize the cytoplasm and B12-dependent enzymes and heal the damage incured due to chronic deficiency.
Paraphrasing Dr. James Neubrander, it could be more appropriate to think in terms of B12 dependency instead of deficiency to understand the beneficial effects of large doses of injected B12.35 And one study concluded, “Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies.”36 German physician Dr. Bernd-M. Löffler aptly put it when he said that B12 injections are easy to undertreat, but impossible to overdose.37
In practice, this means once treatment has been initiated, either by injections or oral intake, one should not focus on blood tests anymore, but only on symptom improvement. Even for diagnosing a deficiency, serum tests are useless in isolation. Homocysteine and MMA are obligatory to test, especially when a serum test comes back normal. No single blood test or combination disproves a deficiency. Only a trial of injections does. It's also cheaper than blood tests, but it goes against the medical culture that needs ill people dependent on the system.
see #4
Ibid.
see #1
see #21