At least 70% of your total B12 is bound to haptocorrin (HC), making it biologically inactive. The rest is bound to transcobalamin-II (TC-II, or in short – TC), comprising a complex known as holoTC, or active B12. Only holoTC is able to deliver vitamin B12 to the cells of your body, which is why we’re avid supporters of the active-B12 test.
However, there is a positive correlation between total-B12 levels and active-B12 levels, as you can see from Axis-Shield’s data below, measuring 468 patients. The correlation coefficient is 0.74, which is high, as 1 would signify a perfect correlation:
Of course, this brings up an argument:
If there’s such a high, positive correlation between total-B12 levels and active-B12 levels, why bother testing for active B12 at all?
Why Test For Active B12?
To answer this question, we’ll have to add two vertical lines to the chart above:
The red dots on the left side represent patients with total-B12 levels of 150pmol/L or below. In many countries, this is the cut-off for B12 deficiency diagnosis. The red dots on the right side represent levels of 301pmol/L or above, where doctors wouldn’t expect to find B12 deficiency. Now, note the high concentration of gray dots in the middle (314 out of 468 patients, exactly two-thirds). We colored these patients gray, because they have total-B12 levels of 151-300pmol/L, a range you could describe as the gray zone.
Why a gray zone? Because the true B12 status of patients in this range is uncertain. To see what we mean, look what happens when we add another line to the chart, this time applying a 35pmol/L cut-off for active-B12, levels indicative of B12 deficiency:
As you can see, many people with “normal B12 levels” of 151-300pmol/L have low active-B12 levels of 35pmol/L or less. These patients would have been dismissed by a normal doctor performing the regular blood test, remaining undetected and untreated, whereas an active-B12 test would reveal their true B12 vitamin deficiency.
It shows you how misleading total-B12 levels can be. Active B12 and total B12 tend to agree at the extremes, but most patients exist in the middle range. And so, a large proportion of patients – anywhere from 30% to 50%, depending on the population – will have total-B12 levels above the 150pmol/L cut-off, but with low active-B12 levels.
What Should We Do About It?
Currently, resolve gray-zone cases
The active-B12 test can help us resolve uncertain cases, where total-B12 levels are in the gray zone of 151-300pmol/L. This is the most immediate utility we have for it. It will help us detect and treat B12 deficiency patients quicker, before damage takes place.
Ultimately, replace the total-B12 test altogether
The endgame is to completely replace the total-B12 test, because once the active-B12 test has been performed, total-B12 levels aren’t useful. The diagnostic accuracy of the active-B12 test would remove the need and cost of all other tests, and help us diagnose patients faster, preventing what could progress to permanent neurological damage.
We can also use the test to screen high-risk people in advance. Active B12 levels are low in patients with signs of B12 deficiency, as in vegetarians, vegans, populations who consume fewer animal products, and in untreated pernicious anemia patients.
As for pregnant women, this gets particularly interesting:
One revIew reported that low total-B12 levels occur in 10-28% of normal pregnancies. Similarly, another study reported that almost 35% of first-trimester pregnancies had total-B12 levels below 150pmol/L, despite an adequate B12 intake. However, there were no visible signs, and the study found that the drop in total-B12 was a result of declining levels of B12 bound to haptocorrin, and not to transcobalamin (active B12). The authors concluded that the drop reflects normal physiological changes in pregnancy.
Likewise, another study found an almost 50% drop in total-B12 levels in late pregnancy among healthy, pregnant Danish women. The decline – which by the way, reversed after birth – was not reflected in active-B12 levels. Here again, it was due to declining levels of haptocorrin-bound B12. For that reason, the authors said that the active-B12 test could be used as a reliable marker for B12 deficiency during pregnancy.
Testing for B12 in pregnancy is important, because healthy levels are crucial. There may even be a link between low B12 levels and the risk of neural tube defects. If we can ensure good levels of active B12 in a mother, we can guard her baby from developmental disasters. This is double as true when she then breastfeeds. The earlier B12 deficiency can be diagnosed in a mother, the earlier we can prevent it in her baby.
Good Levels of Active B12
Now that we’ve established that the active-B12 assay is more diagnostically accurate than the total-B12 assay, here are the numbers you should aim for:
As you see, diagnosis becomes much easier.
Active B12: The Future
The total-B12 test is a poor predictor of B12 status, and is prone to false positives and negatives. Not only is active-B12 significantly more accurate, it also doesn’t require any pre-analytical sample treatment. If you read our article about B12 deficiency tests, we also mentioned the homocysteine and the MMA tests. When it comes to usefulness, the MMA test is the only one that comes close. However, it has more confounding factors. Thus, we would like to see active-B12 becoming the default test at hospitals.
Hopefully it happens soon.