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Question: The Holo-TC test


My name is …….., and … ... I would kindly like to ask you a question about the Holo-TC test.
In the Netherlands patients often encounter difficulties in getting a diagnosis and treatment for disorders in the absorption of cobalamin. In the Netherlands hydroxocobalamin is only available as a prescription drug (unlike in Germany). Therefore, patients are dependent on their doctors to prescribe vitamin b12 injections.
One of the aims of the B12 Deficiency Foundation is to inform people about scientific research.
You have been publishing articles about Holo-Transcobalamin. At this moment some Dutch hospitals have implemented the Holo-TC test to diagnose vitamin b12 deficiency. We are aware that this test potentially has a higher diagnostic sensitivity then does the conventional Total b12 test. But the diagnostic sensitivity depends on the cut off value. For our patients a high diagnostic sensitivity is important because of the irreversibility of neurological disease when treatment is started too late. We believe the cut off value of 20 pmol/l might be too low to identify people with neurological disease timely in order to prevent permanent neurological damage. The risk is that doctors won't recognize patients with higher Holo-TC values as being b12 deficient and will refuse treatment, because they don't know about diagnostic sensitivity.

In one of your articles I read that the diagnostic sensitivity for Holo-TC is 87 % when the cut off value is 35 pmol/l. The notion that at this Holo-TC value cellular cobalamin deficiency might be present, must be the outcome of scientific research. Is there to your knowledge an article that clearly states at which Holo-TC values cellular cobalamin deficiencies have been identified? And what would be the upper value of Holo-TC at which a cellular cobalamin deficiency has been identified?

With this information, based on scientific research, we would be able inform our patients about the scope and limitations of the Holo-TC test. And provide them with information that can aid in getting treatment timely.

I would be very grateful if you can provide me with titles or copies of
articles that contain this information. ….

Yours sincerely,

Answer from Prof. Dr. W. Herrmann:
Dear …..,

thank you for your question. One important fact to be considered for vitamin b12 deficiency is that there is no golden parameter that can definitely tell you if the patient is deficient or not deficient. Holo-TC is the best and the most sensitive laboratory marker available for early detection of vitamin B12 depletion.

According to our research and those from other groups (examples below), the Cut-off value 20 pmol/L seems to be too low. You might loos sensitivity (can not recognize deficient people) by lowering the cut-off.
By increasing the cut-off value to 35, 45, or even 50 you will get more sensitivity to detect a deficiency but you will lose some of the specificity of the test.
That means, by using a higher cut-off you will be able to detect all deficient people, but you might misclassify people without deficiency as deficient.

There is however, no cut-off value for all clinical situations. Renal patients might be severely deficient despite having holoTC in serum of around 60-70 pmol/L. The effects of other diseases (liver, alcoholism, cancer) on holoTC have not been examined yet.

Therefore, we recommend using a cut off of 36-40 pmol/L, but considering also the clinical situation. In many cases, MMA assay (or response to B12 supplement) is important to determine if there is a deficiency or not.

Best regards,
Wolfgang Herrmann

Question: Factors to be considered before testing plasma homocysteine


The first question related to the diet. Is it necessary to take a special diat at the day of the test? Some Dutch hospitals work with a certain diat (methionine poor diat) and other labs don’t.

Answer from Prof. Dr. W. Herrmann:
We think that one should just continue ingesting his/her usual diet. A methionine poor diet is not recommended since a tHcy test aims at detecting elevated tHcy (sporadic test). A diet poor in methionine can differently affect tHcy concentrations depending on vitamin B12, B6 and folate status. Therefore, by following a methionine poor diet you can not get a standardized response of plasma tHcy; subjects with vitamin deficiency might show lower tHcy than usual, and subjects with adequate vitamin status might show almost no difference in their tHcy after following a methionine poor diet. There is no homogeneous between subjects response.

Question: vitamin use and homocysteine test


The next question is whether it is necessary to stop certain kind of medication (vitamine supplements) three months prior to the test. I thought it was not necessary because a patient should have an good vitamin status in order to distinguish a real hyperhomocysteinemia from a high homocystein concentration secondary to a vitamin deficiency.

Answer from Prof. Dr. W. Herrmann:
Regarding the issue of vitamin supplement; As you know the vitamins are co-factors necessary for tHcy catabolism. If you are regularly taking the vitamins then you should test tHcy under vitamin supplementation.
If the aim of vitamin supplementation is to treat pernicious anemia for example, one might like to test the improvement of the metabolic markers between the injections, then you might test tHcy (in addition to MMA and holoTC) before the next injection.