Dr. Ron’s Research Review – February 22, 2017

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This week’s research review focuses on holotranscobalamin as an early marker of vitamin B12 deficiency. (Herrmann and Geisel, 2002) (Golding, 2016) (Herbert, 1994)

The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency.
Holotranscobalamin is cobalamin (vitamin B12) attached to the transport protein transcobalamin, in the serum, for delivery to cells for metabolism. Transcobalamin II is depleted of vitamin B-12 within days after absorption stops.
Victor Herbert proposed a model for the staged development of vitamin B12 deficiency, in which holotranscobalamin (HoloTC) is the first indicator of deficiency.

Vitamin B-12 deficiency can be divided into four stages.
In stages I and II, indicated by a low plasma level of holotranscobalamin II, the plasma and cell stores become depleted.
Stage III is characterized by increased levels of homocysteine and methylmalonic in addition to lowered holotranscobalamin II.
In stage IV, clinical signs become recognizable like macroovalocytosis, elevated MCV of erythrocytes or lowered hemoglobin.

Holotranscobalamin II falls below the bottom of its normal range long before total serum vitamin B-12 (which is mainly vitamin B-12 on haptocorrin) falls below the bottom of its normal range.

 

Dr. Ron


 

Articles

Holotranscobalamin (HoloTC, Active-B12) and Herbert's model for the development of vitamin B12 deficiency: a review and alternative hypothesis.
            (Golding, 2016)  Download
The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency. Victor Herbert proposed a model for the staged development of vitamin B12 deficiency, in which holotranscobalamin (HoloTC) is the first indicator of deficiency. Based on this model, a commercial immunoassay has been controversially promoted as a replacement for the total vitamin B12 test. HoloTC is cobalamin (vitamin B12) attached to the transport protein transcobalamin, in the serum, for delivery to cells for metabolism. Although there have been many published reports supporting the claims for HoloTC, the results of some studies were inconsistent with the claim of HoloTC as the most sensitive marker of vitamin B12 deficiency. This review examines the evidence for and against the use of HoloTC, and concludes that the HoloTC immunoassay cannot be used to measure vitamin B12 status any more reliably than total vitamin B12, or to predict the onset of a metabolic deficiency, because it is based on an erroneous hypothesis and a flawed model for the staged development of vitamin B12 deficiency. The author proposes an alternative model for the development of vitamin B12 deficiency.

Staging vitamin B-12 (cobalamin) status in vegetarians.
            (Herbert, 1994) Download
When one stops eating vitamin B-12 (cobalamins), one passes through four stages of negative cobalamin balance: serum depletion [low holotranscobalamin II, ie, low vitamin B-12 on transcobalamin II (TCII)], cell depletion (decreasing holohaptocorrin and low red cell vitamin B-12 concentrations), biochemical deficiency (slowed DNA synthesis, elevated serum homocysteine and methylmalonate concentrations), and, finally, clinical deficiency (anemia). Serum vitamin B-12 is on two proteins: the circulating vitamin B-12 delivery protein, TCII, and the circulating vitamin B-12 storage protein, haptocorrin. Because TCII is depleted of vitamin B-12 within days after absorption stops, the best screening test for early negative vitamin B-12 balance is a measurement of vitamin B-12 on TCII (holoTCII). HoloTCII falls below the bottom of its normal range long before total serum vitamin B-12 (which is mainly vitamin B-12 on haptocorrin) falls below the bottom of its normal range.


 

Vegetarian lifestyle and monitoring of vitamin B-12 status.
            (Herrmann and Geisel, 2002) Download
Vegetarians are at risk to develop deficiencies of some essential nutrients, especially vitamin B-12 (cobalamin). Cobalamin occurs in substantial amounts only in foods derived from animals and is essential for one-carbon metabolism and cell division. Low nutritional intake of vitamin B-12 may lead to negative balance and, finally, to functional deficiency when tissue stores of vitamin B-12 are depleted. Early diagnosis of vitamin B-12 deficiency seems to be useful because irreversible neurological damages may be prevented by cobalamin substitution. The search for a specific and sensitive test to diagnose vitamin B-12 deficiency is ongoing. Serum vitamin B-12 measurement is a widely applied standard method. However, the test has poor predictive value. Optimal monitoring of cobalamin status in vegetarians should include the measurement of homocysteine (HCY), methylmalonic acid (MMA), and holotranscobalamin II. Vitamin B-12 deficiency can be divided into four stages. In stages I and II, indicated by a low plasma level of holotranscobalamin II, the plasma and cell stores become depleted. Stage III is characterized by increased levels of HCY and MMA in addition to lowered holotranscobalamin II. In stage IV, clinical signs become recognizable like macroovalocytosis, elevated MCV of erythrocytes or lowered haemoglobin. In our investigations, we have found stage III of vitamin B-12 deficiency in over 60% of vegetarians, thus underlining the importance of cobalamin monitoring in this dietary group.

References

Golding, PH (2016), ‘Holotranscobalamin (HoloTC, Active-B12) and Herbert’s model for the development of vitamin B12 deficiency: a review and alternative hypothesis.’, Springerplus, 5 (1), 668. PubMed: 27350907
Herbert, V (1994), ‘Staging vitamin B-12 (cobalamin) status in vegetarians.’, Am J Clin Nutr, 59 (5 Suppl), 1213S-22S. PubMed: 8172125
Herrmann, W and J Geisel (2002), ‘Vegetarian lifestyle and monitoring of vitamin B-12 status.’, Clin Chim Acta, 326 (1-2), 47-59. PubMed: 12417096