Three carrier proteins are involved in the transport of Vitamin B12 around the body – Intrinsic Factor (IF), transcobalamin (TC) and haptocorrin (HC).
When transcobalamin and haptocorrin bind Vitamin B12 the resulting complexes are known as holotranscobalamin (HoloTC) and holohaptocorrin (HoloHC).
Holotranscobalamin represents only 10-30% of the Vitamin B12 circulating in the blood but is the ONLY form of Vitamin B12 that is taken up and used by cells of the body, hence it’s other name… ACTIVE-B12.
Only transcobalamin transports Vitamin B12 from its site of absorption in the ileum to tissues and cells. The vitamin is then internalised as the Active-B12 (vitamin B12 bound to transcobalamin) complex via a specific receptor-mediated uptake. This process delivers Vitamin B12 into the cells of the body and provides the vitamin as an essential co-enzyme for vital cellular functions such as DNA synthesis..
The remaining 70-90% of circulating Vitamin B12 is bound to haptocorrin, the function of which is unknown.
Genetic absence of haptocorrin is rare, is not a serious condition and is usually discovered accidentally (1). On the other hand, genetic absence or abnormality of transcobalamin manifests as the typical haematological and neurological pathologies of Vitamin B12 deficiency (2). This is normally discovered shortly after birth (failure to thrive) and requires aggressive therapy with Vitamin B12 if long term, irreversible neurological damage is to be avoided. Frequently in such cases, Total B12levels are misleading (within the normal range).
Theoretically then, the level of Holotranscobalamin should be the optimal marker of Vitamin B12 status. Because up to 90% of circulating Vitamin B12 is bound tohaptocorrin and is therefore biologically unavailable for most cells, the traditional Total B12 test can give a misleading representation of the patient’s Vitamin B12status. Active-B12, the part of Vitamin B12 bound to transcobalamin (TC), is the portion that delivers Vitamin B12 to the tissues of the body.
Also, Active-B12 has a shorter circulating half-life compared to holohaptocorrin so the earliest change that occurs on entering negative vitamin B12 balance is very likely to be a decrease in Active-B12 concentration (3).
1. Carmel R and Herbert V, Blood, 1969;33: 1-12.
2. Hakami N et al., New Eng J Med., 1971; 285: 1163-70.
3. Herzlich B and Herbert V, Lab Invest., 1988; 58: 332-7.
Victor Herbert MD, who died in 2002, was the prime proponent for the measurement of holotranscobalamin (Active B12). Dr Herbert was a New York based physician/scientist who published prolifically in the nutritional field.
He was perhaps most famous for a self-experiment whereby he induced folate deficiency in himself in order to chart the stages and progress of folate deficiency to the end point of megaloblastic anaemia.
He almost killed himself in the process, waking up on Christmas Day 1961, unable to walk because of potassium deficiency induced by the diet he was consuming (mainly thrice boiled vegetables). An article in memoriam of Victor Herbert, written by Dr Charles Halstedand published in the American Journal of Clinical Nutrition in 2003, can be read here.
Victor Herbert MD, 1927-2002
An adaptation of the general model that he proposed is shown in the diagram below describing the biochemical, metabolic and clinical changes that might be expected as there is progression from vitamin B12 repletion, through depletion and then to clinically evident deficiency.