Vitamin B12 deficiency, beyond megaloblastic anemia: the role of alternative pathways for cellular uptake of vitamin B12
Ángel F. Remacha-Sevilla, Servicio de Hematología, Hospital de la Santa Creu i Sant Pau; Programa Talent Senior, Hospital de la Santa Creu i Sant Pau; CSUR Eritropatología Hereditaria, Hospital Sant Joan de Déu - Hospital de la Santa Creu i Sant Pau; Barcelona, España
Paula San-José, Servicio de Hematología, Hospital de la Santa Creu i Sant Pau; CSUR Eritropatología Hereditaria, Hospital Sant Joan de Déu - Hospital de la Santa Creu i Sant Pau; Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau. Barcelona, España
Nuria González-Álvarez, Servicio de Hematología, Hospital de la Santa Creu i Sant Pau; CSUR Eritropatología Hereditaria, Hospital Sant Joan de Déu - Hospital de la Santa Creu i Sant Pau; Institut de Recerca Sant Pau, Hospital de la Santa Creu i Sant Pau. Barcelona, España
Marta Serra-Ferrer, Servicio de Hematología, Hospital de la Santa Creu i Sant Pau; 3CSUR Eritropatología Hereditaria, Hospital Sant Joan de Déu - Hospital de la Santa Creu i Sant Pau; Barcelona, España
Pilar Leoz-Allegretti, Servicio de Hematología, Hospital de la Santa Creu i Sant Pau, Barcelona, España
Vitamin B12 deficiency (cobalamin [Cbl]) causes megaloblastic anemia with/without neurological alterations. Cbl binds to transcobalamin (TC), giving rise to holotranscobalamin (holoTC), which is taken up by its receptor, TCblR or CD320; this is the canonical uptake pathway for all cells, but there are alternative pathways. Fetuses with congenital disorders of TC and TCblR/CD320 are viable; B12 uptake is mediated by megalin/LRP2. At birth, its expression decreases markedly and these deficiencies become clinically apparent. However, the TC disorder causes severe hematological and neurological manifestations, while the TCblR/CD320 disorder causes mild symptoms and limited to the nervous system. This difference is attributed to the uptake pathway mediated by the LDLR (low-density lipoprotein receptor), present in all cells except in neurological ones. This function was discovered in the study of autoimmune central vitamin B12 deficiency, as these patients present anti- TCbl/CD320 autoantibodies and neurological symptoms without hematological ones. All three are receptors of the LDLR family, and their involvement in the cellular uptake of vitamin B12 opens new perspectives related to neurological symptoms or thrombosis. Finally, the holoTC-TCblR/CD320 uptake pathway is implicated in multiple sclerosis and in the uptake of drugs active against this disease, where Cbl plays an anti-neuroinflammatory role.
Keywords: Cobalamin. Vitamin B12. Transcobalamin, TCblR. CD320. Megalin. LRP2. LDLR. Multiple sclerosis. Pernicious anemia.
