Vitamin B12 deficiency from the perspective of a practicing hematologist

Blood

Volumn 129, Issue 19, 2017, Pages 2603-2611

  Green, Ralph ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYANOCOBALAMIN; FOLIC ACID; HOMOCYSTEINE; INTRINSIC FACTOR; METHYLMALONIC ACID;

ABSORPTION; CYANOCOBALAMIN DEFICIENCY; HEMATOLOGIST; HEMATOLOGY; HUMAN; NONHUMAN; PATHOLOGY; PHYSICIAN ATTITUDE; PRIORITY JOURNAL; REVIEW; VITAMIN BLOOD LEVEL; ANEMIA, MEGALOBLASTIC; ANEMIA, PERNICIOUS; ANIMAL; BLOOD; COMPLICATION; INTESTINE ABSORPTION; METABOLISM; VITAMIN B 12 DEFICIENCY;

ANEMIA, MEGALOBLASTIC; ANEMIA, PERNICIOUS; ANIMALS; FOLIC ACID; HUMANS; INTESTINAL ABSORPTION; VITAMIN B 12; VITAMIN B 12 DEFICIENCY;

EID: 85019671428     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2016-10-569186     Document Type: Review

References (104)

1. Wintrobe MM. Blood, pure and eloquent: a story of discovery, of people, and of ideas. New York: McGraw-Hill; 1980.
2. Coller BS. Blood at 70: its roots in the history of hematology and its birth. Blood. 2015;126(24): 2548-2560.
3. Green R, Miller JW. Vitamin B12. In: Zempleni J, Suttie JW, Gregory JF, Stover PJ, eds. Handbook of Vitamins. 5th ed. ed. Boca Raton, FL: Taylor & Francis; 2014:447-490.
4. Green R. Metabolite assays in cobalamin and folate deficiency. Baillieres Clin Haematol. 1995; 8(3):533-566.
5. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. 1990;34(2): 99-107.
6. Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;318(26): 1720-1728.
7. Green R, Miller JW. Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. Semin Hematol. 1999;36(1):47-64.
8. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. 446. Washington, DC: The National Academies Press; 2000.
9. Green R, Jacobsen DW, van Tonder SV, Kew MC, Metz J. Enterohepatic circulation of cobalamin in the nonhuman primate. Gastroenterology. 1981;81(4):773-776.
10. Green R, Jacobsen DW, Van Tonder SV, Kew MC, Metz J. Absorption of biliary cobalamin in baboons following total gastrectomy. J Lab Clin Med. 1982;100(5):771-777.
11. el Kholty S, Gueant JL, Bressler L, et al. Portal and biliary phases of enterohepatic circulation of corrinoids in humans. Gastroenterology. 1991; 101(5):1399-1408.
12. Nielsen MJ, Rasmussen MR, Andersen CB, Nexø E, Moestrup SK. Vitamin B12 transport from food to the body's cells-a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol. 2012;9(6):345-354.
13. Watkins D, Rosenblatt DS. Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C Semin Med Genet. 2011;157C(1): 33-44.
14. Froese DS, Gravel RA. Genetic disorders of vitamin B12 metabolism: eight complementation groups-eight genes. Expert Rev Mol Med. 2010; 12:e37.
15. Fyfe JC, Madsen M, Højrup P, et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood. 2004;103(5):1573-1579.
16. Steinberg SE, Fonda S, Campbell CL, Hillman RS. Cellular abnormalities of folate deficiency. Br J Haematol. 1983;54(4):605-612.
17. Rondanelli EG, Gorini P, Magliulo E, Fiori GP. Differences in proliferative activity between normoblasts and pernicious anemia megaloblasts. Blood. 1964;24:542-552.
18. Wickremasinghe RG, Hoffbrand AV. Reduced rate of DNA replication fork movement in megaloblastic anemia. J Clin Invest. 1980;65(1): 26-36.
19. Duthie SJ, McMillan P. Uracil misincorporation in human DNA detected using single cell gel electrophoresis. Carcinogenesis. 1997;18(9): 1709-1714.
20. Koury MJ, Horne DW, Brown ZA, et al. Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood. 1997;89(12): 4617-4623.
21. Das KC, Mohanty D, Garewal G. Cytogenetics in nutritional megaloblastic anaemia: prolonged persistence of chromosomal abnormalities in lymphocytes after remission. Acta Haematol. 1986;76(2-3):146-154.
22. Amess JA, Burman JF, Rees GM, Nancekievill DG, Mollin DL. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet. 1978; 2(8085):339-342.
23. O'Leary PW, Combs MJ, Schilling RF. Synergistic deleterious effects of nitrous oxide exposure and vitamin B12 deficiency. J Lab Clin Med. 1985;105(4):428-431.
24. Marsh GW, Stewart JS. Splenic function in adult coeliac disease. Br J Haematol. 1970;19(4): 445-457.
25. Lindenbaum J, Nath BJ. Megaloblastic anaemia and neutrophil hypersegmentation. Br J Haematol. 1980;44(3):511-513.
26. Carmel R, Green R, Jacobsen DW, Qian GD. Neutrophil nuclear segmentation in mild cobalamin deficiency: relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation. Am J Clin Pathol. 1996;106(1):57-63.
27. Green R. Anemias beyond B12 and iron deficiency: the buzz about other B's, elementary, and nonelementary problems. Hematology Am Soc Hematol Educ Program. 2012;2012: 492-498.
28. Dalsania CJ, Khemka V, Shum M, Devereux L, Lachant NA. A sheep in wolf's clothing. Am J Med. 2008;121(2):107-109.
29. Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest. 1969;48(6):963-974.
30. Obeid R, Geisel J, Schorr H, Hübner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002;69(5-6):275-279.
31. Lawler SD, Roberts PD, Hoffbrand AV. Chromosome studies in megaloblastic anaemia before and after treatment. Scand J Haematol. 1971;8(4):309-320.
32. Tanaka T, Scheet P, Giusti B, et al. Genomewide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009;84(4): 477-482.
33. Miller JW, Ramos MI, Garrod MG, Flynn MA, Green R. Transcobalamin II 775G.C polymorphism and indices of vitamin B12 status in healthy older adults. Blood. 2002;100(2): 718-720.
34. Allen RH, Stabler SP. Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am J Clin Nutr. 2008; 87(5):1324-1335.
35. Kolhouse JF, Kondo H, Allen NC, Podell E, Allen RH. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med. 1978;299(15):785-792.
36. Kanazawa S, Herbert V. Noncobalamin vitamin B12 analogues in human red cells, liver, and brain. Am J Clin Nutr. 1983;37(5):774-777.
37. Marshall AC, Alderuccio F, Toh BH. Fas/CD95 is required for gastric mucosal damage in autoimmune gastritis. Gastroenterology. 2002; 123(3):780-789.
38. Stopeck A. Links between Helicobacter pylori infection, cobalamin deficiency, and pernicious anemia. Arch Intern Med. 2000;160(9): 1229-1230.
39. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable hematologic presentation of autoimmune gastritis: agerelated progression from iron deficiency to cobalamin depletion. Blood. 2006;107(4): 1673-1679.
40. Green R, Kuhl W, Jacobson R, Johnson C, Carmel R, Beutler E. Masking of macrocytosis by alpha-thalassemia in blacks with pernicious anemia. N Engl J Med. 1982;307(21):1322-1325.
41. Spivak JL. Masked megaloblastic anemia. Arch Intern Med. 1982;142(12):2111-2114.
42. Herbert V, Zalusky R. Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies. J Clin Invest. 1962;41: 1263-1276.
43. Reynolds EH. What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies. Eur J Clin Nutr. 2016;70(5):537-540.
44. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). 1991;70(4): 229-245.
45. Waters AH, Mollin DL. Observations on the metabolism of folic acid in pernicious anaemia. Br J Haematol. 1963;9:319-327.
46. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85(1):193-200.
47. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci USA. 2007;104(50):19995-20000.
48. Miller JW, Garrod MG, Allen LH, Haan MN, Green R. Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate. Am J Clin Nutr. 2009;90(6): 1586-1592.
49. Mills JL, Von Kohorn I, Conley MR, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 2003;77(6):1474-1477.
50. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013;368(2):149-160.
51. Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008;29(suppl 2): S20-34; discussion S35-27.
52. Carmel R, Aurangzeb I, Qian D. Associations of food-cobalamin malabsorption with ethnic origin, age, Helicobacter pylori infection, and serum markers of gastritis. Am J Gastroenterol. 2001; 96(1):63-70.
53. Toskes PP, Deren JJ, Conrad ME. Trypsin-like nature of the pancreatic factor that corrects vitamin B12 malabsorption associated with pancreatic dysfunction. J Clin Invest. 1973;52(7): 1660-1664.
54. Allen RH, Seetharam B, Podell E, Alpers DH. Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. J Clin Invest. 1978;61(1):47-54.
55. Nyberg W. The influence of diphyllobothrium latum on the vitamin B12-intrinsic factor complex. I. In vivo studies with Schilling test technique. Acta Med Scand. 1960;167:185-187.
56. Ballas SK. Abnormal erythrocyte membrane protein pattern in severe megaloblastic anemia. J Clin Invest. 1978;61(4):1097-1101.
57. Ballas SK, Pielichowski HJ, Stoll DB. Further characterization of the erythrocyte membrane protein abnormality in megaloblastic anemia. J Med. 1982;13(1-2):15-34.
58. Schilling RF, Harris JW. Liver function in untreated Addisonian pernicious anemia. J Lab Clin Med. 1952;40(5):718-725.
59. Emerson PM, Wilkinson JH. Lactate dehydrogenase in the diagnosis and assessment of response to treatment of megaloblastic anaemia. Br J Haematol. 1966;12(6):678-688.
60. Winston RM, Warburton FG, Stott A. Enzymatic diagnosis of megaloblastic anaemia. Br J Haematol. 1970;19(5):587-592.
61. Heller P, Weinstein HG, West M, Zimmerman HJ. Enzymes in anemia: a study of abnormalities of several enzymes of carbohvdrate metabolism in the plasma and erythrocytes in patients with anemia, with preliminary observations of boen marrow enzymes. Ann Intern Med. 1960;53: 898-913.
62. de Klerk G, Rosengarten PC, Vet RJ, Goudsmit R. Serum erythropoietin (EST) titers in anemia. Blood. 1981;58(6):1164-1170.
63. Hussein S, Laulicht M, Hoffbrand AV. Serum ferritin in megaloblastic anaemia. Scand J Haematol. 1978;20(3):241-245.
64. Carmel R, Skikne BS. Serum transferrin receptor in the megaloblastic anemia of cobalamin deficiency. Eur J Haematol. 1992;49(5):246-250.
65. Hansen NE, Karle H. Blood and bone-marrow lysozyme in neutropenia: an attempt towards pathogenetic classification. Br J Haematol. 1971; 21(3):261-270.
66. Corcino JJ, Zalusky R, Greenberg M, Herbert V. Coexistence of pernicious anaemia and chronic myeloid leukaemia: an experiment of nature involving vitamin B12 metabolism. Br J Haematol. 1971;20(5):511-520.
67. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990;76(5):871-881.
68. Skacel PO, Hewlett AM, Lewis JD, Lumb M, Nunn JF, Chanarin I. Studies on the haemopoietic toxicity of nitrous oxide in man. Br J Haematol. 1983;53(2):189-200.
69. Hannibal L, Lysne V, Bjørke-Monsen AL, et al. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Biosci. 2016; 3:27.
70. Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2014;68(5): 541-548.
71. Herbert V, Jacob E, Wong KT, Scott J, Pfeffer RD. Low serum vitamin B12 levels in patients receiving ascorbic acid in megadoses: studies concerning the effect of ascorbate on radioisotope vitamin B12 assay. Am J Clin Nutr. 1978;31(2):253-258.
72. Carmel R. R-binder deficiency. A clinically benign cause of cobalamin pseudodeficiency. JAMA. 1983;250(14):1886-1890.
73. Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. Clin Chem. 2003;49(8): 1367-1374.
74. Cooper BA, Rosenblatt DS. Inherited defects of vitamin B12 metabolism. Annu Rev Nutr. 1987;7:291-320.
75. Clarke R, Sherliker P, Hin H, et al. Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin. Clin Chem. 2007;53(5):963-970.
76. Nexo E, Hvas AM, Bleie Ø, et al. Holotranscobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebocontrolled study. Clin Chem. 2002;48(10): 1768-1771.
77. Obeid R, Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clin Chem Lab Med. 2007;45(12): 1746-1750.
78. Miller JW, Garrod MG, Rockwood AL, et al. Measurement of total vitamin B12 and holotranscobalamin, singly and in combination, in screening for metabolic vitamin B12 deficiency. Clin Chem. 2006;52(2):278-285.
79. Brito AVR, Hertrampf E, Miller JW, et al. Vitamin B-12 treatment of asymptomatic deficient elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs B-12 status response assessed by the combined indicator of vitamin B-12 status. Am J Clin Nutr. 2016;103(1):250-257.
80. Fedosov SN, Brito A, Miller JW, Green R, Allen LH. Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points. Clin Chem Lab Med. 2015;53(8): 1215-1225.
81. Lindgren A, Kilander A, Bagge E, Nexø E. Holotranscobalamin-a sensitive marker of cobalamin malabsorption. Eur J Clin Invest. 1999;29(4):321-329.
82. von Castel-Roberts KM, Morkbak AL, Nexo E, et al. Holo-transcobalamin is an indicator of vitamin B-12 absorption in healthy adults with adequate vitamin B-12 status. Am J Clin Nutr. 2007;85(4):1057-1061.
83. Bor MV, Nexø E, Hvas AM. Holo-transcobalamin concentration and transcobalamin saturation reflect recent vitamin B12 absorption better than does serum vitamin B12. Clin Chem. 2004;50(6): 1043-1049.
84. Green R. Typical and atypical manifestations of pernicious anemia. In: Besser M, Bhatt R, James VHT, Keen H, eds. Thomas Addison and His Diseases: 200 Years On. Vol 1. London: Bristol: Journal of Endocrinology; 1994:377-390.
85. Carmel R. Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr. 2011; 94(1):348S-358S.
86. Smith AD, Refsum H. Do we need to reconsider the desirable blood level of vitamin B12? J Intern Med. 2012;271(2):179-182.
87. Jacobsen DW, Gatautis VJ, Green R, et al. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem. 1994;40(6):873-881.
88. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem. 2004;50(1):3-32.
89. Carmel R, Green R, Rosenblatt D, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program; 2003:62-81.
90. Green R. Screening for vitamin B12 deficiency: caveat emptor. Ann Intern Med. 1996;124(5): 509-511.
91. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood. 2005;105(3): 978-985, author reply 1137.
92. Carmel R. The disappearance of cobalamin absorption testing: a critical diagnostic loss. J Nutr. 2007;137(11):2481-2484.
93. Morkbak AL, Heimdal RM, Emmens K, et al. Evaluation of the technical performance of novel holotranscobalamin (holoTC) assays in a multicenter European demonstration project. Clin Chem Lab Med. 2005;43(10):1058-1064.
94. Greibe E, Nexo E. Vitamin B12 absorption judged by measurement of holotranscobalamin, active vitamin B12: evaluation of a commercially available EIA kit. Clin Chem Lab Med. 2011; 49(11):1883-1885.
95. Carkeet C, Dueker SR, Lango J, et al. Human vitamin B12 absorption measurement by accelerator mass spectrometry using specifically labeled (14)C-cobalamin [published correction appears in Proc Natl Acad Sci U S A. 2006;103(27):10526]. Proc Natl Acad Sci USA. 2006;103(15):5694-5699.
96. Kapadia CR, Donaldson RM Jr. Disorders of cobalamin (vitamin B12) absorption and transport. Annu Rev Med. 1985;36:93-110.
97. Irvine WJ, Davies SH, Teitelbaum S, Delamore IW, Williams AW. The clinical and pathological significance of gastric parietal cell antibody. Ann N Y Acad Sci. 1965;124(2):657-691.
98. Bor MV, von Castel-Roberts KM, Kauwell GP, et al. Daily intake of 4 to 7 microg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12-related biomarkers in a healthy young population. Am J Clin Nutr. 2010;91(3): 571-577.
99. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 2016; 36:211-239.
100. Green R, Miller JW. Vitamin B12 deficiency is the dominant nutritional cause of hyperhomocysteinemia in a folic acid-fortified population. Clin Chem Lab Med. 2005;43(10): 1048-1051.
101. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112(6):2214-2221.
102. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968;184(4):247-258.
103. Ungley CC. Absorption of vitamin B12 in pernicious anaemia. I. Oral administration without a source of intrinsic factor. BMJ. 1950; 2(4685):905-908.
104. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.