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Semin Vasc Med 2005; 5(2): 140-155
DOI: 10.1055/s-2005-872399
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Novel and Established Markers of Cobalamin Deficiency: Complementary or Exclusive Diagnostic Strategies

Jörn Schneede1 , 2 , Per Magne Ueland2
  • 1Department of Clinical Chemistry, Umeå University, Umeå, Sweden
  • 2Locus for Homocysteine and Related Vitamins, University of Bergen, Bergen, Norway
Further Information

Publication History

Publication Date:
27 July 2005 (online)

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ABSTRACT

New developments in diagnostic markers and a better understanding of the limitations of traditional diagnostic strategies have allowed diagnosis of earlier stages and atypical forms of cobalamin deficiency. Still, there are no generally accepted guidelines for the definition, diagnosis, treatment, and follow-up of cobalamin deficiency. The new trend toward defining cobalamin deficiency purely on the basis of biochemical test outcomes in the absence of overt clinical signs and symptoms could, however, be problematic and may result in overdiagnosis and overtreatment. Use of metabolic markers for the assessment of cobalamin deficiency allows the demonstration of tissue deficiency, but the establishment of the cause of deficiency should also be part of the diagnostic approach. Four groups of diagnostic tests are currently available and these include total cobalamin and cobalamin fractions (such as holo-transcobalamin), tests of gastrointestinal dysfunction, tests of metabolic function, and different gene tests. Among the available tests, only homocysteine, methylmalonic acid, holo-transcobalamin, and possibly methylcitric acid are considered to be useful in clinical practice to add to cobalamin. Gastrointestinal function tests may identify the cause of cobalamin deficiency, whereas the diagnostic usefulness of genetic testing needs to be evaluated. This article provides an overview of recent developments and a reappraisal of novel and established diagnostic markers for cobalamin deficiency.

KEYWORDS

Diagnostic markers - cobalamin deficiency - holoTC - homocysteine - methylmalonic acid

REFERENCES

  • 1 Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly.  Arch Intern Med. 1996;  156 1097-1100
    CrossrefPubMedGoogle Scholar
  • 2 Bjorkegren K, Svardsudd K. A population-based intervention study on elevated serum levels of methylmalonic acid and total homocysteine in elderly people: results after 36 months of follow-up.  J Intern Med. 2004;  256 446-452
    CrossrefPubMedGoogle Scholar
  • 3 Chanarin I, Metz J. Diagnosis of cobalamin deficiency: the old and the new.  Br J Haematol. 1997;  97 695-700
    CrossrefPubMedGoogle Scholar
  • 4 Carmel R. Subtle and atypical cobalamin deficiency states.  Am J Hematol. 1990;  34 108-114
    PubMedGoogle Scholar
  • 5 Allen R H, Stabler S P, Savage D G, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency.  FASEB J. 1993;  7 1344-1353
    PubMedGoogle Scholar
  • 6 Stabler S P, Allen R H. Vitamin B12 deficiency as a worldwide problem.  Annu Rev Nutr. 2004;  24 299-326
    CrossrefPubMedGoogle Scholar
  • 7 Savage D, Lindenbaum J. Relapses after interruption of cyanocobalamin therapy in patients with pernicious anemia.  Am J Med. 1983;  74 765-772
    CrossrefPubMedGoogle Scholar
  • 8 Lindenbaum J, Healton E B, Savage D G et al.. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis.  N Engl J Med. 1988;  318 1720-1728
    CrossrefPubMedGoogle Scholar
  • 9 Bjorkegren K, Svardsudd K. Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly Swedes: a population-based study.  J Intern Med. 2003;  254 343-352
    CrossrefPubMedGoogle Scholar
  • 10 Carmel R, Green R, Rosenblatt D S, Watkins D. Update on cobalamin, folate, and homocysteine.  Hematology (Am Soc Hematol Educ Program). 2003;  8 62-81
    PubMedGoogle Scholar
  • 11 Horrigan D, Vilter R W. Direct action of vitamin B12 upon human bone marrow; the effect of instillations of vitamin B12 and folic acid into the bone marrow as studied by histochemical techniques.  J Clin Invest. 1950;  29 823
    PubMedGoogle Scholar
  • 12 Reynolds E H. The neurology of vitamin B12 deficiency. Metabolic mechanisms.  Lancet. 1976;  2 832-833
    PubMedGoogle Scholar
  • 13 Okun J G, Horster F, Farkas L M et al.. Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity.  J Biol Chem. 2002;  277 14674-14680
    PubMedGoogle Scholar
  • 14 Garcia A A, Haron Y, Evans L R, Smith M G, Freedman M, Roman G C. Metabolic markers of cobalamin deficiency and cognitive function in normal older adults.  J Am Geriatr Soc. 2004;  52 66-71
    CrossrefPubMedGoogle Scholar
  • 15 Carmel R. Current concepts in cobalamin deficiency.  Annu Rev Med. 2000;  51 357-375
    CrossrefPubMedGoogle Scholar
  • 16 Schneede J. Prerequisites for establishing general recommendations for diagnosis and treatment of vitamin B12 deficiency and cost-utility evaluation of these guidelines.  Scand J Clin Lab Invest. 2003;  63 369-375
    PubMedGoogle Scholar
  • 17 Lindgren A, Lindstedt G, Kilander A F. Advantages of serum pepsinogen A combined with gastrin or pepsinogen C as first-line analytes in the evaluation of suspected cobalamin deficiency: a study in patients previously not subjected to gastrointestinal surgery.  J Intern Med. 1998;  244 341-349
    CrossrefPubMedGoogle Scholar
  • 18 Stabler S P, Allen R H, Savage D G, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency.  Blood. 1990;  76 871-881
    PubMedGoogle Scholar
  • 19 Wickramasinghe S N, Saunders J. Correlations between the deoxyuridine-suppressed value and some conventional haematological parameters in patients with folate or vitamin B12 deficiency.  Scand J Haematol. 1976;  16 121-127
    PubMedGoogle Scholar
  • 20 Chui C H, Lau F Y, Wong R et al.. Vitamin B12 deficiency-need for a new guideline.  Nutrition. 2001;  17 917-920
    CrossrefPubMedGoogle Scholar
  • 21 Pauker S G, Kassirer J P. The threshold approach to clinical decision making.  N Engl J Med. 1980;  302 1109-1117
    CrossrefPubMedGoogle Scholar
  • 22 Lu S Y, Wu H C. Initial diagnosis of anemia from sore mouth and improved classification of anemias by MCV and RDW in 30 patients.  Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;  98 679-685
    CrossrefPubMedGoogle Scholar
  • 23 Clarke R, Refsum H, Birks J et al.. Screening for vitamin B-12 and folate deficiency in older persons.  Am J Clin Nutr. 2003;  77 1241-1247
    PubMedGoogle Scholar
  • 24 Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the British Committee for Standards in Haematology. BCSH General Haematology Test Force.  Clin Lab Haematol. 1994;  16 101-115
    PubMedGoogle Scholar
  • 25 Lewerin C, Nilsson-Ehle H, Matousek M, Lindstedt G, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B12 and vitamin B6: a randomised trial.  Eur J Clin Nutr. 2003;  57 1426-1436
    CrossrefPubMedGoogle Scholar
  • 26 Kurz R, Koller A, Glatzl J, Haas H. Congenital pernicious anemia [in German].  Padiatr Padol. 1975;  10 192-199
    PubMedGoogle Scholar
  • 27 Gordon M M, Brada N, Remacha A et al.. A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency.  Hum Mutat. 2004;  23 85-91
    CrossrefPubMedGoogle Scholar
  • 28 Carmel R. Cobalamin, the stomach, and aging.  Am J Clin Nutr. 1997;  66 750-759
    PubMedGoogle Scholar
  • 29 Fernandez-Banares F, Abad-Lacruz A, Xiol X et al.. Vitamin status in patients with inflammatory bowel disease.  Am J Gastroenterol. 1989;  84 744-748
    PubMedGoogle Scholar
  • 30 Gregg C R. Enteric bacterial flora and bacterial overgrowth syndrome.  Semin Gastrointest Dis. 2002;  13 200-209
    PubMedGoogle Scholar
  • 31 Guren M G, Schneede J, Tveit K M, Ueland P M, Nexo E, Dueland S. Biochemical signs of impaired cobalamin status during and after radiotherapy for rectal cancer.  Int J Radiat Oncol Biol Phys. 2004;  60 807-813
    CrossrefPubMedGoogle Scholar
  • 32 Dittmar M, Kahaly G J. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up.  J Clin Endocrinol Metab. 2003;  88 2983-2992
    CrossrefPubMedGoogle Scholar
  • 33 Snow C F. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician.  Arch Intern Med. 1999;  159 1289-1298
    CrossrefPubMedGoogle Scholar
  • 34 Savage D G, Ogundipe A, Allen R H, Stabler S P, Lindenbaum J. Etiology and diagnostic evaluation of macrocytosis.  Am J Med Sci. 2000;  319 343-352
    PubMedGoogle Scholar
  • 35 Oosterhuis W P, Niessen R W, Bossuyt P M, Sanders G T, Sturk A. Diagnostic value of the mean corpuscular volume in the detection of vitamin B12 deficiency.  Scand J Clin Lab Invest. 2000;  60 9-18
    PubMedGoogle Scholar
  • 36 Bessman J D, Gilmer Jr P R, Gardner F H. Improved classification of anemias by MCV and RDW.  Am J Clin Pathol. 1983;  80 322-326
    PubMedGoogle Scholar
  • 37 Metz J, McNeil A R, Levin M. The relationship between serum cobalamin concentration and mean red cell volume at varying concentrations of serum folate.  Clin Lab Haematol. 2004;  26 323-325
    CrossrefPubMedGoogle Scholar
  • 38 Westerman D A, Evans D, Metz J. Neutrophil hypersegmentation in iron deficiency anaemia: a case-control study.  Br J Haematol. 1999;  107 512-515
    CrossrefPubMedGoogle Scholar
  • 39 Carmel R, Green R, Jacobsen D W, Qian G D. 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 57-63
    PubMedGoogle Scholar
  • 40 Winston R M, Warburton F G, Stott A. Enzymatic diagnosis of megaloblastic anaemia.  Br J Haematol. 1970;  19 587-592
    PubMedGoogle Scholar
  • 41 Carmel R, Skikne B S. Serum transferrin receptor in the megaloblastic anemia of cobalamin deficiency.  Eur J Haematol. 1992;  49 246-250
    PubMedGoogle Scholar
  • 42 Lindenbaum J, Savage D G, Stabler S P, Allen R H. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations.  Am J Hematol. 1990;  34 99-107
    PubMedGoogle Scholar
  • 43 Joosten E, van den Berg A, Riezler R et al.. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people.  Am J Clin Nutr. 1993;  58 468-476
    PubMedGoogle Scholar
  • 44 Ward P C. Modern approaches to the investigation of vitamin B12 deficiency.  Clin Lab Med. 2002;  22 435-445
    PubMedGoogle Scholar
  • 45 Wertalik L F, Metz E N, LoBuglio A F, Balcerzak S P. Decreased serum B 12 levels with oral contraceptive use.  JAMA. 1972;  221 1371-1374
    CrossrefPubMedGoogle Scholar
  • 46 Shojania A M. Oral contraceptives: effect of folate and vitamin B12 metabolism.  Can Med Assoc J. 1982;  126 244-247
    PubMedGoogle Scholar
  • 47 Sutterlin M W, Bussen S S, Rieger L, Dietl J, Steck T. Serum folate and Vitamin B12 levels in women using modern oral contraceptives (OC) containing 20 microg ethinyl estradiol.  Eur J Obstet Gynecol Reprod Biol. 2003;  107 57-61
    CrossrefPubMedGoogle Scholar
  • 48 Lussana F, Zighetti M L, Bucciarelli P, Cugno M, Cattaneo M. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users.  Thromb Res. 2003;  112 37-41
    CrossrefPubMedGoogle Scholar
  • 49 Koebnick C, Heins U A, Dagnelie P C et al.. Longitudinal concentrations of vitamin B(12) and vitamin B(12)-binding proteins during uncomplicated pregnancy.  Clin Chem. 2002;  48 928-933
    PubMedGoogle Scholar
  • 50 Ermens A A, Vlasveld L T, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in blood.  Clin Biochem. 2003;  36 585-590
    PubMedGoogle Scholar
  • 51 Bowen R A, Wong B Y, Cole D E. Population-based differences in frequency of the transcobalamin II Pro259Arg polymorphism.  Clin Biochem. 2004;  37 128-133
    PubMedGoogle Scholar
  • 52 Carmel R. Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations.  Clin Chem. 2003;  49 1367-1374
    PubMedGoogle Scholar
  • 53 Bose S, Seetharam S, Seetharam B. Membrane expression and interactions of human transcobalamin II receptor.  J Biol Chem. 1995;  270 8152-8157
    CrossrefPubMedGoogle Scholar
  • 54 Yammani R R, Seetharam S, Dahms N M, Seetharam B. Transcobalamin II receptor interacts with megalin in the renal apical brush border membrane.  J Membr Biol. 2003;  193 57-66
    CrossrefPubMedGoogle Scholar
  • 55 Bor M V, Nexo E, Hvas A M. Holo-transcobalamin concentration and transcobalamin saturation reflect recent vitamin B12 absorption better than does serum vitamin B12.  Clin Chem. 2004;  50 1043-1049
    CrossrefPubMedGoogle Scholar
  • 56 Hvas A M, Nexo E. Holotranscobalamin as a predictor of vitamin B12 status.  Clin Chem Lab Med. 2003;  41 1489-1492
    CrossrefPubMedGoogle Scholar
  • 57 Loikas S, Lopponen M, Suominen P et al.. RIA for serum holo-transcobalamin: method evaluation in the clinical laboratory and reference interval.  Clin Chem. 2003;  49 455-462
    PubMedGoogle Scholar
  • 58 Nilsson K, Isaksson A, Gustafson L, Hultberg B. Clinical utility of serum holotranscobalamin as a marker of cobalamin status in elderly patients with neuropsychiatric symptoms.  Clin Chem Lab Med. 2004;  42 637-643
    CrossrefPubMedGoogle Scholar
  • 59 Riedel B, Bjorke Monsen A L, Ueland P M, Schneede J. Effects of oral contraceptives and hormone replacement therapy on markers of cobalamin status.  Clin Chem. 2005;  51 778-781
    PubMedGoogle Scholar
  • 60 Carmel R. Measuring and interpreting holo-transcobalamin (holo-transcobalamin II).  Clin Chem. 2002;  48 407-409
    PubMedGoogle Scholar
  • 61 Anwar W, Gerard P, Moutabarrek A, Namour F, Gueant J L. End-stage renal disease increases plasma transcobalamin and neutralizes influence of TCN 776C>G polymorphism.  Kidney Int. 2004;  66 2092-2093
    PubMedGoogle Scholar
  • 62 Fodinger M, Veitl M, Skoupy S et al.. Effect of TCN2 776C>G on vitamin B12 cellular availability in end-stage renal disease patients.  Kidney Int. 2003;  64 1095-1100
    CrossrefPubMedGoogle Scholar
  • 63 Ulleland M, Eilertsen I, Quadros E V et al.. Direct assay for cobalamin bound to transcobalamin (holo-transcobalamin) in serum.  Clin Chem. 2002;  48 526-532
    PubMedGoogle Scholar
  • 64 Loikas S, Pelliniemi T T, Koskinen P. No bias between the first and the new version of radioimmunoassay for serum holo-transcobalamin by Axis-Shield.  Clin Chem Lab Med. 2004;  42 569-570
    CrossrefPubMedGoogle Scholar
  • 65 Cohen H, Weinstein W M, Carmel R. Heterogeneity of gastric histology and function in food cobalamin malabsorption: absence of atrophic gastritis and achlorhydria in some patients with severe malabsorption.  Gut. 2000;  47 638-645
    CrossrefPubMedGoogle Scholar
  • 66 Toh B H, van Driel I R, Gleeson P A. Pernicious anemia.  N Engl J Med. 1997;  337 1441-1448
    CrossrefPubMedGoogle Scholar
  • 67 Andres E, Loukili N H, Noel E et al.. Vitamin B12 (cobalamin) deficiency in elderly patients.  CMAJ. 2004;  171 251-259
    PubMedGoogle Scholar
  • 68 Pruthi R K, Tefferi A. Pernicious anemia revisited.  Mayo Clin Proc. 1994;  69 144-150
    PubMedGoogle Scholar
  • 69 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 63-70
    CrossrefPubMedGoogle Scholar
  • 70 Samloff I M, Varis K, Ihamaki T, Siurala M, Rotter J I. Relationships among serum pepsinogen I, serum pepsinogen II, and gastric mucosal histology. A study in relatives of patients with pernicious anemia.  Gastroenterology. 1982;  83 204-209
    PubMedGoogle Scholar
  • 71 Biasco G, Paganelli G M, Vaira D et al.. Serum pepsinogen I and II concentrations and IgG antibody to Helicobacter pylori in dyspeptic patients.  J Clin Pathol. 1993;  46 826-828
    PubMedGoogle Scholar
  • 72 Schilling R F. Intrinsic factor studies II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12.  J Lab Clin Med. 1953;  42 860-866
    PubMedGoogle Scholar
  • 73 Carmel R, Sinow R M, Siegel M E, Samloff I M. Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels.  Arch Intern Med. 1988;  148 1715-1719
    CrossrefPubMedGoogle Scholar
  • 74 Chanarin I. Historical review: a history of pernicious anaemia.  Br J Haematol. 2000;  111 407-415
    CrossrefPubMedGoogle Scholar
  • 75 Stevens T, Conwell D, Zuccaro G et al.. Analysis of pancreatic elastase-1 concentrations in duodenal aspirates from healthy subjects and patients with chronic pancreatitis.  Dig Dis Sci. 2004;  49 1405-1411
    CrossrefPubMedGoogle Scholar
  • 76 Gueant J L, Djalali M, Aouadj R, Gaucher P, Monin B, Nicolas J P. In vitro and in vivo evidences that the malabsorption of cobalamin is related to its binding on haptocorrin (R binder) in chronic pancreatitis.  Am J Clin Nutr. 1986;  44 265-277
    PubMedGoogle Scholar
  • 77 Pimentel M, Chow E J, Lin H C. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. A double-blind, randomized, placebo-controlled study.  Am J Gastroenterol. 2003;  98 412-419
    PubMedGoogle Scholar
  • 78 Baik H W, Russell R M. Vitamin B12 deficiency in the elderly.  Annu Rev Nutr. 1999;  19 357-377
    PubMedGoogle Scholar
  • 79 Humbert P, Lopez de Soria P, Fernandez-Banares F et al.. Magnesium hydrogen breath test using end expiratory sampling to assess achlorhydria in pernicious anaemia patients.  Gut. 1994;  35 1205-1208
    PubMedGoogle Scholar
  • 80 Rogers L M, Boy E, Miller J W et al.. Predictors of cobalamin deficiency in Guatemalan school children: diet, Helicobacter pylori, or bacterial overgrowth?.  J Pediatr Gastroenterol Nutr. 2003;  36 27-36
    CrossrefPubMedGoogle Scholar
  • 81 Mardh S, Ma J Y, Song Y H, Aly A, Henriksson K. Occurrence of autoantibodies against intrinsic factor, H,K-ATPase, and pepsinogen in atrophic gastritis and rheumatoid arthritis.  Scand J Gastroenterol. 1991;  26 1089-1096
    PubMedGoogle Scholar
  • 82 Stabler S P, Lindenbaum J, Allen R H. The use of homocysteine and other metabolites in the specific diagnosis of vitamin B-12 deficiency.  J Nutr. 1996;  126 1266S-1272S
    PubMedGoogle Scholar
  • 83 Ellinson M, Thomas J, Patterson A. A critical evaluation of the relationship between serum vitamin B, folate and total homocysteine with cognitive impairment in the elderly.  J Hum Nutr Diet. 2004;  17 371-383
    CrossrefPubMedGoogle Scholar
  • 84 Kolker S, Schwab M, Horster F et al.. Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain.  J Biol Chem. 2003;  278 47388-47393
    CrossrefPubMedGoogle Scholar
  • 85 Hvas A M, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency.  Arch Intern Med. 2001;  161 1534-1541
    CrossrefPubMedGoogle Scholar
  • 86 Carmel R, Rasmussen K, Jacobsen D W, Green R. Comparison of the deoxyuridine suppression test with serum levels of methylmalonic acid and homocysteine in mild cobalamin deficiency.  Br J Haematol. 1996;  93 311-318
    CrossrefPubMedGoogle Scholar
  • 87 Schneede J, Refsum H, Ueland P M. Biological and environmental determinants of plasma homocysteine.  Semin Thromb Hemost. 2000;  26 263-279
    Article in Thieme ConnectPubMedGoogle Scholar
  • 88 Killmann S A. Effect of deoxyuridine on incorporation of tritiated thymidine: difference between normoblasts and megaloblasts.  Acta Med Scand. 1964;  175 483-488
    PubMedGoogle Scholar
  • 89 Matthews J H, Wickramasinghe S N. The deoxyuridine suppression test performed on phytohaemagglutinin-stimulated peripheral blood cells fails to reflect in vivo vitamin B12 or folate deficiency.  Eur J Haematol. 1988;  40 174-180
    PubMedGoogle Scholar
  • 90 Metz J, Kelly A, Swett V C, Waxman S, Herbert V. Deranged DNA synthesis by bone marrow from vitamin B-12-deficient humans.  Br J Haematol. 1968;  14 575-592
    PubMedGoogle Scholar
  • 91 Liaugaudas G, Jacques P F, Selhub J, Rosenberg I H, Bostom A G. Renal insufficiency, vitamin B(12) status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour.  Arterioscler Thromb Vasc Biol. 2001;  21 849-851
    PubMedGoogle Scholar
  • 92 Schneede J, Dagnelie P C, van Staveren W A, Vollset S E, Refsum H, Ueland P M. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets.  Pediatr Res. 1994;  36 194-201
    PubMedGoogle Scholar
  • 93 Obeid R, Kuhlmann M K, Kohler H, Herrmann W. Response of homocysteine, cystathionine, and methylmalonic acid to vitamin treatment in dialysis patients.  Clin Chem. 2005;  51 196-201
    PubMedGoogle Scholar
  • 94 Toth-Pal E, Nilsson G H, Furhoff A K. Clinical effect of computer generated physician reminders in health screening in primary health care-a controlled clinical trial of preventive services among the elderly.  Int J Med Inform. 2004;  73 695-703
    PubMedGoogle Scholar
  • 95 Nexo E, Hansen M, Rasmussen K, Lindgren A, Grasbeck R. How to diagnose cobalamin deficiency.  Scand J Clin Lab Invest Suppl. 1994;  219 61-76
    PubMedGoogle Scholar
  • 96 Oh R, Brown D L. Vitamin B12 deficiency.  Am Fam Physician. 2003;  67 979-986
    PubMedGoogle Scholar
  • 97 Wolters M, Strohle A, Hahn A. Age-associated changes in the metabolism of vitamin B(12) and folic acid: prevalence, aetiopathogenesis and pathophysiological consequences [in German].  Z Gerontol Geriatr. 2004;  37 109-135
    CrossrefPubMedGoogle Scholar
  • 98 Marks P W, Zukerberg L R. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-2004. A 37-year-old woman with paresthesias of the arms and legs.  N Engl J Med. 2004;  351 1333-1341
    CrossrefPubMedGoogle Scholar
  • 99 Challand G S. Lies, damned lies and algorithms.  Ann Clin Biochem. 2000;  37(Pt 6) 741-750
    CrossrefPubMedGoogle Scholar
  • 100 McRae T D, Freedman M L. Why vitamin B12 deficiency should be managed aggressively.  Geriatrics. 1989;  44 70-73,76,79
    PubMedGoogle Scholar

Jörn SchneedeM.D. 

Department of Clinical Chemistry, Umeå University

SE 90187 Umeå, Sweden

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