期刊论文详细信息
BMC Geriatrics
Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits
Lorenz Risch1  Urs Nydegger2  Corina Risch2  Pedro Medina Escobar2  Benjamin Sakem2  Dominik W. Meier2  Martin Risch3 
[1]Private University Triesen, Triesen 9495, Liechtenstein
[2]Labormedizinisches Zentrum Dr. Risch, Waldeggstrasse 37, Liebefeld 3097, Switzerland
[3]Kantonsspital Graubünden, Zentrallabor, Loësstrasse 170, Chur 7000, Switzerland
关键词: Vitamin B12;    Reference interval;    Senescence;    Longitudinal study methylmalonic acid;    Kidney function;    Glomerular filtration rate;    Homocysteine;    Holotranscobalamin;    Folate;    Age;   
Others  :  1219812
DOI  :  10.1186/s12877-015-0060-x
 received in 2014-10-09, accepted in 2015-05-22,  发布年份 2015
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【 摘 要 】

Background

The vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake.

Methods

A total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), ≥60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov’s wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived.

Results

Three age groups: 60–69, 70–79 and ≥ 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (μmol/L) 12, 15 and 16 (p < 0.001), MMA (nmol/L) 207, 221 and 244 (p < 0.001). Hcy and MMA (both p < 0.001), but not holoTC (p = 0.12) and vitamin B12 (p = 0.44) were found to be affected by kidney function. In a linear regression model Fedosov’s wellness score was independently associated with kidney function (p < 0.001) but not with age. Total serum folate and red blood cell (RBC) folate drift apart with increasing age: whereas the former decreases (p = 0.01) RBC folate remains in the same bandwidth across all age groups (p = 0.12) A common reference interval combining age and gender strata can be obtained for vitamin B12 and holoTC, whereas a more differentiated approach seems warranted for serum folate and RBC folate.

Conclusion

Whereas the vitamin B12 and holoTC levels remain steady after 60 years of age, we observed a significant increment in MMA levels accompanied by increments in Hcy; this is better explained by age-related reduced kidney function than by vitamin B12 insufficiency. Total serum folate levels but not RBC folate levels decreased with progressing age.

【 授权许可】

   
2015 Risch et al.

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【 参考文献 】
  • [1]Roman-Garcia P, Quiros-Gonzalez I, Mottram L, Lieben L, Sharan K, Wangwiwatsin A, et al.: Vitamin B12-dependent taurine synthesis regulates growth and bone mass. J Clin Invest 2014.
  • [2]Fenech M: Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res 2012, 733(1–2):21-33.
  • [3]Sanghoon Shin D, Hee Min S, Russell L, Zhao R, Fiser A, Goldman D: Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. Blood 2010, 116(24):5162-5169.
  • [4]Nielsen MJ, Rasmussen MR, Andersen CB, Nexo 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.
  • [5]Li Z, Gherasim C, Lesniak NA, Banerjee R: Glutathione-dependent one-electron transfer reactions catalyzed by a B12 trafficking protein. The Journal of biological chemistry 2014, 289(23):16487-16497.
  • [6]Padmanabhan M, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda MC, et al.: Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 2013, 155(1):81-93.
  • [7]Gos M, Szpecht-Ptocka A: Genetic basis of neural tube defects. II. Genes correlated with folate and methionine metabolism. J Appl Genet 2002, 43(4):511-524.
  • [8]Quadros EV, Nakayama Y, Sequeira JM: The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. Blood 2009, 113(1):186-192.
  • [9]Kung Y, Ando N, Doukov TI, Blasiak LC, Bender G, Servalli J, et al.: Visualizing molecular juggling within a B12-dependent methyltransferase complex. Nature 2012, 484(7393):265-269.
  • [10]Holohan B, Wright WE, Shaj JW: Telomeropathies: An emerging spectrum disorder. Cell biology of disease JCB 2014, 205:289-299.
  • [11]Meziere A, Audureau E, Vairelles S, Krypciak S, Docko M, Monie M, et al.: B12 deficiency increases with age in hospitalized patients. A study on 14.904 samples. J Gerontol A Biol Sci Med Sci 2014, 69(12):1576-1585.
  • [12]Baik HW: Russel: Vitamin B12 deficiency in the elderly. Annu Rev Nutr 1999, 19:357-377.
  • [13]Carmel R: Biomarkers of cobalamin (vitamin B12) status in the epidemiologic setting. a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. 2011.
  • [14]Dullemeijer C, Souverein OW, Doets EL, van der Voet H, van Wijngaarden JP, de Boer WJ, et al.: Systematic review with dose–response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned's prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons. Am J Clin Nutr 2013, 97(2):390-402.
  • [15]Andres E, Lukili MH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al.: Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004, 171(3):251-259.
  • [16]Wibobo AS, Singh M, Reeder KM, Carter JJ, Kovach AR, Meng W, et al.: Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proceedings of the National Academy of Sciences of the United States of America 2013, 110(38):15180-15188.
  • [17]Xiao S, Tang Y, Khan R, Zhang Y, Kusumachi P, Stabler SP, et al.: Infeluence of physiologic folate deficiency on human papilloma type 16 (HPV16)-harboring human keratinocytes in vitro and in vivo. The Journal of biological chemistry 2012, 287:12559-12577.
  • [18]Gamaldo AA, Ferrucci L, Rifkind J, Longo DL, Zonderman AB: The relationship between mean corpuiscular volume and cognitive performance in older adults. J Am Geriatr Soc 2013, 61(1):84-89.
  • [19]Palacios G, Sola R, Barrios L, Pietrizik K, Castillo MJ, Gonzalez M: Algorithm for the early diagnosis of vitamin B12 deficiency in elderly people. Nutricion Hospitalaria 2013, 28:1447-1452.
  • [20]Inker LA, Schmid CH: Estimating glomerular filtration rate from serum creatinine and cystatin C. New Engl J Med 2012, 367(1):20-29.
  • [21]Lewerin C, Ljungman S, Nilsson-Ehle H: Glomerular filtration rate as measuredd by serum cystatin C is an important determinant of plasma h omocysteine and serum methlymalonic acid in the elderly. J Intern Med 2007, 261(1):65-73.
  • [22]Valente E, Scott JM, Ueland PM, Cunningham C, Casey M, Molloy AM: Diagnostic accuracy of holotranscobalamin, methylmalonic acid, serum cobalamin, and other indicators of tissue vitamin B12 status in the elderly. Clinical chemistry 2011, 57(6):856-863.
  • [23]Katayev A, Fleming JK: Patient results and laboratory test accuracy. Int J Health Care Qual Assur 2014, 27(1):65-70.
  • [24]Katayev A, Balciza C, Seccomabe DW: Establishing reference intervals for clinical laboratory test results. Am J Clin Pathol 2010, 133:180-186.
  • [25]Sakem B, Nock C, Stanga Z, Medina P, Nydegger UE, Risch M, et al.: Serum concentrations of 25-hydroxyvitamin D and immunoglobulins in an older Swiss cohort: results of the Senior Labor Study. BMC medicine 2013, 11:176. BioMed Central Full Text
  • [26]Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK: Prognostic indices for older adults: a systematic review. Jama 2012, 307(2):182-192.
  • [27]Culleton BF, Manns BJ, Zhang J, Tonelli M, Klarenbach S, Hemmelgarn BR: Impact of anemia on hospitalization and mortality in older adults. Blood 2006, 107(10):3841-3846.
  • [28]Schmedes A, Brandslund I: Analysis of methlymalonic acid in plasma by liquid chromatography-tandem mass spectrometry. Clinical chemistry 2006, 52(4):754-757.
  • [29]Vogeser M, Lorenzl S: Comparison of automated assays for the determination of vitamin B12 in serum. Clin Biochem 2007, 40(16):1342-1345.
  • [30]Brady J, Wilson L, Mcgregor L, Valent E, Orning L: Active B12: a rapid, automated assay of holotranscobalamin on the Abbott AxSYM Analyzer. Clinical chemistry 2008, 54(3):567-573.
  • [31]Bamonti F, Moscato GA, Novembrino C, Gergori D, Novi C, Degiuseppe R, et al.: Determination of serum holotranscobalamin concentrations with the AxSYM active B(12) assay: cut-off point evaluation in the clinical laboratory. Clinical chemistry and laboratory medicine: CCLM / FESCC 2010, 48(2):249-253.
  • [32]Nexo E: Hoffmann-Luecke E: Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. 2011.
  • [33]Vanpottelbergh G, Vaes B, Adriaensen W, Mathei C, Legrand D, Wallemacq P, Degryse JM: The glomerular filtration rate estimated by new and old equations as a predictor of important oucomes in elderly patients. BMC Medicine 2014, 12(27):doi:10.11186/11741.
  • [34]Segarra A, DelaTorre J, Ramos N, Quiroz A, Garjau M, Torres I, et al.: Assessing glomerular filtration rate in hospitalized patients: a comparison between CKD-EPI and four cystatin C-based equations. Clin J Am Soc Nephrol 2011, 6:2411-2420.
  • [35]Wang TF, Chen SH, Yang SH, Su YC, Chu SC, Li DK: Poor harvest of peripheral blood stem cell in donors with microcytic red blood cells. Transfusion 2012, 53(1):91-95.
  • [36]Fedosov SN: Metabolic signs of vitamin B12 deficiency in humans: computational model and its implications for diagnosis. Metabolism 2010, 59:1124-1138.
  • [37]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. 2015.
  • [38]Risch C, Medina P, Nydegger UE, Bahador Z, Brinkmann T, Von Landenberg P, et al.: The relationship of leukocyte anisocytosis to holotranscobalamin, a marker of cobalamin deficiency. Int J Lab Hematol 2012, 34(2):192-200.
  • [39]CLSI: Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline, Third edition CLSI document C28-A3c. Wayne PA, Clinical and Laboratory Standards Institute; 2008.
  • [40]DeLong ER, DeLong DM, Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988, 44(3):837-845.
  • [41]Krzywinski M, Altman N: Nonparametric tests. Nature Methods 2014, 11(5):467-468.
  • [42]Castillo-Lancellotti C, Margozzini P, Valdivia G, Padilla O, Uauy R, Rozowski J, et al.: Nivel serico de folato y vitamina B12 en adultos mayores chilenos. Resultados de la Encuesta Nacianal de Salud ENS 2009–2010. Rev Med Chile 2013, 141:1107-1116.
  • [43]Macfarlane AJ, Greene-Finestone LS, Shy Y: Vitamin B12 and homocysteine status in a folate-replete population: results from the Canadian Health measures Survey. Am J Clin Nutr 2011, 94:1079-1087.
  • [44]Clarke R, Birks J, Nexo E, Ueland PM, Scheede J, Scotte J, et al.: Low vitamin b12 status and risk of cognitive decline in older adults. Am J Clin Nutr 2007, 86:1284-1291.
  • [45]Clarke R, Evans JG, Schneede J, Nexo E, Bates C, Fletcher A, et al.: Vitamin B12 and folate deficiency in later life. Age and Ageing 2004, 33:34-41.
  • [46]Geisel T, Martin J, Schulze B, Schaefer R, Bach M, Virgin G, et al.: An etiologic profile of anemia in 405 geriatric patients. 2014.
  • [47]Hinds HE, Johnson AA, Webb MC, Graham AP: Iron, folate, and vitamin B12 status in the elderly by gender and ethnicity. J Natl Med Assoc 2011, 103(9–10):870-877.
  • [48]Koenig V, Stanga Z, Zerlauth M, Bernasconi L, Risch M, Huber A, et al.: Prevalence of vitamin B12 depletion and deficiency in Liechtenstein. Public Health Nutr 2012, 17(2):241-247.
  • [49]McCaddon A: vitamin B12 in neurology and ageing; clinical and genetic aspects. Biochimie 2013, 95(5):1066-1076.
  • [50]Petrosyan I, Blaison G, Andres E, Federici L: Anaemia in the elderly: an aetiologic profile of a prospective cohort of 95 hospitalized patients. Eur J Intern Med 2012, 23(6):524-528.
  • [51]Leishear K, Boudreau RM, Studenski SA, Newman AB. The relationship of vitamin B12 and sensory and motor peripheral nerve function in older adults. J Am Geriatr Soc. 2012;6061057–1063.
  • [52]Lachner C, Martin C, John D, Nakkalapu S, Sasan A, Stinley N, et al.: Older adult psychiatric inpatients with non-cognitive disorders should be screened for vitamin B12 deficiency. J Nutr Health Aging 2014, 18(2):20-212.
  • [53]Jiang B, Chen Y, Yao G, Yao C, Zhao H, Jia X, et al.: Effects of differences in serum total homocysteine, folate, and vitamin B 12 on cognitive impairment in stroke patients. BMC Neurol 2014, 14(1):217. BioMed Central Full Text
  • [54]Fedosov SN: Biochemical markers of vitamin B12 deficiency combined in one diagnostic parameter: the age-dependence and association with cognitive function and blood hemoglobin. Clinica chimica acta; international journal of clinical chemistry 2013, 422:47-53.
  • [55]Lildballe DL, Fedosov S, Sherliker P, Hin H, Clarke R, Nexo E: Association of cognitive impairment with combinations of vitamin B(1)(2)-related parameters. Clinical chemistry 2011, 57(10):1436-1443.
  • [56]McNamee T, Hyland T, Harrington J, Cadogan S, Honrari B, Perera K, et al.: Haematinic deficiency and macrocytosis in middle-aged and older adults. PLoSOne 2013., 8(11) Article ID e77743
  • [57]Galloway M, Rushworth L: Red cell or serum ? results from the national pathology alliance benchmarking review. J Clin Pathol 2003, 56(12):924-926.
  • [58]Devalia V, Hamilton MS, Molloy AM: Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Brit J Haematol 2014.
  • [59]Cohen E, Nardi Y, Krause I, Goldberg E, Milo G, Garty M, et al.: A longitudinal assessment of the natural rate of decline in renal function with age. 2014.
  • [60]Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW: The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol A Biol Sci Med Sci 1976, 31(2):155-163.
  • [61]Risch L, Lhotta K, Meier D, Medina-Escobar P, Nydegger UE, Risch M. The serum uromodulin level is associated with kidney function. Clin Chem Lab Med. 2014;10(1515).
  • [62]Lewerin C, Ljungman S, Nilsson-Ehle H: Glomerular filtration rate as measured by serum cystatin C is an important determinant of plasma homocysteine and serum methylmalonic acid in the elderly. J Intern Med 2007, 261(1):65-73.
  • [63]Lewerin C, Nilsson-Ehle H, Jacobsson S, Karlsson MK, Ohlsson C, Mellstrom D: Holotranscobalamin is not influenced by decreased renal function in elderly men: the MrOS Sweden study. Annals of clinical biochemistry 2013, 50(Pt 6):585-594.
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