Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Feb;81(2):466–474. doi: 10.1172/JCI113343

Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry.

S P Stabler 1, P D Marcell 1, E R Podell 1, R H Allen 1, D G Savage 1, J Lindenbaum 1
PMCID: PMC329593  PMID: 3339129

Abstract

To determine if levels of serum total homocysteine are elevated in patients with either cobalamin or folate deficiency, we utilized a new capillary gas chromatographic-mass spectrometric technique to measure total homocysteine in the serum of 78 patients with clinically confirmed cobalamin deficiency and 19 patients with clinically confirmed folate deficiency. Values ranged from 11 to 476 mumol/liter in the cobalamin-deficient patients and 77 of the 78 patients had values above the normal range of 7-22 mumol/liter as determined for 50 normal blood donors. In the cobalamin-deficient patients, serum total homocysteine was positively correlated with serum folate, mean corpuscular volume, serum lactate dehydrogenase, serum methylmalonic acid, and the degree of neurologic involvement, and inversely correlated with platelets and hematocrit. In the folate-deficient patients, values for serum total homocysteine ranged from 17 to 185 mumol/liter and 18 of the 19 patients had values above the normal range. Some patients with pernicious anemia who were intermittently treated with cyanocobalamin were found to have elevated serum levels of total homocysteine while they were free of hematologic and neurologic abnormalities. The measurement of serum total homocysteine will help define the incidence of cobalamin deficiency and folate deficiency in various patient populations.

Full text

PDF
466

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boers G. H., Smals A. G., Trijbels F. J., Fowler B., Bakkeren J. A., Schoonderwaldt H. C., Kleijer W. J., Kloppenborg P. W. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med. 1985 Sep 19;313(12):709–715. doi: 10.1056/NEJM198509193131201. [DOI] [PubMed] [Google Scholar]
  2. Brattstrom L. E., Hardebo J. E., Hultberg B. L. Moderate homocysteinemia--a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke. 1984 Nov-Dec;15(6):1012–1016. doi: 10.1161/01.str.15.6.1012. [DOI] [PubMed] [Google Scholar]
  3. Cole M. G., Prchal J. F. Low serum vitamin B12 in Alzheimer-type dementia. Age Ageing. 1984 Mar;13(2):101–105. doi: 10.1093/ageing/13.2.101. [DOI] [PubMed] [Google Scholar]
  4. Corbeel L., Van den Berghe G., Jaeken J., Van Tornout J., Eeckels R. Congenital folate malabsorption. Eur J Pediatr. 1985 Mar;143(4):284–290. doi: 10.1007/BF00442302. [DOI] [PubMed] [Google Scholar]
  5. Davis J. R., Jr, Goldenring J., Lubin B. H. Nutritional vitamin B12 deficiency in infants. Am J Dis Child. 1981 Jun;135(6):566–567. doi: 10.1001/archpedi.1981.02130300064021. [DOI] [PubMed] [Google Scholar]
  6. Dawson D. W. Diagnosis of vitamin B12 deficiency. Br Med J (Clin Res Ed) 1984 Oct 13;289(6450):938–939. doi: 10.1136/bmj.289.6450.938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Evans D. L., Edelsohn G. A., Golden R. N. Organic psychosis without anemia or spinal cord symptoms in patients with vitamin B12 deficiency. Am J Psychiatry. 1983 Feb;140(2):218–221. doi: 10.1176/ajp.140.2.218. [DOI] [PubMed] [Google Scholar]
  8. Finkelstein J. D., Martin J. J. Methionine metabolism in mammals. Adaptation to methionine excess. J Biol Chem. 1986 Feb 5;261(4):1582–1587. [PubMed] [Google Scholar]
  9. Finkelstein J. D., Martin J. J. Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. J Biol Chem. 1984 Aug 10;259(15):9508–9513. [PubMed] [Google Scholar]
  10. Finkelstein J. D., Mudd S. H. Trans-sulfuration in mammals. The methionine-sparing effect of cystine. J Biol Chem. 1967 Mar 10;242(5):873–880. [PubMed] [Google Scholar]
  11. Freeman J. M., Finkelstein J. D., Mudd S. H. Folate-responsive homocystinuria and "schizophrenia". A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity. N Engl J Med. 1975 Mar 6;292(10):491–496. doi: 10.1056/NEJM197503062921001. [DOI] [PubMed] [Google Scholar]
  12. Frenkel E. P. Abnormal fatty acid metabolism in peripheral nerves of patients with pernicious anemia. J Clin Invest. 1973 May;52(5):1237–1245. doi: 10.1172/JCI107291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. GRASBECK R., GORDIN R., KANTERO I., KUHLBACK B. Selective vitamin B12 malabsorption and proteinuria in young people. A syndrome. Acta Med Scand. 1960 Jul 15;167:289–296. doi: 10.1111/j.0954-6820.1960.tb03549.x. [DOI] [PubMed] [Google Scholar]
  14. Goodman S. I., Moe P. G., Hammond K. B., Mudd S. H., Uhlendorf B. W. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med. 1970 Dec;4(5):500–515. doi: 10.1016/0006-2944(70)90080-3. [DOI] [PubMed] [Google Scholar]
  15. HERBERT V. Minimal daily adult folate requirement. Arch Intern Med. 1962 Nov;110:649–652. doi: 10.1001/archinte.1962.03620230095013. [DOI] [PubMed] [Google Scholar]
  16. Higginbottom M. C., Sweetman L., Nyhan W. L. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. N Engl J Med. 1978 Aug 17;299(7):317–323. doi: 10.1056/NEJM197808172990701. [DOI] [PubMed] [Google Scholar]
  17. Hoey H., Linnell J. C., Oberholzer V. G., Laurance B. M. Vitamin B12 deficiency in a breastfed infant of a mother with pernicious anaemia. J R Soc Med. 1982 Aug;75(8):656–658. doi: 10.1177/014107688207500814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hollowell J. G., Jr, Hall W. K., Coryell M. E., McPherson J., Jr, Hahn D. A. Homocystinuria and organic aciduria in a patient with vitamin-B12 deficiency. Lancet. 1969 Dec 27;2(7635):1428–1428. doi: 10.1016/s0140-6736(69)90975-1. [DOI] [PubMed] [Google Scholar]
  19. Kang S. S., Wong P. W., Bidani A., Milanez S. Plasma protein-bound homocyst(e)ine in patients requiring chronic haemodialysis. Clin Sci (Lond) 1983 Sep;65(3):335–336. doi: 10.1042/cs0650335. [DOI] [PubMed] [Google Scholar]
  20. Kishimoto Y., Williams M., Moser H. W., Hignite C., Biermann K. Branched-chain and odd-numbered fatty acids and aldehydes in the nervous system of a patient with deranged vitamin B 12 metabolism. J Lipid Res. 1973 Jan;14(1):69–77. [PubMed] [Google Scholar]
  21. LAMBERT H. P., PRANKERD T. A., SMELLIE J. M. Pernicious anaemia in childhood. A report of two cases in one family and their relationship to the aetiology of pernicious anaemia. Q J Med. 1961 Jan;30:71–90. [PubMed] [Google Scholar]
  22. Lampkin B. C., Mauer A. M. Congenital pernicious anemia with coexistent transitory intestinal malabsorption of vitamin B12. Blood. 1967 Oct;30(4):495–502. [PubMed] [Google Scholar]
  23. Levy H. L., Mudd S. H., Schulman J. D., Dreyfus P. M., Abeles R. H. A derangement in B12 metabolism associated with homocystinemia, cystathioninemia, hypomethioninemia and methylmalonic aciduria. Am J Med. 1970 Mar;48(3):390–397. doi: 10.1016/0002-9343(70)90070-7. [DOI] [PubMed] [Google Scholar]
  24. Lindenbaum J. Status of laboratory testing in the diagnosis of megaloblastic anemia. Blood. 1983 Apr;61(4):624–627. [PubMed] [Google Scholar]
  25. Magnus E. M., Bache-Wiig J. E., Aanderson T. R., Melbostad E. Folate and vitamin B12 (cobalamin) blood levels in elderly persons in geriatric homes. Scand J Haematol. 1982 Apr;28(4):360–366. doi: 10.1111/j.1600-0609.1982.tb00539.x. [DOI] [PubMed] [Google Scholar]
  26. Marcell P. D., Stabler S. P., Podell E. R., Allen R. H. Quantitation of methylmalonic acid and other dicarboxylic acids in normal serum and urine using capillary gas chromatography-mass spectrometry. Anal Biochem. 1985 Oct;150(1):58–66. doi: 10.1016/0003-2697(85)90440-3. [DOI] [PubMed] [Google Scholar]
  27. 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 Jun;14(6):575–592. doi: 10.1111/j.1365-2141.1968.tb00364.x. [DOI] [PubMed] [Google Scholar]
  28. Mudd S. H., Uhlendorf B. W., Freeman J. M., Finkelstein J. D., Shih V. E. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun. 1972 Jan 31;46(2):905–912. doi: 10.1016/s0006-291x(72)80227-4. [DOI] [PubMed] [Google Scholar]
  29. Nexø E. Variation with age of reference values for P-cobalamins. Scand J Haematol. 1983 May;30(5):430–432. doi: 10.1111/j.1600-0609.1983.tb02530.x. [DOI] [PubMed] [Google Scholar]
  30. Parry T. E. Serum valine and methionine levels in pernicious anaemia under treatment. Br J Haematol. 1969 Mar;16(3):221–229. doi: 10.1111/j.1365-2141.1969.tb00397.x. [DOI] [PubMed] [Google Scholar]
  31. Rosenblatt D. S., Laframboise R., Pichette J., Langevin P., Cooper B. A., Costa T. New disorder of vitamin B12 metabolism (cobalamin F) presenting as methylmalonic aciduria. Pediatrics. 1986 Jul;78(1):51–54. [PubMed] [Google Scholar]
  32. Savage D., Lindenbaum J. Anemia in alcoholics. Medicine (Baltimore) 1986 Sep;65(5):322–338. doi: 10.1097/00005792-198609000-00005. [DOI] [PubMed] [Google Scholar]
  33. Schilling R. F., Fairbanks V. F., Miller R., Schmitt K., Smith M. J. "Improved" vitamin B12 assays: a report on two commercial kits. Clin Chem. 1983 Mar;29(3):582–583. [PubMed] [Google Scholar]
  34. Scott C. R., Hakami N., Teng C. C., Sagerson R. N. Hereditary transcobalamin II deficiency: the role of transcobalamin II in vitamin B 12 -mediated reactions. J Pediatr. 1972 Dec;81(6):1106–1111. doi: 10.1016/s0022-3476(72)80239-7. [DOI] [PubMed] [Google Scholar]
  35. Scott J. M., Dinn J. J., Wilson P., Weir D. G. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet. 1981 Aug 15;2(8242):334–337. doi: 10.1016/s0140-6736(81)90649-8. [DOI] [PubMed] [Google Scholar]
  36. Shipman R. T., Townley R. R., Danks D. M. Homocystinuria, addisonian pernicious anaemia, and partial deletion of a G chromosome. Lancet. 1969 Sep 27;2(7622):693–694. doi: 10.1016/s0140-6736(69)90401-2. [DOI] [PubMed] [Google Scholar]
  37. Stabler S. P., Marcell P. D., Podell E. R., Allen R. H., Lindenbaum J. Assay of methylmalonic acid in the serum of patients with cobalamin deficiency using capillary gas chromatography-mass spectrometry. J Clin Invest. 1986 May;77(5):1606–1612. doi: 10.1172/JCI112476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stabler S. P., Marcell P. D., Podell E. R., Allen R. H. Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry. Anal Biochem. 1987 Apr;162(1):185–196. doi: 10.1016/0003-2697(87)90026-1. [DOI] [PubMed] [Google Scholar]
  39. Vitamin B12 deficiency in strict vegetarians. N Engl J Med. 1978 Dec 7;299(23):1319–1320. doi: 10.1056/NEJM197812072992325. [DOI] [PubMed] [Google Scholar]
  40. Wilcken D. E., Gupta V. J., Reddy S. G. Accumulation of sulphur-containing amino acids including cysteine-homocysteine in patients on maintenance haemodialysis. Clin Sci (Lond) 1980 May;58(5):427–430. doi: 10.1042/cs0580427. [DOI] [PubMed] [Google Scholar]
  41. Wilcken D. E., Reddy S. G., Gupta V. J. Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. Metabolism. 1983 Apr;32(4):363–370. doi: 10.1016/0026-0495(83)90045-8. [DOI] [PubMed] [Google Scholar]
  42. van der Westhuyzen J., Fernandes-Costa F., Metz J. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats : protection by methionine and aggravation by folates. Life Sci. 1982 Nov 1;31(18):2001–2010. doi: 10.1016/0024-3205(82)90039-x. [DOI] [PubMed] [Google Scholar]
  43. van der Westhuyzen J., van Tonder S. V., Gibson J. E., Kilroe-Smith T. A., Metz J. Plasma amino acids and tissue methionine levels in fruit bats (Rousettus aegyptiacus) with nitrous oxide-induced vitamin B12 deficiency. Br J Nutr. 1985 May;53(3):657–662. doi: 10.1079/bjn19850075. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES