Homocysteine, Folate, Vitamin B12, and Transcobalamins in Patients Undergoing Successive Hypo- and Hyperthyroid States

Françoise Barbé, Marc Klein, Abalo Chango, Sophie Frémont, Philippe Gérard, Georges Weryha, Jean-Louis Guéant and Jean-Pierre Nicolas

Departments of Biochemistry A, INSERM XR308 (F.B., A.C., S.F., P.G., J.-P.N.) and INSERM 0014 (P.G., J.-L.G.). and Department of Endocrinology (M.K., G.W.), Centre Hospitalier Universitaire de Nancy, Hôpital de Brabois–Hôpital d’Adultes 54511 Vandoeuvre-les-Nancy, France

To the editor:

In the March 2000 issue of this journal, Lien et al. (1) reported a transient increase in both plasma homocysteine and serum cholesterol during short-term iatrogenic hypothyroidism, which may confer increased cardiovascular risk. The observations of Lien et al. (1) are in accordance with the results of our previous preliminary study (2).

We now repeat plasma homocysteine, serum folate, and vitamin B12 in patients with successive hypo- and hyperthyroid states. Cobalamin-binding proteins, transcobalamins, were also determined to explain changes in vitamin B12 concentrations. Forty-five patients [age, 44.5 ± 12.3 yr (23–78); sex ratio M/F, 11/34] who had undergone total thyroidectomy for well-differentiated thyroid carcinoma were studied 4 weeks after the withdrawal of thyroïdal hormone therapy and then 14 weeks after the resumption of treatment to suppress the thyrotropin concentration. Hypo- and thyrotoxic states were evidenced by TSH concentrations (Table 1Go). Total EDTA-plasma homocysteine, serum folate, cobalamin, serum total B12 binding capacity, apo-haptocorrin, and apo-transcobalamin II were measured by methods described previously (4).


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Table 1. Homocysteine, folate, vitamin B12, and transcobalamin results in patients undergoing successive hypo- and hyperthyroid states

 
Homocysteine concentrations were significantly higher in hypo- than in hyperthyroid state (mean increase, 5.3 ± 4.6 µmol/L; Table 1Go). Furthermore, moderate hyperhomocysteinemia was observed for 10 of 45 patients (22%) with hypothyroidism [range, 17.5–27.2 µmol/L; reference range, 6.0–16.0 µmol/L (5)]. Homocysteinemia was normal in all patients in the hyperthyroid state. On univariate analysis, homocysteine was inversely related to folate (Rho, -0.33; P = 0.02). Our results suggested that folate levels may account in determining homocysteine as we confirmed the observation (1) of a moderate decline in serum folate in hypothyroid state, with a P value at the limit of significance (P = 0.07). Vitamin B12 was significantly higher in the hypothyroid state than in the hyperthyroid state, as found by Lien et al. (1). Transcobalamin levels were determined attempting to explain changes in vitamin B12 concentrations. Except in two cases, apo-haptocorrin was low in all patients in the two states whereas apo-transcobalamin II was not significantly decreased in hypothyroid patients. Vitamin B12 was not correlated to transcobalamins. We concluded that the increased vitamin B12 observed in hypothyroid state could not be explained by changes in transcobalamins.

Lien et al. (1) have compared the results at 2-week intervals during two phases. We compared the results between two states, hypo- and hyperthyroidism, in a larger cohort of patients. The increase in homocysteine concentrations during hypothyroidism may be explained by changes in folate status and also by modifications in enzymes involved in homocysteine metabolism, distribution or clearance (1, 6), and/or by concurrent changes in renal function (1). Changes in activities of 5,10-methylenetetrahydrofolate reductase and methionine synthase have been reported during both hyper- and hypothyroid states in an animal model (7). Data about normalization of hyperhomocysteinemia with levothyroxine are conflicting. Normalization was obtained after 3–9 months in a study of 14 patients (8), but failed after 2 months in a cohort of 14 patients (9).

In conclusion, homocysteine was increased in 22% of our patients in the hypothyroidism stage. This mild hyperhomocysteinemia was rather explained by a modification of folates status, with a mild decrease of blood concentration and a negative correlation between folates and homocysteinemia, than by a modification of vitamin B12 status and transport.

References

  1. Lien EA, Nedrebo BG, Varhaug JE, Nygard O, Aakvaag A, Ueland PM. 2000 Plasma total homocysteine levels during short-term iatrogenic hypothyroidism. J Clin Endocrinol Metab. 85:1049–1053.[Abstract/Free Full Text]
  2. Barbé F, Klein M, Chango A, Weryha G, Nicolas JP, Leclère J. 1999 Hypothyroidism increases plasma homocysteine concentrations. J Endocrinol Invest. 22:28.[Medline]
  3. Ubbink JB, Vermaak WJH, Bissbort S. 1991 Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr. 565:441–446.[Medline]
  4. Namour F, Olivier JL, Abdelmouttaleb I, et al. Transcobalamin codon 259 polymorphism in HT29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood. In press.
  5. Nicolas JP, Chango A. 1997 Dérégulation du métabolisme de l’homocystéine et conséquences pour le système vasculaire. Bull Acad Natle Méd. 181:313–331.
  6. Nedrebo BG, Ericsson UB, Nygard O, et al. 1998 Plasma total homocysteine levels in hyperthyroid and hypothyroid patients. Metabolism. 47:89–93.[Medline]
  7. Nair CPP, Viswanathan G, Noronha J. 1994 Folate-mediated incorporation of ring-2-carbon of histidine into nucleic acids: influence of thyroid hormone. Metabolism. 43:1575–1578.[Medline]
  8. Hussein WI, Green R, Jacobsen DW, Faiman C. 1999 Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann Intern Med. 131:348–351.[Abstract/Free Full Text]
  9. Catargi B, Parrot-Roulaud F, Cochet C, Ducassou D, Roger P, Tabarin A. 1999 Homocysteine, hypothyroidism, and effects of thyroid hormone replacement. Thyroid. 9:1163–1166.[Medline]