Total Plasma Homocysteine in Hypo- and Hyperthyroidism: Covariations and Causality

Ernst A. Lien, Steinar Hustad, Bjørn G. Nedrebø, Ottar Nygård and Per M. Ueland

LOCUS for Homocysteine and Related Vitamins Armauer Hansens hus University of Bergen N-5021 Bergen, Norway

Address correspondence and requests for reprints to: Eldon D. Lehmann, Department of Imaging (MR Unit), National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Sydney Street, London SW3 6NP, United Kingdom. E-mail: info-www{at}2aida.org

To the editor:

There are consistent reports that patients with hypothyroidism have elevated total homocysteine (tHcy) in plasma and that tHcy is reduced following therapy with T4 (1, 2, 3, 4, 5). The withdrawal of thyroid hormone replacement therapy before radioscintigraphy of thyroidectomized patients provides controlled conditions for the study of changes in tHcy under variable thyroid status. This strategy was adopted in a recent study from our group (5) and in the study on 45 patients reported by Barbé et al.

Barbé et al. found lower serum folate in the hypothyroid compared with the hyperthyroid state, and they observed the usual inverse relationship between folate and tHcy. From this observation they inferred that the changes in tHcy may be explained by altered folate status or by a modification of the activity of folate-metabolizing enzymes, as has previously been suggested (2). Like Barbé et al., we found lower levels of serum folate during short-term iatrogenic hypothyroidism (5). We observed, however, that the changes in tHcy concentration during the hypothyroid phase were more strongly associated with changes in serum creatinine than in folate, suggesting a renal mechanism (5).

The covariation between tHcy and serum cholesterol was equally strong, but a mechanistic link between homocysteine and cholesterol metabolism is not readily apparent. The strong relation between tHcy and cholesterol should remind us that covariations certainly do not prove causality.

Thyroid status has a profound influence on a variety of biochemical processes (6, 7, 8), of which some may have secondary effects on homocysteine metabolism. For example, thyroid hormones markedly affect riboflavin metabolism, mainly by stimulating flavokinase and thereby the synthesis of flavin mononucleotide and flavin adenine dinucleotide (FAD; Refs. 7 and 8). Conceivably, these metabolic changes may affect homocysteine metabolism, because flavin mononucleotide and FAD serve as cofactors for enzymes involved in the metabolism of vitamin B6, cobalamin, and folate (9). Among these enzymes, the FAD-dependent methylenetetrahydrofolate reductase should be considered, because this enzyme is recognized as a possible mediator of changes in tHcy level according to riboflavin status (9).

In conclusion, the nice study of Barbé et al. provides longitudinal data in a large number of patients and brings strong support that thyroid status is an important determinant of plasma tHcy and affects serum folate levels. However, the question of the mechanism(s) behind hyperhomocysteinemia in hypothyroid patients remains to be elucidated.

Received January 22, 2001.

Accepted November 14, 2000.

References

  1. Nedrebø B, Ericsson U-B, Ueland PM, Refsum H, Lien EA. 1994 Plasma levels of the atherogenic amino acid homocysteine in hyper- and hypothyroid patients. Eur J Clin Endocrinol. 130(Suppl 2):47.
  2. Nedrebø BG, Ericsson U-B, Nygård O, et al. 1998 Plasma levels of the atherogenic amino acid homocysteine in hyper- and hypothyroid patients. Metabolism. 47:89–93.[Medline]
  3. Catargi B, Parrot-Roulaud F, Cochet C, Ducassou D, Roger P, Tabarin A. 1999 Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid. 9:1163–1166.[Medline]
  4. 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]
  5. Lien EA, Nedrebø BG, Varhaug JE, Nygård 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]
  6. Danforth Jr E. 1983 The role of thyroid hormones and insulin in the regulation of energy metabolism. Am J Clin Nutr. 38:1006–1017.[Abstract]
  7. Lee SS, McCormick DB. 1985 Thyroid hormone regulation of flavocoenzyme biosynthesis. Arch Biochem Biophys. 237:197–201.[Medline]
  8. Rivlin RS. 1979 Hormones, drugs and riboflavin. Nutr Rev. 37:241–245.[Medline]
  9. Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjørke-Monsen AL, Schneede J. 2000 Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem. 46:1065–1071.[Abstract/Free Full Text]




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