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Normalization of Hyperhomocysteinemia with L-thyroxine in Hypothyroidism

Wiam I. Hussein, MD; Ralph Green, MD; Donald W. Jacobsen, PhD; and Charles Faiman, MD
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From The Cleveland Clinic Foundation, Cleveland, Ohio, and the University of California, Davis, Davis, California.

Presented in part at the Seventh Annual Meeting of the American Association of Clinical Endocrinologists, Orlando, Florida, April 1998, and the Second International Conference on Homocysteine Metabolism, Nijmegen, the Netherlands, April 1998.

Acknowledgments: The authors thank S.S. Reddy, MD, for recruiting patients and for support for the study; Jacob Selhub, PhD, Tufts University, for kindly doing the vitamin B6 assays; and Jeff Hammel for statistical analysis and advice.

Grant Support: By a research grant (Research Program Council #5669) from The Cleveland Clinic Foundation and grant HL52234 from the National Institutes of Health (Dr. Jacobsen).

Requests for Reprints: Charles Faiman, MD, Department of Endocrinology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk A30, Cleveland, OH 44195; e-mail, faimanc1@cesmtp.ccf.org.

Current Author Addresses: Dr. Hussein: Saad Medical Center, PO Box 1991, Alkhobar, 31952, Saudi Arabia.

Dr. Green: Department of Pathology, University of California, Davis, Medical Center, 4400 V Street, Sacramento, CA 95817.

Dr. Jacobsen: Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, NC10, Cleveland, OH 44195.

Dr. Faiman: Department of Endocrinology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk A30, Cleveland, OH 44195.

Ann Intern Med. 1999;131(5):348-351. doi:10.7326/0003-4819-131-5-199909070-00005
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Background: Hyperhomocysteinemia is an independent risk factor for coronary, peripheral, and cerebrovascular disease. Elevated plasma homocysteine levels were described in a preliminary report on primary hypothyroidism.

Objective: To determine whether restoration of euthyroidism by L-thyroxine replacement therapy would reduce or normalize plasma homocysteine levels.

Design: Prospective cohort study.

Setting: Outpatient endocrinology department of a tertiary center.

Patients: 14 patients (10 women and 4 men; 25 to 77 years of age): 4 with newly diagnosed chronic (Hashimoto) hypothyroidism and 10 who had been rendered acutely hypothyroid (thyroid-stimulating hormone level > 25 mU/L) by total thyroidectomy for thyroid carcinoma.

Measurements: Total plasma homocysteine levels were measured at baseline and 3 to 9 months later, after euthyroidism had been attained by L-thyroxine replacement therapy.

Results: Median baseline plasma homocysteine levels in both sexes (women, 11.65 µmol/L [range, 7.2 to 26.5 µmol/L]; men, 15.1 µmol/L [range, 14.1 to 16.3 µmol/L]) were higher (P = 0.002) than those in healthy female (n = 35) and male (n = 36) volunteers (women, 7.52 µmol/L [range, 4.3 to 14.0 µmol/L]; men, 8.72 µmol/L [range, 5.94 to 14.98 µmol/L]). Eight patients (57%) had baseline plasma homocysteine levels that exceeded the upper limit of sex-specific reference ranges. Upon attainment of euthyroidism, all patients had a diminution in plasma homocysteine levels. The median overall change of −5.5 µmol/L (range, −15.4 to −1.8 µmol/L) corresponds to a difference of −44% (range, −58% to −13%) (P < 0.001). Homocysteine levels returned to normal in 7 of the 8 patients with elevated pretreatment values.

Conclusions: Hypothyroidism may be a treatable cause of hyperhomocysteinemia, and elevated plasma homocysteine levels may be an independent risk factor for the accelerated atherosclerosis seen in primary hypothyroidism.


Grahic Jump Location
Figure 1.
Vitamin interactions in the remethylation and the transsulfuration pathways of homocysteine metabolism.12CH 3 THFMS6CBS3

Vitamin B and folic acid, as 5-methyltetrahydrofolate ( ), are required for methionine synthase ( )-dependent remethylation of homocysteine. Vitamin B is required for cystathionine β-synthase ( ) activity and the conversion of cystathionine to cysteine in the transsulfuration pathway. DMG = dimethylglycine; S = substrate; SAH = S-adenosylhomocysteine; SAM = S-adenosylmethionine; SCH = methylated substrate; THF = tetrahydrofolate.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Total plasma homocysteine levels by thyroid status and sex before and after normalization of thyroid-stimulating hormone levels byl-thyroxine replacement therapy.P

Dashed lines indicate the reference ranges (mean ± 2 SDs). The overall decline in median total plasma homocysteine levels was statistically significant ( < 0.001).

Grahic Jump Location




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