In the present study, we found that TC, HDL-C, LDL-C, and TG values in the HO group were significantly higher than those in the SHO and control groups. The plasma Hcy levels were also significantly higher in the HO group than in the SHO group and controls. After adjusting for sex, BMI, FT4, and FBG, a significant positive correlation was observed between the Hcy and LDL-C levels in the HO group. We found that a decrease in the Hcy was positively correlated with a decreased in the LDL-C.
In patients with HO, increased Hcy levels may result from 2 mechanisms; increased Hcy formation or decreased renal Hcy clearance due to the direct effects of thyroid hormones on the Hcy metabolism in the liver and clearance by the kidney. Many studies have proven that the plasma Hcy level is an independent risk factor for CAD because it induces endothelial injury, oxidative stress, smooth muscle hypertrophy, and oxidation of LDL-C.[18,19] Our previous study also demonstrated that Hcy might act as an atherogenic factor by promoting the production of chemokines, reactive oxygen species, and oxidized LDL-C, thus enhancing the progression of cardiovascular disease. In HO patients, the plasma Hcy levels were 17.93 ± 6.86 μmol/L. We have previously shown that coronary flow velocity reserve were impaired when Hcy > 15 μmol/L. A population-based prospective cohort study (mean follow-up, 5.3 years) was conducted by Nurk et al, which showed that Hcy was a strong predictor of cardiovascular disease (CVD) in elderly individuals. The study also demonstrated that at baseline, participants with preexisting had higher mean Hcy values than individuals without CVD. Furthermore, multiple risk factor-adjusted CVD hospitalization rate ratios in 5 Hcy categories (<9, 9–11.9, 12–14.9, 15–19.9, and ≥20 μmol/L) were as follows: 1 (reference level), 1.00, 1.34, 1.67, and 1.94, respectively (P < 0.001). The study by Nakano et al suggested that an elevated plasma Hcy level might promote LDL-C nitration and increased scavenger receptor uptake, providing a molecular mechanism that may contribute to CAD. Elevated LDL-C levels may be partly responsible for the high risk of cardiovascular disease associated with HO. This suggests that the total serum Hcy levels might be correlated with the LDL-C level in patients with HO. In this study, we provide data showing a positive correlation between Hcy and LDL-C in patients with HO.
In the present study, the serum TC, HDL-C, LDL-C, and TG levels were significantly higher in patients with HO compared with the SHO and control groups (Table 1, P < 0.05). In our observations, the subjects in the HO group had higher Hcy and LDL-C levels than the subjects in the SHO and control groups. Our results were consistent with the findings of previous studies,[23–26] but were not in agreement with those reported by Orzechowska-Pawilojc et al, who observed that the Hcy levels were nonsignificantly higher in patients with HO compared to healthy subjects. In HO patients, we found that the Hcy levels were positively correlated with the LDL-C level after adjustment for sex, BMI, FT4, and FBG. We observed a higher prevalence of dyslipidemia in HHcy patients. These data are consistent with previous studies that have reported that the enhanced atherosclerosis in hyperhomocysteinemic patients might be partly attributable to Hcy-related LDL-C atherogenicity. We acknowledged the statistical limitations of the study due to the small sample size. All HO should be treated. After the exclusion of 30 patients who were lost to follow-up, 45 of the HO patients experienced L-T4 treatment. L-T4 treatment significantly reduced the BMI, TC, HDL-C, LDL-C, TG, Hcy, and ApoB in our patients. In accordance with our results, Orzechowska-Pawilojc et al also reported a significant decrease in the Hcy levels following L-T4 treatment in women with HO. Thyroid hormone replacement is a routine and conventional clinical practice for patients with HO and has been shown to ameliorate the lipid profiles in patients with atherosclerosis.[29,30] In addition, we found that the decreased Hcy levels positively correlated with decreased LDL-C. The significant improvements in the Hcy and LDL-C levels might be due to the presence of positive mutual interactions.
Dyslipidemia, consisting of high levels of total and LDL cholesterol, is a common finding in patients with HO and SHO. Hcy stimulates the production and secretion of cholesterol by hepatic cells; this may contribute to the association between cholesterol and Hcy observed in the present study. Elevated Hcy levels promote the synthesis of several proinflammatory cytokines in the arterial walls and circulating cells. Our previous studies indicated that the coronary artery endothelial function might be impaired in essential hypertensive patients with HHcy; furthermore, chronic HHcy might contribute to CAD by inducing dysfunction of the coronary artery endothelium. The uncoupling of endothelial nitric oxide synthase (eNOS) induced by HHcy might at least partly explain this adverse effect. Our previous studies also found that the LDL-C level inversely correlated with the coronary flow velocity reserve in patients with Type 2 diabetes. In agreement with the observations made by Engin et al, HO was associated with both systemic oxidative stress and with specific morphological changes in endothelial cells, which are believed to represent very early stages of atherosclerosis.
HHcy may contribute to cardiovascular risk by increasing the LDL-C level and promoting LDL-C recruitment into atherosclerotic plaques. In addition to reducing the plasma levels of Hcy, L-T4 treatment exerts beneficial effects on patients with HO by improving dyslipidemia, such as by decreasing the LDL-C level. On the contrary, studies of subjects with cerebrovascular disease in the Vitamin Intervention for Stroke Prevention (VISP) trial, cardiovascular disease in the Norwegian Vitamin Trial (NORVIT) and Heart Outcomes Prevention Evaluation (HOPE2) trials,[40,41] and vascular disease from chronic renal failure in the HOST trial showed no reduction in stroke or heart attack or improvement in mortality from B vitamin intervention.
Our results suggest that an increased Hcy level is positively correlated with the LDL-C level in HO patients. A potential harmful correlation may exist between Hcy and LDL-C under the condition of HO. In addition to reducing the plasma levels of Hcy, L-T4 treatment exerts beneficial effects on patients with HO by improving dyslipidemia, such as by decreasing the LDL-C level.
We thank the editorial assistance of the NIH Fellows Editorial Board for modifying our manuscript.
1. Jaskanwal DS, Ming Z, Hossein G, et al Hypothyroidism
is associated with coronary endothelial dysfunction in women. J Am Heart Assoc
2. Jones DD, May KE, Geraci SA. Subclinical thyroid disease. Am J Med
3. Cappola AR, Ladenson PW. Hypothyroidism
and atherosclerosis. J Clin Endocrinol Metab
4. Suh S, Kim DK. Subclinical hypothyroidism
and cardiovascular disease. Endocrinol Metab (Seoul)
5. Morris MS, Bostom AG, Jacques PF, et al Hyperhomocysteinemia
and hypercholesterolemia associated with hypothyroidism
in the third US National Health and Nutrition Examination Survey. Atherosclerosis
6. Staels B, Van Tol A, Chan L, et al Alterations in thyroid status modulate apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in. Endocrinology
7. Nakano E, Taiwo FA, Nugent D, et al Downstream effects on human low density lipoprotein of homocysteine exported from endothelial cells in an in vitro system. J Lipid Res
8. Ichiki T. Thyroid hormone and atherosclerosis. Vascul Pharmacol
9. Saeed S, Faramarz F, Mojtaba S, et al Homocysteine, vitamin B12 and folate levels in premature coronary artery disease. BMC Cardiovasc Disord
10. Wang H, Jiang X, Yang F, et al Hyperhomocysteinemia
accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood
11. Li Y, Zhang H, Jiang C, et al Hyperhomocysteinemia
promotes insulin resistance by inducing endoplasmic reticulum stress in adipose tissue. J Biol Chem
12. He L, Zeng H, Li F, et al Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia
. Am J Physiol Endocrinol Metab
13. Hein WH, Kuo L. LDLs impair vasomotor function of the coronary microcirculation: role of superoxide anions. Circ Res
14. Yokoyama I, Ohtake T, Momomura S, et al Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circulation
15. Garber JR, Cobin RH, Gharib H, et al Clinical practice guidelines for hypothyroidism
in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract
16. Nyga[Combining Ring Above]rd O, Nordrehaug JE, Refsum H, et al Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med
17. Orzechowska-Pawiłojć A, Lewczuk A, Sworczak K. The influence of thyroid hormones on homocysteine and atherosclerotic vascular disease. Endokrynol Pol
18. Cui R, Moriyama Y, Koike KA, et al Serum total homocysteine concentrations and risk of mortality from stroke and coronary heart disease in Japanese: the JACC study. Atherosclerosis
19. Medina M, Urdiales JL, Amores-Sánchez MI. Roles of homocysteine in cell metabolism: old and new functions. Eur J Biochem
20. Wang G, Mao JM, Wang X, et al Effect of homocysteine on plaque formation and oxidative stress in patients with acute coronary syndromes. Chin Med J (Engl)
21. Liu J, Xu Y, Zhang H, et al Coronary flow velocity reserve is impaired in hypertensive patients with hyperhomocysteinemia
. J Hum Hypertens
22. Nurk E, Tell GS, Vollset SE, et al Plasma total homocysteine and hospitalizations for cardiovascular disease: the Hordaland Homocysteine Study. Arch Intern Med
23. Gunduz M, Gunduz E, Kircelli F, et al Role of surrogate markers of atherosclerosis in clinical and subclinical thyroidism. Int J Endocrinol
24. Ozmen B, Ozmen D, Parildar Z, et al Impact of renal function or folate status on altered plasma homocysteine levels in hypothyroidism
. Endocr J
25. Diekman MJ, van der Put NM, Blom HJ, et al Determinants of changes in plasma homocysteine in hyperthyroidism and hypothyroidism
. Clin Endocrinol (Oxf)
26. Lien EA, Nedreb⊘ BG, Varhaug JE, et al Plasma total homocysteine levels during short-term iatrogenic hypothyroidism
. J Clin Endocrinol Metab
27. Orzechowska-Pawilojc A, Sworczak K, Lewczuk A, et al Homocysteine, folate and cobalamin levels in hypothyroid women before and after treatment. Endocr J
28. Yun J, Kim JY, Kim OY, et al Associations of plasma homocysteine level with brachial-ankle pulse wave velocity, LDL atherogenicity, and inflammation profile in healthy men. Nutr Metab Cardiovasc Dis
29. Danese MD, Ladenson PW, Meinert CL, et al Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab
30. Wiersinga WM. Thyroid hormone replacement therapy. Horm Res
2001; 56 (suppl 1):74–81.
31. Karmin O, Lyme EG, Chung YH, et al Homocysteine stimulates the production and secretion of cholesterol in hepatic cells. Biochem Biophys Acta
32. Catena C, Colussi G, Nait F, et al Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens
33. Engin AB, Sepici-Dincel A, Gonul II, et al Oxidative stress-induced endothelial cell damage in thyroidectomized rat. Exp Toxicol Pathol
34. Jie Y, Jiang LH, Li YH, et al Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes. J Geriatr Cardiol
35. Saleh AAS. Lipid profile and levels of homocysteine and total antioxidant capacity in plasma of rats with experimental thyroid disorders. J Basic Appl Zool
2015; 72:173–178.doi: 10.1016/j.jobaz.2015.01.001.
36. Bamashmoos SA, Al-Nuzaily MA, Al-Meeri AM, et al Relationship between total homocysteine, total cholesterol and creatinine levels in overt hypothyroid patients. Springerplus
37. Naruszewicz M, Mirkiewicz E, Olszewski AJ, et al Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages. Nutr Metab Cardiovas Dis
38. Ravnskov U, McCully KS. Vulnerable plaque formation from obstruction of vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. Ann Clin Lab Sci
39. Toole JF, Malinow MR, Chambless LE, et al Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA
40. Bonaa KH, Njolstad I, Ueland PM, et al Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med
41. Lonn E, Yusuf S, Malcolm JA, et al Homocysteine lowering with folic acid and B vitamins in vascular disease. The Heart Outcomes Prevention Evaluation (HOPE2) Investigators. N Engl J Med
42. Jamison RL, Hartigan P, Kaufman JS, et al Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal. Disease: a randomized controlled trial. JAMA