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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2007 Dec 11;93(3):888–894. doi: 10.1210/jc.2007-1987

Thyroid Function and Lipid Subparticle Sizes in Patients with Short-Term Hypothyroidism and a Population-Based Cohort

Elizabeth N Pearce 1, Peter W F Wilson 1, Qiong Yang 1, Ramachandran S Vasan 1, Lewis E Braverman 1
PMCID: PMC2266946  PMID: 18073305

Abstract

Context: Relations between thyroid function and lipids remain incompletely understood.

Objective: Our objective was to determine whether lipoprotein subparticle concentrations are associated with thyroid status.

Design and Setting: We conducted a prospective clinical study and cross-sectional cohort analysis at a university endocrine clinic and the Framingham Heart Study.

Subjects: Subjects included 28 thyroidectomized patients with short-term overt hypothyroidism and 2944 Framingham Offspring cohort participants.

Main Outcome Measures: Fasting subclass concentrations of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) particles were measured by nuclear magnetic resonance spectroscopy. TSH values were also measured.

Results: Total cholesterol and LDL-C were increased during short-term overt hypothyroidism. Large LDL subparticle concentrations increased during hypothyroidism (917 ± 294 vs. 491 ± 183 nmol/liter; P < 0.001), but more atherogenic small LDL was unchanged. Triglycerides marginally increased during hypothyroidism, small VLDL particles significantly increased (P < 0.001), whereas more atherogenic large VLDL was unchanged. Total HDL-C increased during hypothyroidism (76 ± 13 mg/dl vs. 58 ± 15 mg/dl; P < 0.001). There was no change in large HDL-C particle concentrations, whereas small (P < 0.001) and medium (P = 0.002) HDL-C particle concentrations decreased. Among Framingham women, adjusted total cholesterol and LDL-C were positively related to TSH categories (P ≤ 0.003). This was due to a positive correlation between adjusted large LDL subparticle concentrations and log-TSH (P < 0.0001); log small LDL subparticle concentrations decreased slightly as log-TSH increased (P = 0.045). Among Framingham men, the only significant association was a positive association between log-TSH and log large HDL subparticle concentrations (P = 0.04).

Conclusions: There is a shift toward less atherogenic large LDL, small VLDL, and large HDL subparticle sizes in hypothyroid women.

In hypothyroid women, there are increases in less atherogenic large low density lipoprotein, small very low density lipoproteins, and large high density lipoprotein subparticle concentrations.

Relations between thyroid function and lipid status remain incompletely understood. Hypothyroidism is relatively common in the U.S. population. In the third National Health and Nutrition Survey (1988–1994), hypothyroidism was present in 4.6% of the population (overt in 0.3% and subclinical in 4.3%) (1). Serum TSH levels higher than 5 mU/liter, consistent with at least mild hypothyroidism, were present in 10.3% of individuals over age 60 from the original cohort of the Framingham Heart Study, with a higher incidence in women (13.6%) than in men (5.7%) (2).

Both overt and subclinical hypothyroidism have been associated with elevated serum lipid concentrations. Elevated serum TSH levels were noted in 9.5% of 25,862 participants in a statewide health fair, 95% of whom had normal serum T4 values, consistent with subclinical hypothyroidism (3). There was a statistically significant gradual increase in fasting total cholesterol, triglyceride, and low-density lipoprotein cholesterol (LDL-C) concentrations as thyroid function declined, including among those with serum TSH values of 5–10 mU/liter.

High concentrations of small, dense LDL-C particles as measured by nuclear magnetic resonance (NMR) spectroscopy are associated with coronary heart disease in multiple cross-sectional and prospective studies (4,5,6). In addition, evidence suggests that high concentrations of large-sized very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) and the two smallest subclasses of high-density lipoprotein cholesterol (HDL-C) may be associated with increased cardiovascular risk (4,5,7). No previous reports have examined the relationship between NMR lipid subparticle concentration and thyroid function. The objective of the present study was to determine whether fasting serum lipoprotein subparticle concentrations vary according to thyroid functional status. We measured lipid subparticle concentrations in patients with short-term overt hypothyroidism both before and after thyroid hormone replacement. To examine the effects of more subtle TSH abnormalities, we also examined the cross-sectional relationship of serum TSH and lipid subparticle concentrations in a large unselected sample, the Framingham Offspring cohort.

Subjects and Methods

Clinical study participants

This sample consisted of 28 patients with differentiated thyroid cancer, mean (± sd) age 45 ± 15 yr, recruited from the Endocrinology Clinic at Boston University Medical Center between December, 2003, and May, 2006. Twenty-five participants were women. After total or near-total thyroidectomy, thyroid hormone therapy (Liothyronine) was withdrawn for 2–3 wk in preparation for radioactive iodine ablation, resulting in overt hypothyroidism. For 10–14 d during their thyroid hormone withdrawal, patients were instructed to maintain a low-iodine diet. TSH values and lipid measurements were obtained after a 12-h fast at baseline, when patients were overtly hypothyroid, and again after resumption of treatment with thyroid hormone, a mean of 148 ± 171 d (range, 40–928 d) after the initial blood draw.

Population study participants

Beginning in 1948, 5209 men and women aged 28–62 yr were enrolled in the Framingham Heart Study as previously described (8). Starting in 1971, 5124 offspring and spouses of offspring were enrolled into the Framingham Offspring Study. Offspring participants underwent examinations approximately every 4 yr; the design and methods have been previously described (9). Individuals included in this study were drawn from the 3523 participants in the Framingham Offspring Study who had frozen plasma available from examination cycle 4 (1987–1990). Sixty participants were excluded because of missing NMR lipoprotein value determinations, and 322 participants were excluded because of missing TSH values. Participants with triglyceride levels more than 400 mg/dl (n = 72) were excluded because of the unreliability of LDL-C and NMR-measured VLDL subclass measurements in this setting. Those taking lipid-lowering medications (n = 125) were excluded. The final sample consisted of 1532 men and 1412 women (mean age 51 ± 10 yr).

Research protocols for both the clinical and population studies were approved by the Boston Medical Center institutional review board. Written informed consent was obtained from all participants.

Laboratory measurements

Clinical study

After a 12-h fast, blood was collected from participants and spun within 2 h. Plasma was stored at −70 C. TSH values for the clinical study participants were measured at Boston Medical Center by chemiluminescence assay on the Bayer Advia Centaur (reference range 0.35–5.50 mU/liter; Bayer Diagnostics, Tarrytown NY). All lipid measurements were performed at Liposcience, Inc. (Raleigh, NC). Concentrations of lipid subparticles were measured using NMR spectroscopy (10). Measurement of total cholesterol, HDL-C, direct LDL-C, and triglyceride concentrations was performed by enzymatic methods (Beckman Synchron CX-4 System, Fullerton, CA).

Population study

Serum TSH values were measured in 1990–1991 using a chemiluminescence assay (reference range 0.51–5.0 mU/liter; London Diagnostics, Eden Prairie, MN). All lipid measurements were obtained after a 12-h fast. Specimens were frozen at −70 C for 6–10 yr until measurements were obtained. Cholesterol, HDL-C, and triglycerides were measured by enzymatic methods (Abbot Diagnostics ABA-200, Abbott Park, IL). LDL-C levels were calculated using the Friedewald equation (11). Aliquots of EDTA plasma were shipped on dry ice to LipoMed, Inc. (Raleigh, NC), for NMR lipoprotein subclass analysis (10). According to LipoMed, freezing does not adversely affect fasting NMR lipoprotein results as long as hypertriglyceridemia is not present. The NMR subparticle size data from examination cycle 4, for which samples were stored frozen for 6–10 yr before measurement, are considered by the Framingham Heart Study investigators to be robust and have been used in multiple other Framingham publications.

Statistical analysis

Clinical study

Lipid subparticle classes were categorized as large, medium, and small VLDL; IDL; large, medium, and small LDL; and large, medium, and small HDL. Paired t tests were used to compare mean lipid concentrations and lipid subparticle concentrations during thyroid hormone withdrawal and after thyroid hormone resumption. P values < 0.05 were considered significant.

Population study

TSH was analyzed both as a log-transformed continuous variable and as a categorical variable (TSH < 0.5, 0.5–2.5, 2.5–5, and >5.0 mU/liter). VLDL, HDL, and LDL subclasses were each categorized as large, medium, and small. The large and medium VLDL, IDL, medium LDL, small LDL, and large HDL subparticle concentrations were logarithmically transformed because of nonnormality of the data. Sex-stratified analysis of covariance was used to determine whether each lipid variable differed across the four TSH categories, adjusting for the following covariates known to affect serum lipid profiles: age, body mass index, systolic blood pressure, use of antihypertensive medications, presence or absence of diabetes mellitus, and smoking status. Because small LDL subparticle concentrations are positively correlated with serum triglyceride values and inversely correlated with HDL-C values, the analysis was also adjusted for total HDL-C and total triglyceride concentrations. Diabetes was defined as fasting blood glucose of at least 126 mg/dl and/or the use of oral hypoglycemic medications or insulin. Participants were classified as smokers if they reported any cigarette smoking during the 12 months before their cycle 4 examination. Menopausal status and use of estrogen replacement therapy was also considered as a covariate in women. Multiple linear regression was used to determine whether log TSH was associated with each lipid variable.

A two-tailed P value of <0.05 was considered significant. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC) and Microsoft Excel. Values are reported as mean ± sd.

Results

Clinical study

At baseline (hypothyroid), the mean TSH value was 80.7 ± 33.5 mU/liter (range, 23.3–154.4 mU/liter) (Table 1). After resumption of l-T4, the mean TSH value was 0.7 ± 1.3 mU/liter (range, <0.01–5.6 mU/liter; 16 of the 28 patients had TSH values < 0.35 mU/liter). Total cholesterol and LDL-C were markedly increased when patients were hypothyroid (284 ± 52 vs. 181 ± 39 mg/dl and 171 ± 39 vs. 98 ± 24 mg/dl, respectively; P < 0.001). The increase in LDL-C during hypothyroidism was primarily due to increases in the concentration of less atherogenic large LDL particles (917 ± 294 vs. 491 ± 183 nmol/liter; P < 0.001) (Fig. 1).

Table 1.

Mean laboratory values for clinical study participants during hypothyroidism and then after resumption of thyroid hormone therapy

Measurement Mean during thyroid hormone withdrawal (mean ± sd), n = 28 Mean after thyroid hormone resumption (mean ± sd), n = 28 P value (paired t test)
TSH (mU/liter) 73 ± 31 0.74 ± 1.3 <0.001
Total cholesterol (mg/dl)a 284 ± 52 181 ± 39 <0.001
Direct LDL-C (mg/dl)a 171 ± 39 98 ± 24 <0.001
Triglycerides (mg/dl)a 160 ± 142 102 ± 64 0.04
HDL-C (mg/dl)a 76 ± 13 58 ± 15 <0.001
Large VLDL subparticles (nmol/liter) 2.4 ± 3.1 2.1 ± 3.1 0.4
Medium VLDL subparticles (nmol/liter) 36 ± 24 19 ± 12 <0.001
Small VLDL subparticles (nmol/liter) 79 ± 30 39 ± 19 <0.001
IDL subparticles (nmol/liter) 107 ± 90 41 ± 35 <0.001
Large LDL subparticles (nmol/liter) 917 ± 294 491 ± 183 <0.001
Medium LDL subparticles (nmol/liter) 91 ± 137 95 ± 70 0.9
Small LDL subparticles (nmol/liter) 420 ± 583 370 ± 269 0.6
Large HDL subparticles (nmol/liter) 8.7 ± 3.6 8.1 ± 4.3 0.4
Medium HDL subparticles (nmol/liter) 1.3 ± 2.2 3.8 ± 4.2 0.002
Small HDL subparticles (nmol/liter) 17 ± 6 21 ± 6 <0.001
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a

To convert mg/dl into mmol, multiply total cholesterol, LDL-C, and HDL-C values by 0.0259 and multiply values for triglycerides by 0.0113. 

Figure 1.

Figure 1

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FIG. 1. LDL subparticle concentrations during thyroid hormone withdrawal and after resumption of thyroid hormone in the clinical study. The mean total LDL-C concentration was 171 mg/dl during hypothyroidism and 98 mg/dl after thyroid hormone replacement.

Population study

The mean TSH was 2.1 ± 2.0 mU/liter for men and 2.4 ± 3.7 for women. The prevalence of serum TSH categories by gender is summarized in Table 2.

Table 2.

Prevalence of TSH categories at the Framingham Offspring Study cohort examination cycle 4 (1987–1990)

TSH category Prevalence, n (%)
Men Women Total
<0.5 mU/liter 37 (2) 95 (5) 132
0.5–2.5 mU/liter 1400 (76) 1316 (73) 2716
2.5–5.0 mU/liter 349 (19) 278 (16) 627
>5.0 mU/liter 57 (3) 105 (6) 162
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There were statistically significant differences in adjusted mean total cholesterol values across TSH categories in men (P = 0.004) and in women (P < 0.001) (Table 3). Similarly, there were significant differences in adjusted mean LDL-C across TSH categories in men (P = 0.02) and in women (P = 0.003). Mean HDL-C values in men and women did not differ by TSH category. There were significant differences in mean triglyceride values across TSH categories in men (P = 0.002) but not in women.

Table 3.

Adjusted mean lipid concentrations by TSH categories in men and women from the Framingham Offspring Study cohort at examination cycle 4 (1987–1990)

Lipid measurement (mg/dl) TSH < 0.5 mU/liter TSH 0.5–2.5 mU/liter TSH 2.5–5.0 mU/liter TSH > 5 mU/liter P value for difference across TSH categories (ANCOVA)
Men
 Total cholesterol 203 203 211 207 0.004
 Calculated LDL-C 131 133 140 139 0.02
 HDL-C 43 44 43 44 0.5
 Triglycerides 136 112 126 111 0.002
Women
 Total cholesterol 190 206 205 220 <0.001
 Calculated LDL-C 114 125 126 137 0.003
 HDL-C 58 57 57 58 0.9
 Triglycerides 89 99 97 106 0.3
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Lipid concentrations are adjusted for age, body mass index, systolic blood pressure, use of antihypertensive medications, presence or absence of diabetes mellitus, and smoking status, and for women, also menopausal status and use of estrogen replacement therapy. ANCOVA, Analysis of covariance. 

There was a significant positive association between adjusted large LDL subparticle concentrations and log-transformed serum TSH values (P < 0.0001) and a similar trend toward increasing less atherogenic large LDL subparticle concentrations across increasing TSH categories (P = 0.004) in women (Table 4). Adjusted log-transformed small, more atherogenic, LDL subparticle concentrations were inversely related to log TSH (P = 0.045) in women, and a similar trend was seen when TSH was considered as a categorical variable (P = 0.03). After adjustment, there were significant positive associations between log TSH and small VLDL subparticle concentrations (P = 0.008) as well as log-transformed large HDL subparticle concentrations (P = 0.009) in women; however, these associations were not significant when TSH was considered as a categorical variable. Log-transformed medium VLDL subparticle concentrations were inversely associated with log TSH in women (P = 0.01), but this association was not significant when TSH was considered as a categorical variable. There were no associations between log TSH values or TSH categories and IDL concentrations, medium LDL subparticle concentrations, log-transformed large VLDL subparticle concentrations, or small or medium HDL subparticle concentrations in women. In men, medium LDL subparticle concentrations differed across TSH categories (P = 0.04), but there was no association between log TSH and medium LDL subparticle concentrations when TSH was considered as a continuous variable (P = 0.2). In adjusted models, there was a significant positive association between log TSH and log-transformed large HDL subparticle concentrations (P = 0.04). There were no other significant associations between lipid subparticle concentrations and serum TSH values in men.

Table 4.

Lipid subparticles and log-TSH in women from the Framingham Offspring Study cohort at examination cycle 4 (1987–1990)

Lipid subparticle (nmol/liter) β-Coefficienta Standard error of β P value for multiple linear regression
Log large VLDL −0.009 0.015 0.6
Log medium VLDL −0.032 0.013 0.01
Small VLDL 1.27 0.47 0.008
Log IDL 0.020 0.017 0.2
Large LDL 5.51 1.23 <0.0001
Log medium LDL 0.031 0.024 0.2
Log small LDL −0.049 0.024 0.05
Log large HDL 0.029 0.011 0.009
Medium HDL −0.27 0.23 0.3
Small HDL −0.18 0.17 0.3
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a

For the increment in lipid or log-lipid measure for a 1-U increase in log-TSH, adjusted for age, body mass index, systolic blood pressure, use of antihypertensive medications, presence or absence of diabetes mellitus, smoking status, total HDL and total triglyceride concentrations, menopausal status, and use of estrogen replacement therapy. 

Discussion

Many epidemiological studies have examined the associations between thyroid status and serum lipid concentrations (12,13), the largest being the Colorado Thyroid Disease Prevalence Study, which found statistically significant, gradual increases in fasting total cholesterol, LDL-C, and triglyceride levels as thyroid function declined (3). Effects of overt hypothyroidism on HDL-C concentrations have been variable in previous studies, some studies showing increased HDL-C values, some normal values, and others decreased values (14,15,16). No effect of thyroid status on HDL-C concentrations was noted in the Colorado study (3).

There are several known mechanisms for the observed effect of thyroid status on lipid concentrations. In overt hypothyroidism, lipid synthesis is actually decreased (12). However, because the number of LDL receptors expressed in fibroblasts, liver, and other tissues is decreased to an even greater extent, LDL-C accumulates in the serum (13). Concentrations of cholesteryl ester transfer protein, which transfers cholesterol from HDL-C to LDL-C and VLDL, are increased by thyroid hormone (17). Thyroid hormone also appears to regulate hepatic lipase, which alters HDL-C subfractions. The activity of lipoprotein lipase, which lowers triglyceride levels through hydrolysis of triglyceride-enriched lipoproteins and facilitation of cholesterol transfer from these lipoproteins to HDL-C, is increased by thyroid hormone (18). Finally, thyroid hormone increases expression of the HDL-C receptor scavenger receptor class-B, type I (SR-BI) (19).

It has been postulated that subclinical and overt hypothyroidism would increase the risk for cardiovascular disease, due to reported associations between hypothyroidism and hyperlipidemia as well as potential associations with other cardiovascular risk factors such as abnormal endothelial reactivity, enhanced LDL oxidation, inflammation, and hyperhomocysteinemia (20,21). However, results of prospective studies have been inconsistent (22,23,24,25,26,27,28). Recent metaanalyses have concluded that subclinical hypothyroidism is associated with an increased risk for coronary heart disease (29) and with circulatory, but not all-cause, mortality (30,31).

Lipid subparticle concentrations, as well as total serum lipid values, are related to cardiovascular risk. Small, dense LDL are particularly atherogenic because particles are more concentrated in arterial walls, more prone to oxidation, and have a reduced affinity for LDL receptors compared with larger LDL particles (32). Small, dense LDL subparticles measured by analytical and density gradient ultracentrifugation, chromatography, and gradient gel electrophoresis, have been associated with significantly increased cardiovascular risk in cross-sectional and prospective studies (33). Although not universally accepted (34), the concentration of small LDL subparticles when measured by NMR has been associated with an increase in cardiovascular risk even in multivariate analyses and does appear to be an independent cardiovascular risk factor (4,5,6,32). Evidence also suggests that high concentrations of large-sized VLDL and IDL and the two smallest subclasses of HDL-C as measured by NMR may be associated with increased cardiovascular risk (4,5,7).

In the present clinical study, total cholesterol and LDL-C levels were higher in overtly hypothyroid patients, and levels were greater across increasing TSH categories in the Framingham cohort. Importantly, the increase in LDL-C in hypothyroidism is due to increases in less atherogenic large LDL subparticle concentrations, a finding that was strongly significant and consistent across both the patients with short-term hypothyroidism and the women from the Framingham Offspring study. There was no change in the more atherogenic small or medium LDL subparticle concentrations during overt hypothyroidism in the clinical study, and among women in the population study, small LDL subparticles were inversely related to serum TSH.

Only two previous studies have examined the effects of thyroid function on LDL subparticle size. Roscini et al. (35) found no significant difference in LDL size, as measured by gel electrophoresis, in 50 overtly hypothyroid postmenopausal women before and after l-T4 treatment. These results may have differed from the present study because of the different methodology used for measurement of LDL subparticles. Ozcan et al. (36) demonstrated that small, dense LDL particle concentrations (measured by precipitation and centrifugation) were significantly lower in 84 untreated women with subclinical hypothyroidism than in euthyroid controls; levels were normalized after l-T4 therapy. Interestingly, it has been demonstrated that oxidizability of LDL-C is increased in overt hypothyroidism (37,38). Although LDL oxidation was not measured in the present study, the finding that LDL subparticle size increases in hypothyroidism suggests that increased LDL oxidation in hypothyroidism is unlikely to be related to LDL subparticle size.

Increased IDL levels and normal to increased levels of triglyceride and VLDL have previously been reported in overt hypothyroidism (39). In our clinical study, triglyceride levels were increased in overtly hypothyroid participants. There was a nonsignificant trend toward increasing triglycerides with increasing TSH categories in women from the Framingham cohort (P = 0.3); in men, triglyceride levels differed significantly by TSH category without a clear linear trend. The overall increase in triglycerides in the clinical study was due primarily to increases in small VLDL subparticles, also seen in the Framingham women. The more atherogenic large VLDL subparticle concentrations, not previously studied, were not related to thyroid status in either study. IDL concentrations were significantly increased during overt hypothyroidism in the clinical study, an effect not seen in the Framingham sample.

HDL-C concentrations increased in the overtly hypothyroid clinical study patients but were not associated with thyroid status in the population study. Large HDL subparticle concentrations were nonsignificantly increased in the overtly hypothyroid subjects in the clinical study and increased with higher TSH values among the women in the population study. In the clinical study, small and medium HDL subparticle concentrations were significantly decreased during hypothyroidism. Historically, HDL-C particles have been categorized by size into the larger HDL2 [primarily incorporating the protein apolipoprotein (Apo) A-I] and smaller HDL3 (incorporating both Apo A-II and Apo A-I) subfractions. Small and medium HDL subparticles as measured by NMR roughly correlate with HDL3, whereas large HDL subparticles, as measured by NMR, correlate with HDL2 (40). The shift toward larger HDL subparticle sizes in the present study is consistent with previous studies describing increases in HDL2 in hypothyroid patients (41,42).

A strength of the present study was the consistency of the major findings across both the clinical and the population studies, at least among women. It is not clear why the population study findings differed by sex. One possibility is that no correlations were observed between lipid measures and TSH values in men because there were too few men with very high TSH levels. The trends in lipid subparticle concentrations for men in the clinical study were identical with those that were significant in women, but with only three male participants, these did not achieve statistical significance in sex-stratified analyses. More studies will be required to determine whether or not the lipid effects seen in the present study are truly specific to women. Although the clinical study patients served as their own controls, their diet and exercise may have differed during their period of short-term hypothyroidism. Other strengths of the population study included the use of a large community-based, single-site sample and the use of rigorous and standardized criteria for the collection and analysis of laboratory specimens and for the ascertainment of information about covariates. A weakness of the population study was the limited amount of available thyroid data. Free peripheral thyroid hormone levels were not measured, making it impossible to assign definitive thyroid diagnoses. Finally, the marked changes in lipid concentrations seen in the clinical study occurred after only 2–3 wk of thyroid hormone withdrawal. It is not known whether additional alterations in lipid subparticle concentrations would occur in hypothyroidism of longer duration.

In conclusion, these data suggest that alterations in lipid subparticle concentration occur in individuals with both overt and mild hypothyroidism. Although total cholesterol and LDL-C are increased in hypothyroid patients, the subparticle types that are increased are those that are less atherogenic. This may help to ameliorate the cardiovascular risk from the total cholesterol and LDL-C increases observed in hypothyroid individuals.

Acknowledgments

We are indebted to the late Clark T. Sawin, M.D., for the collection of the thyroid function data from the Framingham study participants.

Footnotes

This work was supported by the National Institutes of Health (5K23DK4611 to E.N.P.; 2K24HL04334 to R.S.V.).

Disclosure Statement: None of the authors have any disclosures to report.

First Published Online December 11, 2007

Abbreviations: Apo, Apolipoprotein; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; NMR, nuclear magnetic resonance; VLDL, very-low-density lipoprotein.

References

  1. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE 2002 Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489–499 [DOI] [PubMed] [Google Scholar]
  2. Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P 1985 The aging thyroid: thyroid deficiency in the Framingham Study. Arch Int Med 145:1386–1388 [PubMed] [Google Scholar]
  3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC 2000 The Colorado Thyroid Disease Prevalence Study. Arch Int Med 160:526–534 [DOI] [PubMed] [Google Scholar]
  4. Freedman DS, Otvos JD, Jeyarajah EJ, Barboriak JJ, Anderson AJ, Walker JA 1998 Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary disease. Arterioscler Thromb Vasc Biol 18:1046–1053 [DOI] [PubMed] [Google Scholar]
  5. Mackey RH, Kuller LH, Sutton-Tyrell K, Evans RW, Holubkov R, Matthews KA 2002 Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the Healthy Women Study. Am J Cardiol 90:71i–76i [DOI] [PubMed] [Google Scholar]
  6. Kuller L, Arnold A, Tracy R, Otvos J, Burke G, Psaty B, Siscovick D, Freedman DS, Kronmal R 2002 Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 22:1175–1180 [DOI] [PubMed] [Google Scholar]
  7. Rosenson RS, Otvos JD, Freedman DS 2002 Relations of lipoprotein subclass levels and low-density lipoprotein size to progression of coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-1) trial. Am J Cardiol 90:89–94 [DOI] [PubMed] [Google Scholar]
  8. Dawber TR, Meadors GF, Moore Jr FE 1951 Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 41:279–281 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP 1979 An investigation of coronary heart disease in families: the Framingham Offspring Study. Am J Epidemiol 110:281–290 [DOI] [PubMed] [Google Scholar]
  10. Freedman DS, Otvos JD, Jeyarajah EJ, Shalaurova I, Cupples LA, Parise H, D’Agostino RB, Wilson PW, Schaefer EJ 2004 Sex and age differences in lipoprotein subclass measured by nuclear magnetic resonance spectroscopy: The Framingham Study. Clin Chem 50:1189–1200 [DOI] [PubMed] [Google Scholar]
  11. Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultracentrifuge. Clin Chem 18:499–502 [PubMed] [Google Scholar]
  12. Duntas LH 2002 Thyroid disease and lipids. Thyroid 12:287–293 [DOI] [PubMed] [Google Scholar]
  13. Pearce EN 2004 Hypothyroidism and dyslipidemia: modern concepts and approaches. Curr Cardiol Rep 6:451–456 [DOI] [PubMed] [Google Scholar]
  14. Agdeppa D, Macaron C, Mallik T, Schnuda ND 1979 Plasma high density lipoprotein cholesterol in thyroid disease. J Clin Endocrinol Metab 49:726–729 [DOI] [PubMed] [Google Scholar]
  15. Aviram M, Luboshitzky R, Brook JG 1982 Lipid and lipoprotein pattern in thyroid dysfunction and the effect of therapy. Clin Biochem 15:62–66 [DOI] [PubMed] [Google Scholar]
  16. Lithell H, Boberg J, Hellsing K, Ljunghall S, Lundqvist G, Vessby B, Wide L 1981 Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein-lipase activity in overt and subclinical hypothyroidism: the effect of substitution therapy. Eur J Clin Invest 11:3–10 [DOI] [PubMed] [Google Scholar]
  17. Tan KCB, Shiu SWM, Kung AWC 1998 Plasma cholesteryl ester transfer protein activity in hyper- and hypothyroidism. J Clin Endocrinol Metab 83:140–143 [DOI] [PubMed] [Google Scholar]
  18. Lam KS, Chan MK, Yeung RT 1986 High-density lipoprotein cholesterol, hepatic lipase and lipoprotein lipase activities in thyroid dysfunction: effects of treatment. Q J Med 59:513–521 [PubMed] [Google Scholar]
  19. Johanssen L, Rudling M, Scanlan TS, Lundasen T, Webb P, Baxter J, Angelin B, Parini P 2005 Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc Natl Acad Sci USA 102:1297–1302 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Biondi B, Palmieri EA, Lombardi G, Fazio S 2002 Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 137:904–914 [DOI] [PubMed] [Google Scholar]
  21. Nyirenda MJ, Clark DN, Finlayson AR, Read J, Elders A, Bain M, Fox KA, Toft AD 2005 Thyroid disease and increased cardiovascular risk. Thyroid 15:718–724 [DOI] [PubMed] [Google Scholar]
  22. Walsh JP, Bremner AP, Bulsara MK 2005 Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 165:2467–2472 [DOI] [PubMed] [Google Scholar]
  23. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW 2006 Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 295:1033–1041 [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Evans JG, Rodgers H, Tunbridge F, Young ET 1996 The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 6:155–160 [DOI] [PubMed] [Google Scholar]
  25. Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfeld S, Harris TB, Bauer DC 2005 Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 165:2460–2466 [DOI] [PubMed] [Google Scholar]
  26. Parle J, Maisonneuve P, Sheppard M, Betteridge J, Boyle P 2001 A single low thyrotropin (TSH) concentration predicts increased all-cause mortality in older persons in the community: a 10-year cohort study. Lancet 358:861–865 [DOI] [PubMed] [Google Scholar]
  27. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, Usa T, Ashizawa K, Yokoyama N, Maeda R, Nagataki S, Eguchi K 2004 Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 89:3365–3370 [DOI] [PubMed] [Google Scholar]
  28. Gussekloo J, van Exel E, de Craen AJM, Meinders AE, Frolich M, Westendorp RGJ 2004 Thyroid status, disability and cognitive function, and survival in old age. JAMA 292:2591–2599 [DOI] [PubMed] [Google Scholar]
  29. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC 2006 Subclinical hypothyroidism and the risk of coronary heart diseased: a meta-analysis. Am J Med 119:541–551 [DOI] [PubMed] [Google Scholar]
  30. Völzke H, Schwahn C, Wallachofski H, Dorr M 2007 The association of thyroid dysfunction with all-cause and circulatory mortality: is there a causal relationship? J Clin Endocrinol Metab 92:2421–2429 [DOI] [PubMed] [Google Scholar]
  31. Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R, Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol, in press [DOI] [PubMed] [Google Scholar]
  32. Rizzo M, Berneis K 2006 Low-density lipoprotein size and cardiovascular risk assessment. QJM 11:1–14 [DOI] [PubMed] [Google Scholar]
  33. Carmena R, Duriez P, Fruchart JC 2004 Atherogenic lipoprotein particles in atherosclerosis. Circulation 109:2–7 [DOI] [PubMed] [Google Scholar]
  34. Sacks FM, Campos H 2003 Low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 88:4525–4532 [DOI] [PubMed] [Google Scholar]
  35. Roscini AR, Lupattelli G, Siepi D, Pagliaricci S, Pirro M, Mannarino E 1999 Low-density lipoprotein size in primary hypothyroidism: effects of hormone replacement therapy. Ann Nutr Metab 43:374–379 [DOI] [PubMed] [Google Scholar]
  36. Ozcan O, Cakir E, Yaman H, Akgul EO, Erturk K, Beyhan Z, Bilgi C, Erbil MK 2005 The effects of thyroxine replacement on the levels of serum asymmetric dimethylarginine (ADMA) and other biochemical cardiovascular risk markers in patients with subclinical hypothyroidism. Clin Endocrinol 63:203–206 [DOI] [PubMed] [Google Scholar]
  37. Sundaram V, Hanna HF, Koneru L, Newman HAI, Falko JM 1997 Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab 82:3241–3244 [DOI] [PubMed] [Google Scholar]
  38. Diekman T, Diemacker PN, Kastelein JJP, Stalenhoeff AFH, Wiersinga WM 1998 Increased oxidizability of low-density lipoproteins in hypothyroidism. J Clin Endocrinol Metab 83:1752–1755 [DOI] [PubMed] [Google Scholar]
  39. Franklyn JA 2000 Metabolic changes in hypothyroidism. In: Braverman LE, Utiger RD, eds. The Thyroid. 8th ed. Philadelphia: Lippincott Williams, Wilkins; 833–836 [Google Scholar]
  40. Otvos J, Jeyarajah E, Bennett D 1996 A spectroscopic approach to lipoprotein subclass analysis. J Clin Ligand Assay 19:184–189 [Google Scholar]
  41. Tan KCB, Shiu SWM, Kung AWC 1998 Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. J Clin Endocrinol Metab 83:2921–2924 [DOI] [PubMed] [Google Scholar]
  42. Pazos F, Alvarez JJ, Rubies-Prat J, Varela C, Lasuncion MA 1995 Long-term thyroid replacement therapy and levels of lipoprotein(a) and other lipoproteins. J Clin Endocrinol Metab 80:562–566 [DOI] [PubMed] [Google Scholar]

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