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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 3 888-894
Copyright © 2008 by The Endocrine Society

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

Elizabeth N. Pearce, Peter W. F. Wilson, Qiong Yang, Ramachandran S. Vasan and Lewis E. Braverman

Section of Endocrinology, Diabetes, and Nutrition (E.N.P., L.E.B.), Boston University Medical Center, and Department of Biostatistics (Q.Y.), Boston University School of Public Health, Boston, Massachusetts 02118; Department of Medicine (P.W.F.W.), Cardiology Division, Emory University School of Medicine, Atlanta, Georgia 30306; and National Heart, Lung, and Blood Institute’s Framingham Heart Study (R.S.V.), Framingham, Massachusetts 01702

Address all correspondence and requests for reprints to: Elizabeth N. Pearce, M.D., M.Sc., Boston University Medical Center, 88 East Newton Street, Evans 201, Boston, Massachusetts 02118. E-mail: elizabeth.pearce{at}bmc.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
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
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical study

At baseline (hypothyroid), the mean TSH value was 80.7 ± 33.5 mU/liter (range, 23.3–154.4 mU/liter) (Table 1Go). 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. 1Go).


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  		TABLE 1. Mean laboratory values for clinical study participants during hypothyroidism and then after resumption of thyroid hormone therapy

 

Figure 1
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  		FIG. 1. 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 2Go.


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  		TABLE 2. Prevalence of TSH categories at the Framingham Offspring Study cohort examination cycle 4 (1987–1990)

 
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 3Go). 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.


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  		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)

 
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 4Go). 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.


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

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
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.

Received September 5, 2007.

Accepted December 4, 2007.


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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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