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Department of Internal Medicine and National Research Council Institute of Clinical Physiology, University of Pisa, Pisa 56126, Italy
Address all correspondence and requests for reprints to: Fabio Monzani, M.D., Metabolism Unit, Department of Internal Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy. E-mail: fmonzani{at}med.unipi.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although the relationship between sHT and an atherogenic lipoprotein profile is still under debate (3, 8, 10, 11), a metaanalysis of 13 intervention studies showed that levothyroxine (L-T4) therapy led to a significant reduction in both serum total and low-density lipoprotein (LDL) cholesterol levels (12). Moreover, in a randomized, placebo-controlled study, we recently demonstrated that in sHT patients serum LDL cholesterol levels are specifically and reversibly increased to an extent that may translate into a sizable cardiovascular risk (13). Also, one fourth of these patients showed elevated lipoprotein (a) [Lp(a)] values, which were unaffected by thyroid hormone replacement. Raised homocysteine levels have been described in overt hypothyroid patients and might contribute to their higher cardiovascular risk (14, 15). In contrast, in sHT serum homocysteine levels do not seem to be affected, although scant data are so far available (16, 17).
Whether L-T4 replacement is able to improve the cardiovascular risk profile and slow down the progression of early atherosclerotic vascular wall lesions in sHT patients is still controversial. The assessment of subclinical atherosclerosis in the carotid arteries can be accomplished by means of B-mode ultrasonography (18). Intima-media thickness (IMT) is, at present, a close marker of early atherosclerotic changes and a widely accepted surrogate end point for cardiovascular events (19, 20, 21). The association of carotid artery IMT with major cardiovascular risk factors has been demonstrated in several studies (22, 23, 24, 25, 26), and both cross-sectional and prospective studies have clearly established its relationship with systemic atherosclerosis and coronary heart disease (27, 28, 29). Nagasaki et al. (30) recently described carotid artery intima-media thickening in patients with overt hypothyroidism, which was reversed by L-T4 replacement therapy.
Aims of the present study were to assess IMT as well as the lipoprotein profile and serum homocysteine values in a carefully selected group of sHT patients in comparison with matched euthyroid controls and test the effect of L-T4 replacement therapy on these variables in a placebo-controlled fashion.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Forty-five sHT patients (eight men and 37 women) were recruited from the outpatient clinic of the Department of Internal Medicine of the University of Pisa. Thirty-six patients had Hashimoto’s thyroiditis and were positive for both antithyroid peroxidase (TPO-Ab) and antithyroglobulin (Tg-Ab) autoantibodies, whereas nine developed sHT after radioiodine therapy for toxic adenoma or multinodular toxic goiter and had never shown positive autoantibody titers. To be enrolled, patients had to have documented sHT (TSH > 3.6 mIU/liter) for at least 6 months before the study. Thirty-two euthyroid subjects matched to the patients group for sex (27 women, 5 men), age, and body mass index (BMI) were recruited among staff and relatives of patients and served as the control group (Table 1
). Thyroid autoimmunity was detected in none of the controls. All subjects were in good health, all women were premenopausal with regular menses, and none was pregnant. Individuals over age 55 yr; obese (BMI > 30 kg/m2) subjects; smokers; and those with hypertension, diabetes mellitus, renal and hepatic failure, or other systemic diseases were excluded from the study. Routine laboratory chemistry was normal in all, and none was taking any drug. All subjects were on a free diet and were advised to maintain their dietary habits throughout the study. All study subjects gave their written informed consent to the study, which was approved by the Institutional Ethical Committee.
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At baseline, blood samples were drawn at 0800 h after an overnight fast for the determination of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, LDL cholesterol (LDLc), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), Lp(a), total homocysteine (tHcy), folic acid, and vitamin B12 concentrations. For tHcy, vitamin Bl2, and folate measurements, blood was drawn into tubes containing EDTA, placed on ice, and immediately centrifuged. Samples were stored at –70 C until analysis.
IMT assessment
Carotid arteries were investigated by high-resolution ultrasonography. The same investigator (C.P., blinded to the treatment status of the patients) performed all examinations using commercially available equipment (SONOS 2500, Hewlett-Packard, Andover, MA) and a 7.5-MHz linear transducer (Hewlett-Packard). Both image acquisition and IMT measurements were carried out according to the Atherosclerosis Risk in Communities study protocol (18, 31). The carotid images were obtained with the patient in the supine position with the neck mildly extended and the head rotated contralaterally to the side. The imaging protocol involved obtaining longitudinal B-mode image of the distal 10 mm of the right and left common carotid arteries; the carotid bifurcation; and the internal carotid artery from the anterior, lateral, and posterior angle. The whole imaging session was recorded on videotape. Good-quality images of internal carotid artery were obtained in 64% of subjects, and this segment was not included into IMT evaluation. Therefore, in the whole study population, the final analysis was performed with IMT images of both the near and far wall of the right ad left common carotid artery and carotid bifurcation. The recordings were evaluated by the same reader (M.K.) blinded to the clinical data, using a high-resolution video recorder (AG-MD830, Panasonic, Secaucus, NJ) coupled with the computer-driven image analysis system (Medical Image Processing; Institute of Clinical Physiology, National Research Council, Pisa, Italy) (32). Diastolic frames of each carotid segment were digitized. Lines were drawn along the lumen-intimal and medial-adventitial interfaces in all analyzed segments, and the IMT of each segment was automatically computed as an average of several measurements. For statistical analysis, IMT readings in all the eight carotid segments were averaged (mean IMT). In addition, the maximal thickness in any particular segment was also measured (maximal IMT). In our laboratory, the intra- and interobserver coefficients of variation for mean carotid IMT are 3.2 and 4.2%, respectively.
Study protocol
Patients were then randomly assigned to L-T4 replacement (n = 23) or placebo (n = 22) in a blinded manner. Tablets containing L-T4 or placebo were accurately counted and given to each patient. L-T4 treatment always started with 25 µg, the dose being then gradually increased. All patients returned after 3 months for repeat thyroid function tests. One of us (N.C.) had access to the treatment code and increased the dose of L-T4 by 25 µg if the TSH level was still higher than 3.6 mIU/liter. This process continued until euthyroidism was reached; the mean final replacement dose of L-T4 was 70 µg daily. Patients taking placebo completed an identical protocol, some of them being given additional placebo tablets to maintain the blindness of the study. Six months after the normalization of serum TSH level (median 10.5 months, range 9–15 from the beginning of the study in the L-T4-treated group) or 6 months after the final dosage was assigned (median 10.5 months, range 9–12 in the placebo-treated group), the patients were readmitted for repeat evaluations of all parameters.
Analytical measurements
Serum FT3 and FT4 concentrations were measured by specific RIA (Techno-Genetics Recordati, Milan, Italy). Serum TSH levels were determined by an ultrasensitive immunoradiometric assay (IRMA) method (Cis Diagnostici, Tronzano Vercellese, Italy). Anti-Tg-Abs were measured by a specific IRMA assay (TG-Ab IRMA, Biocode, Sclessin, Belgium); anti-TPO-Abs were measured by a specific RIA (AB-TPO; Sorin Biomedica, Saluggia, Italy). TC and TG were assayed using enzymatic methods (Roche Diagnostics, Mannheim, Germany). high-density lipoprotein cholesterol was measured enzymatically after precipitation of LDL and very low-density lipoprotein with Mg2+-dextran (Roche Diagnostics). LDLc was calculated by Friedewald’s formula. ApoA1 and ApoB were determined immunochemically (Nephelometer, Behring Diagnostics, Marburg, Germany). Lp(a) concentrations were determined in serum by nephelometry (N latex Lp(a) reagent, Behring Diagnostics). tHcy was measured by HPLC as previously described (33). Vitamin B12 as well as folic acid was measured by specific RIA (ICN Pharmaceuticals, Costa Mesa, CA). Normal ranges in our laboratory are as follows: FT4 = 5.6–13 pg/ml (6.8–20 pmol/liter); FT3 = 2.3–5.6 pg/ml (4.3–8.6 pmol/liter); TSH = 0.30–3.60 mIU/liter; Tg-Ab less than 50 IU/ml and TPO-Ab less than 10 IU/ml; ApoA1= 95–230 mg/dl; ApoB = 55–165 mg/dl; Lp(a) less than 30 mg/dl; tHcy = 5–15 µmol/liter; vitamin B12 = 261-1330 pg/ml (193–982 pmol/liter); folate = 1.3–7.5 ng/ml (3–17 nmol/liter).
Statistical analysis
Data were expressed as the mean ± SD unless otherwise stated. A Mann-Whitney U test was used for each comparison between two independent groups. Two-way ANOVA for repeated-measures (Friedman’s rank test with Tukey multiple comparison) was used to compare data before and after therapy in L-T4- and placebo-treated patients. Relationships among parameters were tested by Spearman correlation coefficient; in case of significant correlation between mean-IMT and the tested variable, a linear regression plot was also obtained. Stepwise regression analysis was performed with log-transformed mean-IMT as the dependent variable. The following continuous variables were selected for the stepwise regression model: age, TSH, FT3, LDL, TG, Lp(a), ApoB, and systolic blood pressure. Correlation and regression analyses were always carried out on data from sHT patients. Significance was assumed for P < 0.05. SPSS for Windows XP (SPSS Inc., Chicago, IL) was used as statistical software.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. Euthyroid controls and sHT patients were well matched with respect to age, BMI, and gender. Except for serum TC, LDLc, and ApoB concentrations, there were no significant differences in clinical parameters between the two groups. Although serum Lp(a) values did not differ between patients and controls, elevated Lp(a) levels (>30 mg/dl) were significantly more frequent in sHT (33% of patients vs. 7% of controls, P = 0.01).
Baseline clinical and biochemical characteristics of sHT patients randomized to L-T4 or placebo treatment were not significantly different (Table 2). After therapy, serum TSH levels had returned within the normal range in the L-T4-treated group and were now significantly lower than in the placebo group (P < 0.0001). Serum FT3 and FT4 levels remained within the normal range during the entire treatment period both in placebo and L-T4-treated patients; however, FT4 levels rose significantly in the L-T4-treated group (Table 2).
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and 2). Similarly, no significant changes were observed in serum tHcy, folic acid, and vitamin B12 levels (Table 2). However, the two patients with elevated baseline tHcy showed a reduction (62.6 vs. 20.0 and 83.4 vs. 46.9 µmol/liter, baseline, and after L-T4 therapy, respectively), with a concomitant increment of plasma folate levels [0.6 vs. 2.6 and 1.6 vs. 4.7 ng/ml (1.4 vs. 5.9 and 3.6 vs. 10.7 nmol/liter), baseline, and after L-T4 therapy, respectively]. In the placebo group, no significant changes in any of the biochemical parameters were seen. IMT
The mean-IMT of sHT patients as a group was significantly higher than that of euthyroid controls (Table 1). Similar results were obtained when analyzing only the subgroup of sHT patients (n = 35) with serum TSH levels lower than 10 mIU/liter (median 5.23, range 3.65–9.32): mean-IMT 0.71 ± 0.10 mm, P < 0.0001 vs. euthyroid controls. Although we excluded subjects older than 55 yr as well as postmenopausal women, the mean-IMT was examined also in two age strata (older and younger than 35 yr) in view of the powerful effect of age on IMT. The number of sHT patients and euthyroid controls was comparable in both age strata (n = 24 and n = 15 in the older group; n = 21 and n = 17 in the younger group, respectively). The mean-IMT of sHT patients was significantly higher than that of controls in the older group (0.84 ± 0.10 vs. 0.64 ± 0.06 mm, P < 0.0001), whereas slightly, not significantly, increased in the younger group (0.66 ± 0.09 vs. 0.61 ± 0.07 mm, P = 0.20).
Six months of stable euthyroidism induced a significant decrease of mean-IMT, averaging 0.09 mm [95% confidence interval (CI) 0.06–0.11] or –10%. In particular, 19 patients (83%) showed a decrease in mean-IMT (Fig. 1A), whereas four (17%) had either no change (n = 3) or an increase (n = 1) (Fig. 1B). Although still slightly higher than in euthyroid controls (P = 0.056), mean-IMT of the L-T4 treated group had become significantly lower (P = 0.03) than that of the placebo-treated group at the follow-up examination (Tables 1 and 2). L-T4 replacement therapy was effective in also reducing mean-IMT in the subgroup of 18 sHT patients with serum TSH levels lower than 10 mIU/liter (mean reduction 0.08 mm, 95% CI 0.05–0.11) or –10% (P < 0.0001 vs. pretreatment). Furthermore, 6 months of stable euthyroidism induced a significant decrease of mean-IMT in both younger (n = 9) and older (n = 14) sHT patients, averaging 0.07 mm (95% CI 0.01–0.12) or –9% (P = 0.03 vs. pretreatment) in the former group and 0.09 mm (95% CI 0.05–0.13) or –11% (P = 0.0003 vs. pretreatment) in the latter group. Thus, in the younger group of sHT patients mean-IMT became equivalent to that of euthyroid controls (0.61 ± 0.08 vs. 0.61 ± 0.07 mm, respectively).
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Significant positive relationships were found between serum TSH and TC (r = 0.39, P = 0.009) and LDL levels (r = 0.42, P = 0.005). A positive relationship between the absolute decrements of both TC and LDL and the reduction of serum TSH was also observed (r = 0.56, P = 0.0002 and r = 0.66, P < 0.0001, respectively).
In addition to age (r = 0.66, P < 0.0001), mean-IMT correlated significantly with TC (r = 0.55, P = 0.0003) and LDLc (r = 0.54, P = 0.0003), TG (r = 0.35, P = 0.02), and ApoB (r = 0.49, P = 0.003). A strong positive relationship was also found between mean-IMT and serum TSH levels (r = 0.51, P = 0.0008) (Fig. 2). The absolute mean-IMT reduction was directly related to the absolute decrements of both serum TC and TSH values (r = 0.35, P = 0.02 and r = 0.61, P = 0.0001, respectively).
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In the final model that explained 71% of the variation in mean-IMT (r2 = 0.71, P < 0.0001), age had the highest standardized coefficient (0.46), followed by TSH (0.34) and LDLc (0.25), whereas the other parameters were excluded.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although consensus on the association between sHT and dyslipidemia is still lacking, most reports had documented a relationship between sHT and a reversible atherogenic lipoprotein profile (12). Two randomized, placebo-controlled studies recently demonstrated that in sHT serum LDL cholesterol levels are specifically and reversibly increased to an extent that may translate into a sizable cardiovascular risk (13, 34). The present study confirms this association and the efficacy of 6 months of stable euthyroidism in reducing both TC and LDLc (by 10 and 13%, respectively). It should be emphasized that the observed decrease in LDLc induced by L-T4 replacement therapy is significant in terms of risk reduction for coronary heart disease (35). In fact, although comparable data are not available for premenopausal women, the Helsinki Heart Study has shown that in men a decrease by only 7% in serum LDLc levels is associated with a 15% reduction in the incidence of coronary heart disease (36). Because raised Lp(a) concentrations have been associated with the development of atherosclerosis and are viewed as a strong predictor of ischemic heart disease (37), attention has focused on serum Lp(a) levels in thyroid diseases. However, the relationship between hypothyroidism and Lp(a) levels and the effect of L-T4 therapy are still under debate (38, 39). In agreement with the reported primary genetic determination of serum Lp(a) levels (40), we have recently shown that raised Lp(a) values are more frequent in sHT patients than controls, in association with a positive family history for coronary heart disease and/or diabetes mellitus (13). Accordingly, in the present study, elevated serum Lp(a) concentrations were detected in 33% of sHT patients vs. 7% of euthyroid controls but were unaffected by L-T4 replacement therapy. All in all, these and our previous findings suggest that altered Lp(a) values of sHT patients reflect a genetic influence rather than resulting from reduced thyroid hormone action; however, they may conspire with the atherogenic lipoprotein profile of untreated patients to enhance cardiovascular risk.
In recent years several novel risk factors for atherosclerotic cardiovascular disease have been identified, including hyperhomocystinemia. Several studies have demonstrated reversibly elevated homocysteine levels in overt hypothyroidism, with serum FT4 being an independent determinant of homocysteine concentrations (14, 41). Furthermore, in adults with endemic goiter and raised TSH levels tHcy was shown to be significantly higher than in controls (42). Previous studies, however, failed to demonstrate an association between sHT and hyperhomocystinemia (1, 16). Accordingly, our results indicate that tHcy levels are not altered in sHT and are not changed by effective L-T4 therapy. Besides renal function, plasma folic acid and vitamin B12 levels are known determinants of tHcy (16). Because vitamin B12 and folate deficiency are more frequently observed in overt than in subclinical hypothyroidism (43), it is possible that hyperhomocystinemia results from vitamin deficiency rather than thyroid hormone lack per se. Indeed, in the present study, the only two patients with elevated tHcy also had low plasma folate values and, after restoring euthyroidism the reduction of plasma homocysteine, was concomitant with an increment of folate levels.
The IMT measurement by carotid ultrasound represents a noninvasive, standardized, and validated approach for early atherosclerosis screening and provides a reliable surrogate end point to assess intervention (18, 19, 20, 21, 44, 45). A thickening of carotid artery intima-media complex reflects not just regional alterations but also generalized atherosclerosis. In fact, a direct correlation between mean-IMT and the risk of myocardial infarction and stroke has been demonstrated (19). In the current study, the carotid artery mean-IMT was significantly higher in sHT patients than in euthyroid controls. As expected, mean-IMT correlated with most of lipid variables (TC, LDLc, ApoB, and TG) as well as with age. Interestingly, our data show a strong positive relationship between mean-IMT and serum TSH value, which emerged as one of the most important predictors of mean-IMT variation in stepwise regression analysis, preceded only by age and followed by LDLc. Furthermore, after 6 months of restored euthyroidism, carotid artery mean-IMT was reduced by almost 10%, and the absolute mean-IMT reduction was directly related to the absolute decrements of both serum TC and TSH values. Because no consensus exists on the issue of treatment of sHT when serum TSH level is slightly elevated (46), it is noteworthy that, in the current study, L-T4 replacement therapy was effective in reducing mean-IMT also in the subgroup of sHT patients with serum TSH levels lower than 10 mIU/liter.
Although only a slight, not significant, difference in mean-IMT was observed, at baseline, between patients and controls younger than 35 yr, 6 months of stable euthyroidism induced a significant reduction of carotid artery mean-IMT in both the older (>35 yr) and younger group of sHT patients. Furthermore, mean-IMT became equivalent to that of euthyroid controls only in the latter group of patients. Strong evidence exists for the role of age as a major determinant of carotid IMT (21, 47). However, in addition to age, thickening of the arterial wall is also related to the cumulative exposure over time to various cardiovascular risk factors, such as hyperlipidemia and, possibly, hypothyroidism. Indeed, although the long-held association between hypothyroidism and hypercholesterolemia probably underlies much of the accelerated atherosclerotic disease described in patients with sHT (12, 13, 34), our data also suggest a direct effect of mild thyroid hormone deficiency. Accordingly, we recently demonstrated that in sHT, besides dyslipidemia, mild thyroid hormone deficiency per se is responsible for reversible endothelial dysfunction and reduced nitric oxide availability, which act as promoters of atherosclerosis (48).
The intimal and medial layers of the arterial wall cannot be distinguished from each other by ultrasound; thyroid hormones also exert a direct effect on the peripheral vasculature, which is best demonstrated by the reversible increase in systemic vascular resistance observed in humans and experimental animals with hypothyroidism (49). Accordingly, Mizuma et al. recently described the presence of an iodothyronine deiodinase in human vascular smooth muscle (VSM) cells (50). Although the target genes for T3 action in VSM cells remain unknown, it could be speculated that, as described in cardiac myocytes, they are involved in the modulation of sarcoplasmic reticulum and sarcolemmal ion flux and VSM contractility (49). Indeed, the presence of an iodothyronine deiodinase suggests that VSM cells, which are in physiologic cross-talk with endothelium, may be a target for thyroid hormone action and lends support to the hypothesis of a direct involvement of thyroid hormone deficiency in IMT thickening. On the other hand, although significantly improved after restoration of euthyroidism, mean-IMT remained slightly higher in sHT patients than controls. This finding may be, at least in part, explained by the unchanged Lp(a) values; however, a possible additional role of autoimmunity and inflammation in the accelerated atherosclerotic process of sHT patients should not be overlooked and may account for the residual intima-media thickening (16).
Overall, our data indicate that early carotid artery wall lesions, as detected by B-mode ultrasound, are present in sHT patients mainly from the fourth decade of life onward. Whether such IMT increase is related to an early atherosclerotic involvement of the arterial wall cannot be clearly decided on the basis of the present results. However, the fact that L-T4 replacement therapy was able to improve both the atherogenic lipoprotein profile and intima-media thickening suggests that lipid infiltration of arterial wall may represent a major mechanism underlying IMT increase in this selected subset of patients. Nonetheless, other pathologic processes can theoretically contribute to IMT elevation, namely VSM cells swelling and water accumulation in the arterial wall due to protein deposition in extracellular space as well as an increased capillary permeability (51). Advances in tissue characterization techniques by ultrasound may allow in the near future to get information, from quantitative acoustic densitometry of images, on at least some of pathologic changes of the arterial wall.
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Acknowledgments |
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Footnotes |
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Abbreviations: ApoA1, Apolipoprotein A1; ApoB, apolipoprotein B; BMI, body mass index; CI, confidence interval; FT3, free T3; FT4, free T4; IMT, intima-media thickness; IRMA, immunoradiometric assay; LDL, low-density lipoprotein; LDLc, LDL cholesterol; Lp(a), lipoprotein(a); L-T4, levothyroxine; sHT, subclinical hypothyroidism; TC, total cholesterol; TG, triglyceride; Tg-Ab, antithyroglobulin autoantibody; tHcy, total homocysteine; TPO-Ab, antithyroid peroxidase autoantibody; VSM, vascular smooth muscle.
Received September 24, 2003.
Accepted February 16, 2004.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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