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Long-Term Cardiovascular Effects of Levothyroxine Therapy in Young Adults with Congenital Hypothyroidism

Department of Pediatrics (M.S., T.L., D.M.M., D.C.) and Department of Clinical Medicine and Cardiovascular Sciences (U.O., V.G., L.Sal., A.L., L.Sac., A.C.), University "Federico II," 80131 Naples, Italy

Address all correspondence and requests for reprints to: Antonio Cittadini, M.D., Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Via S. Pansini, 5, 80131 Naples, Italy. E-mail: antonio.cittadini{at}unina.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn and is routinely treated with life-long levothyroxine replacement therapy. Although several studies have demonstrated that such therapy may impact on the cardiovascular system, little is known with regard to the effects of long-term levothyroxine administration in patients with CH.

Objective: The aim of the current study was to evaluate whether long-term levothyroxine replacement therapy in young adults with CH is associated with cardiovascular abnormalities.

Patients and Methods: Thirty young adults with CH aged 18.1 ± 0.2 yr and 30 age- and sex-matched controls underwent cardiac and carotid Doppler ultrasound and symptom-limited cardiopulmonary exercise testing. Hypothyroidism was diagnosed by neonatal screening, and levothyroxine treatment was initiated within the first month of life and carefully adjusted to maintain TSH levels in the normal range and free T₄ in the high-normal range.

Results: Compared with controls, hypothyroid patients exhibited left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness. At multiple regression analysis, the number of episodes of plasma TSH levels less than 0.5 mU/liter and greater than 4.0 mU/liter from the age of 1 yr onward, and mean TSH plasma levels during puberty were independent predictors of diastolic filling and cardiopulmonary performance indexes (multiple r values: 0.61–0.75).

Conclusions: Long-term levothyroxine treatment in young adults with congenital hypothyroidism is associated with impaired diastolic function and exercise capacity and increased intima-media thickness.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Congenital hypothyroidism (CH) is the most prevalent endocrine disorder in the newborn, with a rather constant worldwide incidence of permanent CH of 1:3000 to 1:4000 newborns (1, 2). Newborn screening programs have represented a major achievement insofar as early diagnosis and long-term treatment with levothyroxine (L-T4) have resulted in normal development in the vast majority of patients, with only up to 10% of patients affected by residual problems regarding mental development and neurological symptoms.

The cardiovascular system is very sensitive to thyroid hormones, and a wide spectrum of cardiovascular changes has long been recognized in overt and, more recently, in subclinical thyroid dysfunction (3, 4, 5). In this regard, patients with CH receiving long-term L-T4 replacement therapy may represent a subset of patients at risk of subclinical dysthyroidism. Indeed, previous studies have reported common episodes of L-T4 overtreatment and undertreatment in patients with CH, which are commonly attributed to both the need to maintain serum TSH levels within normal range even though this requires increased free T₄ (FT4) concentration and to the patients’ inadequate compliance (6, 7).

Therefore, the aim of the current study was to evaluate whether long-term L-T4 replacement therapy in young adults with CH is associated with cardiovascular abnormalities.

	Patients and Methods

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Patient population

Thirty-two adolescents (21 females,11 males) affected with CH aged 16.0–20.0 yr (18.1 ± 0.2 yr) participated in the study. All patients were detected by neonatal screening and followed longitudinally, from the time of diagnosis to the time of the study. The diagnosis was confirmed by serum thyroid function tests. L-T4 replacement therapy was started, immediately after the first evaluation, at a mean age of 26 ± 0.9 d (range 12–30 d) and at a mean initial dose of 6.4 ± 0.2 kg/d. Replacement therapy was modified during follow-up according to clinical and hormonal evaluation to maintain normal serum TSH and serum FT4 in the upper normal range (2, 8). The etiological diagnosis of CH was made on the basis of 99m Tc-pertechnetate or iodine-123 thyroid scans at the time of diagnosis or the age of 3 yr, after the withdrawal of L-T4 therapy for 6 wk. Cases were classified into three groups: athyreosis (n = 7), ectopic (n = 18), and eutopic gland (n = 7). At study entry, all subjects had completed their pubertal development, and females had regular menstrual cycles. All patients had already reached their adult height (defined as a growth of less than 1.0 cm/yr during the preceding year) (8). Serum TSH and thyroid hormones and routine blood analysis were periodically assessed (every 6 months). At the time of cardiac testing, all subjects were euthyroid. Five patients were mild smokers (less than 10 cigarettes per day) and three were moderate drinkers (beer or wine occasionally). Previous or current cardiovascular, respiratory, renal, or other chronic diseases as well as obesity were exclusion criteria for entering the study.

Thirty-two healthy adolescents comparable for age, sex, body mass index (BMI), and smoking and alcohol use rates and physical activity, including recreational exercise, participated in the study as controls. All of subjects from the control group were from the same geographic region of patients with CH and were matched by their socioeconomic status. Informed consent was obtained by all patients or their parents (if the patient was under 18 yr of age), and the study was approved by the Ethics Committee of the Federico II University.

Study protocol

At study entry, all subjects underwent height, weight, heart rate, systolic and diastolic blood pressure measurement. The degree of adiposity was expressed as BMI. To evaluate the influence of thyroid hormone status on cardiac performance during puberty, mean values were calculated from all serum TSH (mTSH) and FT4 evaluation carried out from the onset of puberty to the time of the study. The mean L-T4 dose taken in the same period of time was also calculated (9). Based on the normal TSH range in our laboratory (0.5–4.0 mU/liter), we also calculated an index of overtreatment (number of episodes when serum TSH was < 0.5 mU/liter during follow-up from the age of 1 yr onward) and an index of undertreatment (number of episodes of serum TSH > 4.0 mU/liter). We also pooled all episodes of overtreatment and undertreatment as an index of patients’ inadequate treatment. Measurements younger than 1 yr of age were excluded because TSH serum levels were still above the normal range in a vast majority of patients. To assess the degree of TSH derangement, i.e. the deviation from the range 0.5–4.0 mU/liter used, we calculated the average of all TSH values greater than 4.0 and less than 0.5 for each patient.

Patients were evaluated with the following tests: 12-lead scalar electrocardiogram, body weight, systolic and diastolic blood pressure, Doppler echocardiography, cardiopulmonary stress test, and carotid ultrasound. Heart rate was calculated from the electrocardiogram and systolic and diastolic blood pressure were measured by a cuff manometer after 15 min of supine rest.

Echocardiography

An ultrasound system equipped with a 2.5-MHz multifrequency transducer (Toshiiba Aplio CV; Toshiba Corporation, Tokyo, Japan) was used for complete M-mode, two-dimensional, Doppler and tissue Doppler imaging (TDI) echocardiographic analyses. M-mode and two-dimensional recordings were made with the patients in the lateral recumbent position, according to the updated recommendations for chamber quantification (10). The investigator reading the echoes was blinded to the study protocol. The methods are described in detail elsewhere (11). Measures of left ventricular (LV) architecture and function were assessed according to standard formulae. The following parameters of diastolic function were measured as the mean of three to five consecutive beats: diastolic transmitral peak velocities, the maximal early diastolic flow velocity (E)/maximal late diastolic flow velocity (A) ratio, the isovolumic relaxation time, and mitral deceleration time. Quantitative diastolic data were derived from TDI analysis. The sample volume (4 mm³) was placed in the LV basal portions of the anterior, inferior, septal, and lateral walls (using the two and four chambers images) (12). The following parameters were derived early (E') and late (A') diastolic velocities and the E'/A' ratio. Peak early diastolic mitral annular velocity provides a relatively load-insensitive measure of LV relaxation and progressively decreases with increasing severity of diastolic dysfunction.

Cardiopulmonary exercise test

Symptom-limited cardiopulmonary exercise testing (Treadmills Rammill Series; Morgan Italia, Bologna, Italy) was performed, according to the Cornell-modified multistage treadmill protocol (2 min step increments) with a commercially available equipment (Benchmark exercise test system, Morgan Italia) (13). Measurements of oxygen consumption (VO₂), were taken at rest and during exercise using a moving average of eight breaths. During each stage of exercise, data on heart rate and rhythm and blood pressure were collected. All patients were encouraged to exercise until they felt unable to continue because of dyspnea and/or fatigue. The maximum VO₂ was defined as the highest VO₂ value measured (peak VO₂). The anaerobic threshold was determined by the V-slope method, in which CO₂ production is plotted as a function of VO₂, and the break point at which CO₂ production increases more rapidly than VO₂ is taken as the anaerobic threshold (13).

Carotid ultrasound examination was performed in each subject using a validated protocol (14), with a 7.5-MHz multifrequency linear-array probe (Toshiba Aplio CV; Toshiba Corporation, Tokyo, Japan). Briefly, ultrasound examination was made with the subject in a supine position, with a slight rotation of the neck. Both the common and the internal carotids were scanned bilaterally by experienced vascular sonographers (U.O., L. Sal.), blinded to the subject’s clinical features. The probe was placed along the vessel axis, and carotid arteries were explored with longitudinal (anterior, lateral, and posterior) and transverse scan. The probe was manipulated so that the near and far walls were parallel to the probe, and the lumen diameter was maximized in the longitudinal plane. The origin of carotid bifurcation was identified and served as a reference point for the start of the measurements. Intima-media thickness (IMT) values were obtained at the far wall on both sides of the carotid bifurcation using a digital caliper and a semiautomated edge detection system (Toshiba), which provided the average thickness across a 1-cm segment. The ultrasonographic pictures were also stored according to DICOM standards for subsequent supervision of adherence to the imaging protocol by a senior investigator (U.O.) with more than 10 yr of experience in ultrasound examination of carotid vessels.

Statistics

Data were handled, stored, and analyzed using the SPSS package (SPSS Inc., Chicago, IL). Independent-sample t test for unpaired data, linear regression analyses, and Fisher’s exact test (two tailed) were used when appropriate. Multiple regression analysis with the backward elimination procedure was carried out. To evaluate determinants of altered diastolic filling, exercise performance, and IMT, the following clinical and hormonal characteristics of the patient groups were the independent variables tested: mTSH, number of episodes of TSH greater than 4.0 or less than 0.5 mU/liter and their summation, the average of all TSH values greater than 4.0 mU/liter and less than 0.5 for each patient, free T₃, FT4, heart rate, and systolic and diastolic blood pressures. A univariate P < 0.05 was required for each independent variable to enter the equation. Data are reported as mean ± SEM.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
As expected, the study groups were matched for age, sex, and BMI. There were no differences in baseline blood pressure and heart rate (Table 1). LV architecture and systolic function were also similar in the two study groups, whereas patients with CH exhibited impaired LV diastolic function. In particular, there was evidence for a mild impaired relaxation pattern (15), documented by prolonged isovolumic relaxation and mitral deceleration time, and reduced E/A and E'/A' ratio (Table 2). CH patients did not report any reduction of daily activities, compared with controls. However, exercise capacity and cardiopulmonary performance were significantly lower in patients with CH, compared with normal controls, as documented by reduced values of peak VO₂ consumption (–19% vs. controls), anaerobic threshold, and workload (Table 2). Both common and internal carotid IMT mean values were significantly increased in congenitally hypothyroid patients, compared with controls (Table 2, P < 0.0001 and 0.001 vs. controls, respectively). Follow-up TSH evaluations revealed frequent episodes of overtreatment and undertreatment. Specifically, an average of 17% of TSH evaluations detected subclinical hyperthyroidism (TSH < 0.5 mU/liter) and 38% detected subclinical hypothyroidism (TSH > 4.0 mU/liter) in our patient population.

No significant differences in cardiovascular parameters were observed when the patients were subdivided on the basis of etiological defects, athyreosis, ectopic, and eutopic gland nor between patients with mild or severe CH at diagnosis (data not shown). Furthermore, we did not find any significant correlation between serum T₄ levels at the time of diagnosis and the long-term cardiac function

Univariate analysis showed a significant correlation between LV diastolic filling indexes and cardiopulmonary test variables (Fig. 1). Specifically, E'/A' ratio was directly correlated with peak VO₂, isovolumic relaxation time with VO₂ at anaerobic threshold and peak workload, and mitral deceleration time with peak workload. Variables derived from carotid ultrasound did not correlate with biochemical indexes; the only correlation was found between IMT of common carotid artery and E'/A' ratio.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Linear regression analyses between cardiopulmonary test parameters and indexes of LV diastolic filling.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

To our knowledge, long-term cardiac function has never been investigated in children and adolescents with congenital hypothyroidism detected by neonatal screening and treated from the first month of life. Few and conflicting data have been reported only in untreated neonates with congenital hypothyroidism. Specifically, cardiac function has been reported to be either normal (15, 16) or impaired (17, 18). Recent data suggest that at the time of diagnosis, neonates with CH may exhibit left and right ventricular systolic and diastolic dysfunction, which can be reversed by early L-T4 substitutive treatment (19).

The impairment of diastolic performance in CH is supported by a broad array of Doppler indexes and resembles the typical pattern of a mild relaxation abnormality (20). The relaxation phase is indeed an energy-dependent phase of LV filling, characterized by calcium reuptake toward the sarcoplasmic reticulum (21). LV relaxation is very sensitive to even mild energy depletion, and its impairment often precedes systolic dysfunction. Abnormal relaxation results in persistent pressure generation at end diastole and may thus lead to reduced LV distensibility, which in turn is known to contribute to exercise intolerance (22). Exercise intolerance is largely dependent on reduced stroke volume during exercise caused by the limited increase in the LV end-diastolic volume despite normal ejection fraction and the increased LV filling pressure and left atrial pressure during exercise. Such speculation is supported by the significant relationship between E'/A' and peak VO₂. Heart rate response to exercise was not different between the two study groups, whereas aerobic work capacity and efficiency was equally impaired as indicated by lower VO₂ and anaerobic threshold. CH patients exhibited a decrease in not only exercise duration and maximal O₂ uptake but also anaerobic threshold. Exercise duration and maximal O₂ uptake are indexes of work capacity that may not be entirely objective because they may be limited by symptoms or patient motivations. The anaerobic threshold is the exercise level above which aerobic energy production is supplemented by anaerobic mechanism and is therefore more objective (23). Despite the fact that exercise capacity was impaired, CH patients did not experience any difference in daily activities, compared with healthy controls. This finding might be explained by the fact that most daily activities occur at low levels of oxygen consumption.

Congenitally hypothyroid patients also displayed a significant increase of carotid IMT, a surrogate marker of atherosclerotic disease (24). This alteration was present for each side on carotid axis in patients with CH and caused a diffuse and homogeneous increase of the arterial wall thickness in both the common and internal carotid arteries. In this regard, recent evidence support an independent association between thyroid function and carotid IMT. Specifically, in a large population-based survey, patients with low TSH levels (<0.3 mU/liter) had the highest IMT values (25). On the other hand, also subclinical hypothyroidism is associated with increased IMT in several cross-sectional analyses (26, 27). These observations provide a solid background for increased IMT in patients who present with frequent episodes of subclinical thyroid dysfunction.

Several lines of experimental evidence support the concept that subclinical thyroid dysfunction is associated with a broad array of cardiovascular abnormalities, which may confer enhanced risk for atherosclerosis, myocardial infarction, and cardiovascular death (4, 28, 29). Specifically, we and others have previously demonstrated that subclinical hyperthyroidism is associated with increased heart rate, increased LV mass with mild concentric remodeling, reduced exercise performance, and impaired ventricular relaxation (30, 31). The cardiovascular phenotype of subclinical hypothyroidism is that of impaired diastolic function, altered systolic function under effort, and increased IMT (32, 33).

Taken together, the cardiovascular abnormalities displayed by patients with CH may well depend on the summation of multiple episodes of subclinical hypo- and hyperthyroidism. In fact, the cardiac phenotype of hypothyroid patients was characterized by impaired LV relaxation, reduced exercise capacity, and increased IMT. Such speculation is supported by the multivariate analysis that demonstrated that the number of episodes of overtreatment and undertreatment and their summation, and mTSH predicted the alterations of peak VO₂ consumption, peak VO₂ at anaerobic threshold, peak workload, and E'/A' ratio. However, association does not necessarily imply a mechanistic link, and potential causes of cardiovascular abnormalities other than L-T4 treatment should be taken into account, such as fetal programming of adult cardiac function.

Our data are congruent with previous reports showing that congenitally hypothyroid patients often present with TSH serum concentration above or below the normality range, particularly during adolescence when treatment compliance becomes less regular, notwithstanding an accurate biochemical follow-up and frequent adjustments (7).

The prevalence of inadequate compliance, with increased levels of TSH, is particularly high in children and adolescents with CH. Indeed, inadequate control has been demonstrated in 74% of children older than 12 yr (7). To date, most reports have focused on the effects of over- or undertreatment on mental, psychomotor, and behavioral outcome in children with CH. Indeed, low IQ scores, increased level of both anxiety and inattention, and delayed progression during elementary school have been shown to correlate with the number of episodes of undertreatment (6, 25, 26). On the contrary, the effects of moderate overtreatment are still debatable, with both lower verbal scores or no impairment of cognitive development being reported (7, 27).

The reasons underlying episodes of overtreatment may depend on the current recommendations for treatment of CH, that increased L-T4 dose from 5–8 to 10–15 µg/kg·d to achieve a more rapid normalization of T₄. Furthermore, the optimal therapeutic target aims at normal TSH levels with T₃ and T₄ levels in the upper normal range, thus potentially leading in the long term to phases of subclinical hyperthyroidism.

In view of a long-term replacement therapy with L-T4, one must be aware that frequent episodes of subclinical hypothyroidism and hyperthyroidism may occur and should be avoided to prevent cardiovascular abnormalities. Moreover, a careful cardiovascular follow-up should be performed, and future studies will clarify whether these abnormalities may result in clinically relevant cardiovascular diseases.

	Footnotes

 
This study was supported by a grant of the Italian Ministerof Research and University (n° 2006069049, to M.S.).

Disclosure Statement: All the authors have nothing to declare.

First Published Online April 29, 2008

Abbreviations: A, Late diastolic flow velocity; BMI, body mass index; CH, congenital hypothyroidism; E, early diastolic flow velocity; FT4, free T₄; IMT, intima-media thickness; L-T4, levothyroxine; LV, left ventricular; mTSH, serum TSH; peak VO₂, highest VO₂ value measured; TDI, tissue Doppler imaging; VO₂, oxygen consumption.

Received October 17, 2007.

Accepted April 21, 2008.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Salerno, M. Articles by Cittadini, A. Search for Related Content PubMed PubMed Citation Articles by Salerno, M. Articles by Cittadini, A. Related Collections Pediatric Endocrinology Thyroid Cardiovascular Endocrinology