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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 1 204-212
Copyright © 2002 by The Endocrine Society

Other Original Articles

Cardiac Involvement in Thyroid Hormone Resistance

George J. Kahaly, Clare H. Matthews1, Susanne Mohr-Kahaly, Chris A. Richards and V. Krishna K. Chatterjee

Departments of Endocrinology/Metabolism (G.J.K.) and Cardiology/Angiology (S.M.-K.), Gutenberg University Hospital, Mainz 55101, Germany; and Department of Medicine, University of Cambridge, Addenbrooke’s Hospital (C.H.M., C.A.R., V.K.K.C.), Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Prof. George J. Kahaly, University Hospital, Mainz 55101, Germany. E-mail: kahaly{at}endokrinologie.klinik.uni-mainz.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To analyze the cardiovascular alterations thought to occur in resistance to thyroid hormone (RTH), cardiac involvement in 54 patients with RTH was investigated with the help of two-dimensional and Doppler echocardiography. Data from 41 of 54 adult subjects with RTH were also compared with those of 24 and 20 cases with hyperthyroidism (H) and hypothyroidism (h), respectively, as well as 22 healthy euthyroid controls (C). With respect to the type of mutations, no correlation was found between cardiovascular features and genotype. Compared with affected adults, children with RTH showed markedly higher serum free T3 (FT3), free T4 (FT4), and baseline TSH concentrations. Compared with healthy children of comparable age, RTH children had significantly higher heart rate and lower left ventricular (LV) ejection fraction (P = 0.006). Also, higher heart rate and FT4 as well as shorter diastolic relaxation of the myocardium (all P = 0.001) between RTH subjects with and without thyrotoxic cardiovascular features were found. Cardiac symptoms (palpitations, 32% vs. 71%) and signs (sinus tachycardia, 26% vs. 79%; atrial fibrillation, 6% vs. 17%) were significantly less frequent in RTH vs. H (all P = 0.001). Compared with C and h, heart rate, cardiac output, stroke volume, and systolic aortic flow velocity were strongly increased in RTH (all P = 0.0001) and H, although ejection (P = 0.0012) and shortening (P = 0.0001) fractions of the LV were markedly lower in RTH vs. H. Diastolic parameters, such as isovolumic relaxation (P = 0.0001) and deceleration time (P = 0.013), were shorter in RTH vs. h and C. In RTH, positive correlations between FT3 and heart rate, and between FT4 and LV ejection fraction were observed, whereas negative correlations between both FT3 and FT4 and isovolumic relaxation were noted. In conclusion, these findings indicate a modulated hyperthyroid effect on cardiac systolic and diastolic function of the myocardium in RTH, whereas other parameters, such as ejection and shortening fractions of the LV, systolic diameter, and LV wall thickness, were comparable to C. Differences in term of cardiovascular changes were smaller between the RTH and C groups than the RTH and the H or h groups. Thus, an incomplete cardiac response to thyroid hormone is present in RTH.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RESISTANCE TO THYROID hormone (RTH) is a dominantly inherited condition of impaired tissue responsiveness to thyroid hormone (TH) (1, 2, 3, 4, 5, 6). With a few exceptions, RTH is caused by mutations in the TRß gene (7, 8, 9). The mutant TR molecules have either reduced affinity for T3 or impaired interaction with one of the cofactors involved in the mediation of TH action (10, 11, 12, 13). These mutants TR interfere with the function of the normal TR, which explains the dominant mode of inheritance (14). After a tight linkage was reported between the TRß locus (15) and RTH, about 600 other cases have been described (16). The first patient had a homozygous deletion of the TRß1 allele, which was the exception to the rule, as all other cases had point mutations or small deletions in the TRß1 gene. Interestingly all mutations found to date cluster in three areas of the TR, with some amino acid positions very prone to mutation (17, 18). TR mutants have also been found that do bind T3, but release the corepressor slower than normal (19, 20). Disruption of the TRß gene in mouse models shows a phenotype reminiscent of the first RTH patients identified to harbor a homozygous deletion (21, 22). Recently, a number of cases have been reported where no mutation has been found in the TRß gene even though biochemical evidence was present (23). It has been argued that the origin of the resistance in these cases is a faulty cofactor (24, 25). This is supported by the recent finding that RXR{gamma} knockout mice display pituitary RTH-like symptoms (26) and that steroid receptor coactivator-1 knockout mice manifest RTH symptoms (27).

The clinical presentation of RTH is heterogeneous and highly variable. The first patients described with RTH had a very specific phenotype consisting of short stature, delayed bone maturation, and deaf-autism (1). Future research has shown, however, that a wide variety of symptoms exist in this patient group (28, 29, 30, 31). Some subjects may manifest symptoms suggestive of TH deprivation, such as growth retardation, whereas others show signs of TH excess, such as tachycardia. The expression of mutant TRß in mice results in an animal model of RTH with lower body weight, hyperactivity, and learning problems, similar to the problems found in humans (32, 33). Depending on the clinical presentation, RTH has in the past been divided into two classes (34, 35). Patients who are able to maintain peripheral euthyroidism by increasing the T4 production, which compensates for the decreased tissue sensitivity, or who present with hypothyroid symptoms were classified as generalized resistance (GRTH). Those patients who presented with hyperthyroid symptoms were classified as having pituitary resistance (PRTH). Unfortunately the distinction is not as clear as it may appear at first glance and has no firm pathophysiological basis. Hyperthyroid symptoms have also been found in patients with GRTH; furthermore, no significant differences between GRTH and PRTH exist when parameters such as age, sex, goiter frequency, and TH levels are compared (3, 28).

The only instance of death attributed to RTH is that of an 8-yr-old child, homozygous for a deletion of one amino acid in the TRß molecule, who succumbed to heart failure (36, 37). The spectrum of the phenotypic expression of RTH, including cardiac manifestations, is a reflection of the variability of tissue sensitivity within and between kindreds. Formerly, the cardiovascular response to TH was assessed by two imperfect parameters, QKd and systolic time intervals, both lacking reproducibility and precision (38). To analyze cardiac activity and alterations of cardiovascular function thought to occur in RTH as well as to look for differences between subjects with and without thyrotoxic cardiac features, we used M-mode, two-dimensional, and Doppler echocardiography, an accurate noninvasive technique for the evaluation of global and regional left ventricular (LV) function (39, 40, 41). Further, with the help of this technique, early and subtle alterations in cardiac function can be detected by analysis of LV wall motion and measurement of the ejection fraction. These results were compared with those in groups of hyperthyroid (H) patients, hypothyroid (h) patients, and euthyroid healthy controls (C). We speculated that echocardiography would be a useful technique to quantify and monitor cardiac function in the three groups of patients. We hypothesized that the resting cardiovascular changes associated with H or h would be significantly different from those observed with RTH.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Cardiac involvement in 54 patients with RTH [32 females, aged 4–64 yr; mean ± SD, 38 ± 12 yr; weight, 65 ± 13 kg; height, 1.61 ± 0.08 m; body surface area, 1.68 ± 0.18 m2; free T4 (FT4), 36 ± 14 pmol/liter; FT3, 13.2 ± 6 pmol/liter; TSH, 2.46 ± 2.3 mU/liter; 17 unrelated families] was investigated, and the findings for 41 of 54 adult subjects (>18 yr) with RTH were compared with those for 24 cases with autoimmune H, 20 cases with h, and 22 euthyroid healthy C (Table 1Go). The ethical committee approved the investigations, and informed consent was obtained from all patients and C before participation. We selected H subjects with no history of arrhythmia, valvular or coronary heart disease, or neuromuscular or pulmonary disease. The diagnosis of H (or h) was based on increased (or decreased) FT3 and FT4 levels, as well as suppressed (elevated) TSH. Serum FT3 (range, 3–7.5 pmol/liter), FT4 (9–20 pmol/liter), and TSH (0.4–4 mU/liter) were measured using commercially available kits. The diagnosis of RTH was confirmed in V. K. K. Chatterjee’s laboratory (University of Cambridge, Cambridge, UK) by DNA analysis for detection of mutations in the TRß gene (exons 9 and 10). The noted mutations were R243W (n = 1), A279V (n = 2), R282S (n = 4), S314Y (n = 6), R320C (n = 1), R320L (n = 2), Y321S (n = 4), G332E (n = 2), M334R (n = 3), R338W (n = 2), I431T (n = 1), H435Y (n = 1), R438C (n = 8), R438H (n = 9), C446R (n = 3), F451S (n = 3), and P453S (n = 2). In 2 of 54 (4%) RTH subjects (twin sisters), no mutations were found.


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  		Table 1. Clinical characteristics and hormonal pattern of the four adult study groups

 
Echocardiography

A complete two-dimensional echocardiography and Doppler examination was performed in all patients at the time of study entry using an ultrasound system (Vingmed CFM 800, Sonotron, Horton, Norway) equipped with a 2.5-MHz transducer and an integrated echocardiography digitizing system (Macintosh, Echo PAC, version 4.1.3). Patients performed the identical protocol at baseline and were free of cardiovascular medication. An M-mode echocardiogram directed by two-dimensional imaging was recorded simultaneously with an electrocardiogram, phonocardiogram, and carotid pulse tracing. Images were stored on videotape and on magneto-optical disks in digital format. Analysis of echographic and Doppler measurements was performed using an off-line workstation (Echo-com) by one experienced cardiologist (S.M.K.), blinded to the patient’s TH status. Measures included LV shortening fraction and cardiac output (both parameters of global LV function), stroke volume (a parameter of systolic global LV function), systolic preejection period (the isovolumic contraction time of the LV before opening of the aortic valve), diastolic isovolumic relaxation period (the time interval between the aortic valve closure and the mitral valve opening), and deceleration time of the E-wave (the early passive diastolic inflow in the LV). End-diastolic and end-systolic volumes were measured from apical two- and four-chamber views, stroke volume and LV ejection fraction were calculated using the modified Simpson technique according to the guidelines of the American Society of Echocardiography. LV wall thickness was measured from parasternal M-mode echocardiograms. LV diastolic function parameters, mitral E and A wave velocities, and isovolumetric relaxation and deceleration times of the E wave as well as maximal aortic flow velocity were recorded by pulsed wave Doppler. LV dimension measurements were related to body surface area. LV diameters are one-dimensional measurements derived from M-mode echocardiogram, whereas LV volumes are derived from two-dimensional echocardiography using the Simpson method. All measurements were made on three representative cardiac cycles, and mean values were calculated. For evaluation of LV size and function by echocardiography in children with RTH, normal values of echocardiographic measurements for 2036 healthy mid-Europeans infants, children, and young adults without heart disease or a history of cardiac involvement in infectious, neuromuscular, or metabolic disorders, recently examined at the Department of Pediatric Cardiology, Gutenberg University Hospital (Mainz, Germany), were considered (42).

Statistical analysis

Data are expressed either as the median value and range or as the mean value ± SD. Kruskal-Wallis, Wilcoxon’s for paired observations, and Spearman’s tests were performed using SAS software (43). The Mann-Whitney U test for multiple comparisons and the Wilcoxon signed-rank test were used as appropriate. Paired comparisons of more than two proportions were analyzed using the Bonferroni adjustment. The correlation coefficients were generated with either the Pearson (homogeneous distribution) or the Spearman rho bivariate correlation test. Statistical significance was accepted at the 95% confidence level (P < 0.05).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Cardiovascular symptoms and signs were significantly less frequent in RTH vs. H (Fig. 1Go). A mitral valve prolapse with an audible murmur was present in only 2 RTH cases. According to a clinical scale for H (44), cardiovascular symptoms (palpitations, dyspnea, sweating, heat tolerance, weakness, etc.) were more frequent and severe among patients with H (median score, 24; range, 10–31) than in those with RTH (median, 9; range, 2–18; P = 0.0001). Cardiac symptoms and signs (e.g. sinus tachycardia and atrial fibrillation) were different within family members with the same mutation. Six RTH patients had thyroid surgery and were receiving levothyroxine substitution (0.1–0.2 mg/d), and six were receiving antithyroid drugs (carbimazole, 5–20 mg/d). In these 12 RTH subjects, the number of cardiac symptoms as well as the magnitude of the heart rate were not significantly different.



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  		Figure 1. Cardiovascular symptoms (palpitations and dyspnea) and signs (sinus tachycardia, atrial fibrillation, and mitral valve prolapse) in 54 patients with RTH ({square}) and 24 subjects with autoimmune Graves’ hyperthyroidism ({blacksquare}).

 
Cardiovascular features according to genotype

No correlation was found between cardiovascular features and the type of mutation. Four major cardiovascular parameters (heart rate, cardiac output, and ejection and shortening fractions of the LV; Fig. 2Go) showed no significant differences in eight groups of RTH patients with different mutations. Heart rate was high, especially in subjects with the mutations Y321S (two children and two adults), M334R (two children and one adult), and C446R (two children and one adult). At least half of the RTH subjects showed a hyperdynamic heart, e.g. ejection (>60%) and shortening (>35%) fractions of the LV. Also, no significant differences were observed regarding the number of subjects with cardiovascular features within the five groups of families with the most observed mutations, R282S, S314Y, Y321S, R438H, and R438C (Table 2Go).



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  		Figure 2. Cardiovascular features [A; heart rate (HR), beats per min (bpm)], cardiac output (B; CO), LV ejection fraction (C; EF), and LV shortening fraction (D; FS) according to eight different types of mutations (R282S, S314Y, Y321S, M334R, R438C, R438H, C446R, and F451S).

 

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  		Table 2. Cardiovascular features in affected families and in RTH subjects with the most frequent type of mutations

 
RTH subjects with and without thyrotoxic cardiovascular features

Median age, heart rate, baseline TSH, and FT4 were higher, and diastolic isovolumic relaxation time was shorter in the RTH subjects with thyrotoxic cardiac symptoms and signs compared with those without palpitations and tachycardia (Table 3Go). All other cardiovascular parameters showed no significant differences between the two RTH groups.


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  		Table 3. RTH subjects without and with thyrotoxic cardiovascular features

 
Children with RTH

Table 4Go compares the cardiovascular findings of the RTH children (n = 13; median age, 10 yr; median weight and height, 27.5 and 1.36 m, respectively; FT3: median, 18; range, 9.0–21.6 pmol/liter; FT4: median, 38; range, 25–65 pmol/liter; baseline TSH: median, 2.5; range, 1.4–8.9 mU/liter) with a large group of healthy controls of comparable age. A significantly higher heart rate and a larger diameter of the left atrium as well as a lower LV ejection fraction were noted in affected children.


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  		Table 4. Cardiovascular data of RTH children and of a large healthy control group of comparable age

 
Comparison among the four adult study groups

Heart rate, stroke volume, cardiac output, and maximal aortic flow velocity were significantly lower in RTH compared with H, but were higher compared with C and h (P = 0.0001, by Kruskal-Wallis test among all 4 study groups). Stroke volume, cardiac output, aortic flow velocity, and isovolumic relaxation time showed a hyperthyroid pattern, whereas the systolic and diastolic diameters of the LV were not significantly different from C. In RTH, ejection and shortening fractions of the LV were comparable to C and significantly different from H. Diastolic relaxation time was shortest in H, followed by RTH, C, and h. Other diastolic parameters did not show any conclusive differences. In subjects with H, hyperkinetic LV wall motion was noted, whereas in RTH, no wall motion abnormalities were registered. Furthermore, in the RTH group, there was a tendency for increased volume of both the LV as well as the left atrium without hypertrophy of the myocardium. In this group, aortic diameter (2.78 ± 0.42 cm) and thickness of the LV posterior wall (0.75 ± 0.14 cm) were at the upper level of the normal range. All in all, RTH patients demonstrated intermediate cardiac systolic and diastolic function parameters between H and C, but clearly different from h. Table 5Go lists 15 different measurements showing 9 similarities between RTH and C, 6 similarities between RTH and H individuals, and only 2 similarities between RTH and h subjects.


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  		Table 5. Comparison of the cardiovascular data among the four adult study groups

 
Relation between TH levels and cardiovascular parameters

In subjects with RTH, positive correlations between FT3 and heart rate (r = 0.52; P = 0.002) and between FT4 and LV ejection fraction (r = 0.359; P = 0.012) were observed, whereas negative correlations between both FT3 and FT4 and isovolumic relaxation time (r = -0.7; P = 0.0032 and r = -0.6; P = 0.0039, respectively), were noted as well as between FT4 and both end-diastolic diameter (r = -0.41; P = 0.005) and stroke volume of the LV (r = -0.302; P = 0.030; Fig. 3Go).



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  		Figure 3. In subjects with RTH, positive correlations between free T3 and heart rate [HR, beats per min (bpm); r = 0.52; P = 0.002; A) and between free T4 and LV ejection fraction (EF; r = 0.359; P = 0.012; B) were observed, whereas negative correlations between both FT3 and FT4 and isovolumic relaxation time (IVR; r = -0.7; P = 0.0032 and r = -0.6; P = 0.0039, respectively; C and D) were noted, as well as between FT4 and LV diastolic diameter (LVDD; r = -0.41; P = 0.005; E) and stroke volume of the LV (SV; r = -0.302; P = 0.030; F).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Cardiovascular data

This is the first prospective controlled study systematically evaluating cardiovascular involvement in a large group of children and adults with RTH compared with at least 20 subjects from each of 3 groups, namely, h, H, and C. It is even more significant because interpretational bias has been removed through the services of an experienced cardiologist blinded to the patient’s diagnoses or group assignment. Many of the RTH patients we investigated were family members who had been picked up by biochemical screening. In this manuscript the data were analyzed according to genotype and showed no significant correlation with the type of mutation. Data have also been analyzed based on whether the RTH patients did or did not have associated peripheral thyrotoxic signs or symptoms. In particular, cardiac manifestations have been correlated. To analyze cardiac performance in this syndrome, we used M-mode, 2-dimensional, and Doppler echocardiography, the best noninvasive method to study diastolic and systolic function in members of kindreds with RTH. Comparing four groups of subjects (RTH, H, h, and C), cardiac investigation revealed enhanced LV contractile function as well as shorter diastolic parameters in patients with RTH in contrast to C and h, whereas compared with H subjects, Doppler velocities were slower, and systolic cardiac performance was still in the normal range. The findings bring out the fact that some parameters in RTH were moving toward H (cardiac output and stroke volume as well as isovolumic relaxation and deceleration times), but others were not. Typically, H is characterized by an increased LV systolic contractile function and diastolic relaxation, whereas the opposite is observed in h. This study shows that subjects with RTH displayed more evidence of H at the level of the heart compared with h. For many parameters, RTH patients had values that were between H and C. These findings indicate a modulated hyperthyroid effect on cardiac systolic and diastolic function of the myocardium in RTH, whereas other parameters, such as ejection and shortening fractions of the LV, systolic diameter, and wall thickness, were comparable to those in C. Differences in terms of cardiovascular changes were smaller between the RTH and C groups than between the RTH and the H and h groups. This is based on Table 5Go, which lists 15 different cardiac measurements showing 9 similarities between RTH and C. Thus, in this study an incomplete response of the heart to TH was present in RTH.

Cardiovascular symptoms and signs

Tachycardia has been reported as a cardinal feature of RTH, and the results of this study support this concept, at least in resting conditions. In contrast, Brucker-Davis et al. (45) found resting tachycardia in only 16% of subjects with RTH (compared with 12.5% of unaffected C), and the resting pulse overall was similar in subjects of the same age who did not have RTH. As Holter monitoring was not performed during this study, no information can be derived for heart rate while sleeping or during exercise. Interestingly, cardiac symptoms and signs were different within family members with the same TRß mutation. Furthermore and in contrast to Brucker-Davis’ paper, only 2 of our 54 RTH subjects (4%) had mitral valve prolapse, a condition reported to be frequent in autoimmune thyroid disease (46, 47). Moreover, our 3 RTH cases with arrhythmia suggest less resistance in the heart than in the pituitary for these patients. TH has complex direct and indirect actions on the heart, including possible nonnuclear effects. The heart is relatively less resistant than other organs, possibly because TR{alpha} and TRß genes are predominant in the atrial myocardium (48). The liver and pituitary express predominantly TRß, whereas TR{alpha} is the major species detected in myocardium. Therefore, mutations in TRß are likely to be associated with pituitary and liver resistance, whereas the tachycardia may represent retention of cardiac sensitivity to TH acting via a normal {alpha} receptor (49). Indeed, TRß-deficient RTH mice have a normal TH-dependent increase in heart rate, whereas mice deficient in TR{alpha}1 manifest bradycardia (50). Of interest and to investigate the direct cardiac effects of mutant TR expression on cardiac function, a transgenic mouse that expresses the mutant ß1 isoform exclusively in the heart was recently generated (51). In these mice, there was marked induction of the ß-myosin heavy chain (ß-MHC) mRNA and reduction in {alpha}-MHC expression, which recapitulated the changes observed in h. Treatment of these mice with TH was not associated with either down-regulation of ß-MHC expression or up-regulation of {alpha}-MHC expression indicating RTH. Contractile function showed cardiac abnormalities similar to those present in h animals, such as prolonged QRS in the electrocardiogram.

Children with RTH

Compared with healthy subjects of comparable age, our RTH children had significant differences with respect to heart rate and diameter of the left atrium. Further and probably due to the enhanced heart rate, the LV ejection fraction was highly significantly lowered in our RTH children. In contrast to our findings, in a previous paper from the NIH (45), no significant differences in heart rate, LV contractility, or diastolic function were found between affected children and unaffected C despite significant differences in TH. In the NIH study, in affected RTH adults, echocardiography showed an enhanced systolic cardiac performance, with a smaller diameter of the LV during systole and increased LV shortening fraction, suggesting enhanced cardiac sensitivity with age. Furthermore, in adults treated with T3 with normalization of TSH, the isovolumic contraction time (or preejection period) was decreased compared with unaffected C. Resting pulse tended to be faster in subjects with RTH as a group, but not after adjustment for age. Thus, in the NIH study, adults, but not children, with RTH showed increased cardiac contractility, as found in H, but contractility was still less than that expected given the level of TH, indicating some degree of resistance in the ventricle. This could suggest that a child’s heart may be more resistant to TH. One possible mechanism for a relative decrease in cardiovascular resistance with age could involve a decrease in the mutant/normal receptor ratio.

RTH subjects with and without thyrotoxic cardiovascular features

Compared with RTH subjects without cardiac signs, median age, heart rate, and TH levels were higher, and diastolic relaxation was shorter in those with palpitations and tachycardia. Nevertheless, all other cardiovascular parameters showed no significant differences. Clinical studies have been unable to demonstrate that the peripheral tissues of patients with PRTH have different sensitivity to TH than those of patients with GRTH. In favor of PRTH are in vitro studies showing that some TRß mutations may interfere more strongly with the suppressive than stimulatory effects of TH (52). Yet subjects harboring the same mutations have been classified as having GRTH and PRTH. It has therefore been argued that the distinction between the two is artifactual and based on the poor definition of the symptoms. PRTH and GRTH can therefore be viewed as two sides of a spectrum of a single gene disease. A possible reason for the variability in symptoms could be that not all individuals express the same levels of TR (both mutant and normal) in their tissues (53). When the ratio between mutant and normal TR changes, so will the final effect of the mutant receptor. Furthermore, not all mutations have the same effect on T3 binding (54). Another factor could be the different tissue distribution of the TR. For instance, the heart is a predominantly TR{alpha} tissue. As the TR{alpha} is normal in RTH patients, but their FT3 levels are high, it can be expected that they will react to the extra amount of T3 in a hyperthyroid manner as far as the heart is concerned. Furthermore, not every individual will express the same amount of TR or corepressors/coactivators in a particular tissue, leading to differences between individuals. An interesting observation in this context is that some mutations are more deleterious when present in the TRß2 then in the TRß1. As the TRß2 expression is restricted to the pituitary, it may be expected to give rise to a PRTH phenotype.

Thus, we now believe that RTH is a single genetic entity. We have documented the same receptor mutations in GRTH and PRTH cases, and these phenotypes often exist even within one family (55). The most likely explanation for the variable clinical manifestations of this apparently monogenic condition is the genetic heterogeneity of the many cofactors that modulate the receptor-dependent action of TH. On the other hand, it is interesting that we found some differences (higher heart rate, shorter diastolic relaxation) in RTH subjects with cardiac features. Overall, the numbers of patients we studied were too small to draw any clear conclusions. Nevertheless, in the future, it would be interesting to analyze more cases with a PRTH phenotype, particularly those harboring mutations (e.g. R338W/L, V349M, R383H, R429Q, and I431T), where there is increasing evidence from us and others of an association with a relative lack of peripheral tissue resistance.


   Acknowledgments
 
We are indebted to Joachim Pohlenz, M.D., Department of Pediatrics, Gutenberg University Hospital (Mainz, Germany), for critically reading the manuscript as well as for the fruitful discussions regarding the presentation of data. We also thank Dipl. Stat. Gerd Rippin, Ph.D., and Prof. Dipl. Stat. Gerhard Hommel, Ph.D., Department of Medical Statistics and Documentation, Gutenberg University School of Medicine, for excellent statistical advice. Finally, we thank Charles Graham, Department of Medicine, University of Cambridge (Cambridge, UK), for his assistance with echocardiography.


   Footnotes
 
This work was supported by the Wellcome Trust (to V.K.K.C.).

1 C.H.M. is a Wellcome Trust Advanced Training Fellow. Back

Abbreviations: C, Control; FT3, free T3; FT4, free T4; GRTH, generalized resistance to thyroid hormone; H, hyperthyroidism; h, hypothyroidism; LV, left ventricular; ß-MHC, ß-myosin heavy chain; PRTH, pituitary resistance to thyroid hormone; RTH, resistance to thyroid hormone; TH, thyroid hormone.

Received February 6, 2001.

Accepted October 8, 2001.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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