PEDIATRICS Vol. 111 No. 5 May 2003, pp. 1055-1060
Treatment for Congenital Hypothyroidism: Thyroxine Alone or Thyroxine Plus Triiodothyronine?
* Department of Pediatrics, University of Bologna, Bologna, Italy
Department of Pharmacology, S Orsola Hospital, Bologna, Italy
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objective. To compare the effects of therapy with thyroxine (T4) plus triiodothyronine (T3) versus T4 alone from the first days of life in screened congenital hypothyroid (CH) infants.
Methods. We examined 14 CH infants diagnosed by neonatal screening and a group of control infants. CH patients were divided randomly into 2 groups, 1 treated with T4 alone (group 1) and the other treated with T4 plus T3 (liothyronine; group 2). In all patients electrocardiography and thyroid hormone evaluations were performed before and 15 and 30 days and 3, 6, and 12 months after the beginning of therapy. Psychological tests were also performed at 6 and 12 months of age in CH patients and in other matched controls.
Results. After 15 days of treatment, serum thyrotropin (TSH) levels become normal in 5 of 7 cases of group 1 (median TSH level 10.7 µU/ml) and in 1 of 7 cases of group 2 (median TSH level 72.5 µU/ml). At the same period, serum-free thyroid hormone levels were within the normal range in both groups, but free T4 values were significantly higher in group 1 than in group 2 and in controls. At the subsequent examinations, free T4 values were within the upper normal limit in group 1, whereas they remained within the normal range in group 2. No clinical or electrocardiographic signs of heart disease were found in any of the patients. The psychometric quotient in CH infants was significantly lower than in controls, but similar in patients of group 1 and group 2.
Conclusions. The combined treatment with T4 plus T3 seems not to show significant advantages, at least in our experimental conditions, compared with the traditional treatment with T4 alone in early treated CH infants. A further longer and more extensive follow-up is mandatory.
Key Words: congenital hypothyroidism • neonatal screening • thyroid hormone replacement therapy
Abbreviations: T4, thyroxine • T3, triiodothyronine • CH, congenital hypothyroid • TSH, thyrotropin • fT4, free thyroxine • fT3, free triiodothyronine
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INTRODUCTION |
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Synthetic thyroxine (T4; levothyroxine) is today the drug of choice for treating congenital hypothyroid (CH) infants diagnosed by neonatal screening. It is well-known that only a smaller proportion (
20%) of the daily production of triiodothyronine (T3) is secreted directly by the thyroid gland while the major source derives from the deiodination of T4 in extrathyroidal tissues. Although also thyroidal T3 synthesis is deficient in subjects with primary hypothyroidism, the current hypothesis is that peripheral conversion of the orally administered T4 to T3 is able to compensate for this slight deficiency and to ensure euthyroidism.1–3 For this reason, the discovery of synthetic levothyroxine made the extracts of animal thyroid tissue previously used rapidly obsolete. These extracts contained both T4 and T3, but suffered from variable potency and possible adverse cardiac effects.4 However, in the early 1980s, minimal brain dysfunction was observed also in CH infants treated early with levothyroxine,5,6 and studies thereafter gradually uncovered various controversial aspects of this treatment.7–9 Some authors believed initial high doses were necessary to maintain circulating T4 concentrations within the upper limits of the normal range to ensure the best therapeutic results in all cases,7 whereas others felt it was more useful to vary therapy according to the severity of the CH, pointing out possible long-term side effects from overtreatment in the first few months of life.8,9 Although this debate is taking place, recent studies in thyroidectomized rats have concluded that not all tissues are equally able to convert T4 to T3 and that euthyroidism is not restored in plasma and in all tissues using T4 alone, but only using the combined therapy with T4 and T3.3,10 More recently, Bunevicius and colleagues11 have reported a significant improvement in mood and neuropsychological function in adult hypothyroid patients treated with a combination of T4 and T3 compared with a higher dose of T4 alone.
To our knowledge, no studies have been conducted on this combined replacement therapy in CH infants screened and treated precociously in the postnatal period. Therefore, we examined 14 CH infants diagnosed by neonatal screening and a group of control infants; the CH infants were divided randomly into 2 groups, 1 treated with T4 alone and the other treated with T4 plus T3 (liothyronine).
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METHODS |
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Patients and Study Design
Fourteen consecutive CH infants diagnosed at our Center between February 1999 and May 2000 by neonatal screening were enrolled in the study with parental consent. Patients were all at term/normal weight infants and congenital heart defects and/or serious medical illnesses were excluded.
Before starting replacement therapy, each CH infant was assigned randomly to group 1 or group 2 alternately. Patients in group 1 received a drug preparation with T4 alone (initial dose 10 µg/kg per day); patients in group 2 received a drug preparation in which every 25 µg of the levothyroxine dose calculated for body weight was replaced by 20 µg of T4 and 1 µg of T3. This dose was chosen on the basis of patient’s age, pharmacological effects of T3, and reported T4/T3 molar ratio for human thyroid production.1 Table1 reports neonatal parameters and spot values in CH infants of both groups.
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The CH patients were examined in a longitudinal study for the first time at 15 (8–24) days of age before starting therapy, after 15 and 30 days from the beginning of therapy and then at 3, 6, and 12 months of age during the first year of therapy (Tables 2–4). The dosage of T4 and T4 plus T3 was adjusted in an attempt to keep the serum thyrotropin (TSH) and free thyroid hormone concentrations within the normal range for our laboratory.12 At each examination, in all patients pulse rate was recorded, electrocardiography was performed, and blood samples were taken to determine TSH and free thyroid hormone serum levels. Serum-free thyroid hormone and TSH levels were measured by commercial chemiluminescent assay (Bayer, Fenwald, Germany).
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At 6 and 12 months of age, the CH infants underwent psychomotor evaluation by means of the Brunet-Lezine test.13
Controls
Two different cohorts of control infants (obtained cross-sectionally) were examined.
For the comparison with thyroid function, TSH and free thyroid hormone levels were measured in 6 different groups of healthy infants age- and sex-matched with CH infants at each examination (42 infants in all; 14–376 days old; Table2). The blood samples taken from these controls were incidental to venipuncture for other purposes (eg, screening control or normal humoral control after an acute disease).
For the comparison with psychomotor function, for each CH patient at 6 and 12 months of age a control subject matched for age, sex, and socioeconomic condition was examined by means of the Brunet-Lezine test (Table5). These controls came from a survey conducted by the school authorities with the consent of the parents in the local crèches. The examiner was the same for all pathologic and control subjects and was unaware of the patients’ treatment assignation.
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Statistical Analysis
All statistical analyses were performed using the computer program Statistical Package for the Social Sciences (SPSS, Inc, Chicago, IL). Nonparametric statistical analysis (Mann-Whitney U, Kruskal-Wallis, and Wilcoxon tests) was considered suitable for a low amount of data. All results were expressed as median and range.
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RESULTS |
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TSH Levels
Pretherapy serum TSH levels were significantly higher in group 2 than in group 1. After 15 days of treatment, they decreased in both groups, although more significantly so in group 1 than in group 2 (Table2). In group 2, TSH serum concentration decreased >90% compared with pretherapy levels in 3 of 7 cases (Table4, cases 2, 4, and 5) corresponding to the subjects with less severe forms of CH (presence of thyroidal tissue and T4 spot values >4 µg/dL). In group 1, this kind of decrease was found in 7 of 7 cases, regardless of the degree of severity of prenatal CH. Furthermore, TSH values became
10 µU/ml at the first control after the beginning of therapy in only 1 of 7 cases in group 2 (Table4, case 5) and in 5 of 7 cases in group 1 (Table3, cases 1 and 4–7). After 1 month of treatment, serum TSH levels were unchanged in group 1; they further decreased in group 2, but remained significantly higher than in controls (Table2). These differences disappeared subsequently.
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Free Thyroid Hormone Levels
After 15 days of treatment, serum free T3 (fT3) levels were within the normal range in both groups. Free T4 (fT4) values were significantly higher in subjects of group 1 than in subjects of group 2 and in controls (Table2); 4 of 7 subjects in group 1 (Table3, cases 1, 3, 4, and 7) showed fT4 levels that were higher than the upper limit of the normal range, whereas all subjects in group 2 showed fT4 levels within the normal range. At subsequent examinations fT3 and fT4 levels remained within the normal range in patients of group 2, serum fT4 levels were sometimes in the upper limit of the normal range in patients of group 1 (Tables3 and 4).
Therapeutic Doses and Side Effects
In patients of group 1, the therapeutic dose was increased only in 1 of 7 cases (Table3, case 2) at the first examination after 15 days of treatment. In another patient (Table3, case 3) the therapeutic dose was increased only at the subsequent examination after 30 days of treatment because of strongly decreased TSH levels and to fT3 and fT4 levels in the upper limit of the normal range observed after 15 days of treatment. In patients of group 2 at the first examination after 15 days of treatment the therapeutic dose was increased in 6 of 7 cases (Table4, cases 1–4, 6, and 7). In the first 6 months of therapy, the therapeutic dose was adjusted more than once in only 1 of 7 patients in group 1 (Table3, case 2) and in 4 of 7 patients in group 2 (Table4, cases 1–3 and 6). No clinical or electrocardiographic signs of heart disease were found in any of the patients.
Psychomotor Assessment
At the 6th and 12th month of life, the psychometric quotient in CH infants was significantly lower than in controls (P < .05), but similar in patients of group 1 and group 2 (Table5).
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DISCUSSION |
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The aim of hormonal replacement therapy is to ensure an adequate supply of the missing hormone to mimic, as far as possible, its physiologic secretion. The treatment with T4 alone, which is the main but not the only product of the thyroid gland, may appear, in this sense, a less physiologic approach. In fact, in the early 1980s, Silva and Larsen,14 in experimental studies, characterized different deiodinative pathways in different tissues and pointed out their role in regulating a different T3 intracellular production, even when circulating levels of thyroid hormone were normal.14–16 This idea of "a biochemical euthyroidism that is not always the expression of euthyroidism of the tissues" was recently resumed by Escobar-Monreale and colleagues3 in studies on thyroidectomized rats. The authors concluded that only the combined treatment with T4 plus T3 could normalize the hormone concentration simultaneously in plasma and in all tissues examined and pointed out the possible implications of these results in the treatment of hypothyroidism in man. The only data in the literature concern a group of adult hypothyroid patients and appear to confirm the hypothesis derived from experimental studies on the therapeutic benefits of combined therapy.11
Although performed in a small sample of patients, our study is, to our knowledge, the first in the literature to compare the effects of treatment with T4 plus T3 and with T4 alone from the first days of life in CH infants. Its results seem to indicate that levothyroxine alone is more effective than combined treatment in fast restoring euthyroidism, especially at the hypothalamus-pituitary level, as assessed on the basis of different normalization times of circulating TSH levels at onset of therapy in the 2 groups of patients. However, it should be noted that there is still disagreement on the main aims of CH treatment in the postnatal period, which is a critical time for brain development. Many authors believed that the rapid decrease in plasma TSH levels was the main indicator for the normalization of the biological effects of thyroid hormones in tissues and hence 1 of the most desirable therapeutic effects.7 Others suggested that, at least in certain cases, fetal hypothyroidism could affect the threshold value of pituitary feedback and that rapid normalization "at any cost" of TSH levels could lead to a risk of overtreatment.8,9 In fact, the group 1 patients in our study, although treated with levothyroxine doses that were not very high compared with those reported in literature, showed circulating levels of fT4 after the start of therapy that was significantly higher than controls, in some cases within the thyrotoxic range. Although less marked during the subsequent follow-up, this pattern did not completely disappear. In this regard, the studies by Escobar-Monreale seem to indicate that, at least in experimental animals, these supraphysiological hormone concentrations are not just seen in plasma but can affect also many tissues examined.10
From this point of view combined T4 and T3 treatment seems to be a more physiologic approach: in fact, during follow-up, patients of group 2 showed serum fT3 levels similar to those of group 1 without ever reaching supraphysiological fT4 levels. However, the coexistent delay in TSH normalization and the need for a greater number of therapeutic adjustments indicate a certain difficulty in achieving and maintaining euthyroidism in all tissues also using this therapy.
Moreover, it should be pointed out that the failure to benefit from the combined therapy may have been masked by some characteristics of the CH patients we examined. We could test only 14 consecutive CH infants randomly allocated to the 2 different treatment groups. Presumably attributed to the small numbers studied, the groups were quite different in prenatal severity of hypothyroidism (T4 spot values) and in pretherapy TSH serum levels. The latter were significantly higher in patients of group 2, where in fact the greater decrease of TSH after 15 days of therapy was observed in the subjects with a milder form of hypothyroidism. The size and function of residual thyroid tissue can vary greatly, especially as regards T3 secretion and can cause an interference unlikely to be evaluated in the results of combined treatment. From this point of view the administration of T4 alone seems to produce a more homogeneous therapeutic effect. In fact, in our study we found a similar proportion of decrease in TSH levels in the subjects of group 1 although they had different degrees of thyroid defect.
Undoubtedly, the combined administration of T4 and T3 is a replacement therapy that is more difficult to carry out than T4 alone, especially in the early months of life. First, there are no studies in the literature evaluating the molar ratio of the 2 iodothyronines as secreted by the gland in normal or hypothyroid subjects in the early months of life. In the only in vivo study in human adults Pilo and colleagues1 found that the production of T3 by the normal human thyroid represents a much lower amount than in experimental animals (molar ratio T4:T3 equal 14:1 in man and 6:1 in rats) and in currently available commercial preparations.1,3,17 The dose of T3 we supplied is the lowest reported in literature. However, it is also the dose which most mimics the physiologic thyroid production rate found in adults. Furthermore, we observed none of the most commonly reported side effects, especially cardiac-related, in adult patients treated with higher doses.
Another problem with combined treatment is the route of administration. Oral administration of a single daily dose of levothyroxine represents the usual clinical practice, but problems can arise when 2 hormones with different residence times and intestinal absorption rates are administered. In fact, the mean residence time of T3 is shorter and its intestinal absorption is faster than T4 and this can lead to wide and frequent fluctuations in circulating and tissue T3 concentrations. In accordance with Toft,18 we think it could be useful to combine T4 with a slow-release form of T3, but this kind of preparation is currently not available.
It should finally be pointed out that the main aim of early treatment of CH is to achieve a normal brain development. In the above-mentioned studies, the cerebral cortex proved to be the only tissue able to maintain steady and normal concentrations of T3 over a wide range of circulating thyroid hormone levels.10 The factors behind this efficient homeostatic mechanism (modulation of iodothyronine deiodinase, availability of endogenous enzyme cofactors, characteristics of the blood brain barrier) are not yet fully understood, but the mechanism does undoubtedly provide a metabolic protection of cerebral tissue against wide changes in thyroid hormone availability. The first results of the psychomotor assessment conducted in our CH infants indicate psychometric quotients that are not significantly different in the 2 treatment groups but which nonetheless are lower than in matched controls. Therefore, in our experience, the 2 types of treatment, at least at the doses we used, show the same efficacy but are not optimal in an early normalization of the neuropsychological performances of CH infants. In contrast, Bunevicius et al11 found an improvement in mood and neuropsychological function after combined treatment with T4 plus T3; however, these results derived from adult hypothyroid patients treated with very high doses of T3 in whom, in our opinion, the psychological tests, at least in part, may have been influenced by subjective evaluation of well-being.
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CONCLUSIONS |
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These preliminary data seem to indicate that the combined treatment with T4 plus T3 does not show any significant advantage, at least in the short-term, compared with the traditional treatment with T4 alone in early treated CH infants. However, we believe that some parameters need to be reexamined before these results can be considered conclusive. In fact, the fear of provoking undesired side effects and the lack of any reference data in the literature for infants in the first months of life prompted us to use doses of T3 that may have been insufficient and a T4:T3 ratio that was not perhaps optimal. Furthermore, the sample was undoubtedly small and nonhomogeneous, while the follow-up was too short. A further, longer, and more extensive experimental phase with more comparable groups of patients is in our opinion required to provide more reliable indications in an area as controversial as that of early effective CH replacement therapy.
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FOOTNOTES |
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Received for publication May 30, 2002; Accepted Nov 26, 2002.
Reprint requests to (E.C.) Department of Pediatrics, University of Bologna, Via Massarenti 11, 40138 Bologna, Italy. E-mail: cacciari{at}alma.unibo.it
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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