Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2134
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1434-1437
Copyright © 2007 by The Endocrine Society
Recombinant Thyrotropin in the Diagnosis of Congenital Hypothyroidism
Dov Tiosano,
Lea Even,
Zila Shen Orr and
Ze’ev Hochberg
Division of Endocrinology (D.T., Z.H.), Meyer Children’s Hospital, and Endocrine Laboratory (Z.S.O.), Rambam Medical Center, Haifa 31096, Israel; Department of Pediatrics (L.E.), Nahariya Hospital, Nahariya 22100, Israel; and Technion-Israel Institute of Technology (L.E., Z.H.), Haifa 32000, Israel
Address all correspondence and requests for reprints to: Dov Tiosano, Meyer Children’s Hospital, POB 6092, Haifa 31096, Israel. E-mail: d_tiosano{at}rambam.health.gov.il.
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Abstract
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Context: A modern approach to congenital hypothyroidism requires a definitive diagnosis of the underlying mechanisms; this can be achieved within the first weeks of life. When uncertainty persists, treatment is commenced, and the definitive diagnosis of congenital hypothyroidism is deferred to the age of 3 yr.
Objectives: The interruption of thyroid replacement treatment is perceived as risky by parents and physicians. The aim of this pilot study was to test the possibility of a definitive diagnosis during thyroid replacement treatment, using stimulation of thyroid tissue by recombinant human (rh)TSH.
Subjects: Eight patients, three boys and five girls, age 5–15 yr (mean, 9.5 ± 3.7 yr), with congenital hypothyroidism that had been diagnosed by the neonatal screening program, and having their diagnosis verified between the ages of 3–4 yr, were reevaluated while on thyroid replacement therapy.
Interventions: Patients received im 0.6 mg/m2 rhTSH on two consecutive days.
Results: rhTSH pharmacokinetics, maximal concentration, t1/2, and area under the curve in children were different as compared with adults. In the patients with intact TSH receptors, free T4 levels decreased after the first and the second injection of rhTSH (P = 0.0137 and P = 0.0149, respectively). All eight children showed identical scintigraphy after rhTSH administration as compared with thyroid replacement withdrawal.
Conclusions: The use of rhTSH is effective for definitive diagnosis of congenital hypothyroidism during thyroid replacement treatment, and no safety issues were encountered.
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Introduction
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THE INTRODUCTION OF screening for congenital hypothyroidism in 1974 advanced and revolutionized the prognosis of children with congenital hypothyroidism (1). A modern approach to congenital hypothyroidism requires a definitive diagnosis of the underlying mechanisms, which include thyroid dysgenesis and a spectrum of genetic defects. Whereas in many cases, this can be achieved within the first weeks of life and before therapy, in other cases, the answer is not forthcoming. When uncertainty persists, treatment is commenced, and the definitive diagnosis of congenital hypothyroidism is deferred to the age of 3 yr (2).
For diagnostic purposes, thyroid replacement is then discontinued at the age of 3 yr for up to 6 wk. On the last day off thyroid replacement, thyroid hormones are measured, thyroid ultrasonography and thyroid scintigraphy with 99mTc are performed, and a perchlorate washout test with 123I is performed if iodide organification defect is suspected (3).
The hypothesis of this study was that this goal is now feasible with the advent of recombinant human (rh)TSH. rhTSH has been developed for the diagnosis of metastatic thyroid cancer (4, 5) and has proven capable of stimulating a remnant thyroid tissue without interruption of thyroid replacement in cancer patients.
The aim of this pilot study was to test the possibility of a definitive diagnosis during thyroid replacement treatment, using stimulation of thyroid tissue by rhTSH.
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Patients and Methods
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The Helsinki Committee of the Rambam Medical Center, Haifa, approved the protocol, and a written informed consent was obtained from parents. The subjects of this study were three boys and five girls, age 5–15 yr (mean, 9.5 ± 3.7 yr), with congenital hypothyroidism that had been diagnosed by the neonatal screening program. Their diagnosis was then verified between the ages of 3–4 yr (Table 1
). The definitive diagnosis was made after a withdrawal of L-thyroid replacement for up to 6 wk, measuring thyroid hormone levels, cervical ultrasonography, technetium scintigraphy, and perchlorate discharge test with 123I if an iodide organification defect is suspected. Two had a final diagnosis of thyroid agenesis, two had ectopic sublingual thyroid glands, two had an iodide organification defect, and two had TSH receptor defect.
While on thyroid replacement therapy, patients received the usual adult dose of 0.6 mg/m2 im rhTSH (Thyrogen; Genzyme, Kfar-Saba, Israel) at 0 and 24 h. At 48 h, thyroid function tests and technetium scintigraphy were performed. The first two patients that were studied had a complete loss-of function TSH receptor mutation, which prevents any TSH activity. They were chosen as candidates to study the pharmacokinetics of rhTSH. In these two patients, blood samples were obtained initially every 2 h for 8 h and then 8-hourly.
The blood samples were analyzed for TSH, free T4 (fT4), total T3 (tT3), and thyroglobulin (Tg). Serum TSH, fT4, and tT3 concentrations were measured using a Corning automatic chemiluminescence system (Ciba Corning Diagnostics Corp., Medfield, MA). Serum Tg was measured using a Kronus kit (Kronus Corp., San Clements, CA). The data were analyzed by paired Student’s t tests.
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Results
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Pharmacokinetics of rhTSH in children
This was conducted in two children with congenital hypothyroidism due to a loss-of function mutation in the TSH receptor (6), because no side effects were expected from high TSH levels in these children (Fig. 1). After the first injection, patients 1 and 2 reached maximal serum TSH levels of 300 and 120 mIU/liter at 6 or 24 h, respectively, decreasing in patient 1 to 180 mIU/liter at 24 h. After the second injection, TSH levels increased to 851 and 320 IU/ml, decreasing to 42 and 64 mIU/liter, respectively. Maximal serum concentration (Cmax) of TSH after the first rhTSH injection in all eight patients was 602 ± 914 mIU/liter (mean ± SD; range. 104-2851 mIU/liter) and was reached in six of eight children at 8 h (Fig. 2). In the other two patients, Cmax was at 16 and 24 h. Twenty-four hours after the first injection, and before the second injection, TSH levels were 115 ± 60 mIU/liter (mean ± SD; range, 45–310 mIU/liter). After the second injection, seven of the eight patients reached Cmax 700 ± 912 mIU/liter at 8 h; the remaining patient reached Cmax at 16 h. At 48 h, serum TSH levels were lower than the levels at 24 h, 86 ± 43 mIU/liter (P = 0.047). One patient with sublingual thyroid gland reached TSH levels as high as 2800 mIU/liter after the second injection (Fig. 3). Despite these high levels, there were no signs of headaches, nausea, or vomiting in any of the subjects. TSH Cmax did not correlate with the age, sex, body mass index, or the etiology of congenital hypothyroidism. The mean t1/2 of serum TSH was 8.93 h in an exponential model and 11.25 h in a linear model (Fig. 4). The t1/2 in adults was reported at 22.3 ± 8.54 h. The area under the curve of TSH during the 48 h was 14,936 ± 17,859 mIU/h·liter (the area under the curve was in adults was calculated for 90 h and was 5088 ± 1728 mIU/h·liter).
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FIG. 2. TSH pharmacokinetics after rhTSH injections in six patients with congenital hypothyroidism and a normal TSH receptor.
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Thyroid hormones
After the administration of rhTSH, fT4 levels remained unchanged in the two patients with the TSH receptor mutation. In the patients with intact TSH receptors, fT4 levels decreased after the first and the second injection by 13.8 ± 2.8 and 17.22 ± 4.4%, respectively (P = 0.0137 and P = 0.0149, respectively) (Table 2). Tg levels were detectable in the young child with the TSH receptor mutation and in those with sublingual thyroid glands and iodide organification defects. On rhTSH, Tg levels increased from 13–41 to 20–86 ng/ml.
Scintigraphy
All eight children showed identical results after rhTSH administration, compared with scintigraphy obtained after thyroid replacement withdrawal at the age of 3 yr. In children with the TSH receptor mutation, no thyroid gland was visible at scintigraphy. In patients with thyroid agenesis, thyroid scintigraphy revealed uptake only in the submandibular salivary glands. In children with ectopic thyroid glands, both scintigraphy scans showed sublingual uptake, and in iodide organification defects, normal-enhanced uptakes were observed. Representative scintigrams are presented in Fig. 5.
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Discussion
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The etiology of congenital hypothyroidism in the majority of the cases is still an enigma. In an attempt to understand the etiology and tell between genetic and sporadic disease, the modern approach to congenital hypothyroidism requires a definitive diagnosis of the underlying mechanisms. Some causes of congenital hypothyroidism produce persistent hypothyroidism, and others cause transient hypothyroidism. Some causes are clearly related to potentially heritable abnormalities because thyroid dysgenesis and others are heritable and may result from a spectrum of genetic defects.
Whereas in many cases, this can be achieved within the first weeks of life and before therapy (7), in other cases, the answer is not forthcoming. When uncertainty persists, treatment is commenced, and the definitive diagnosis of congenital hypothyroidism is deferred to the age of 3 yr, after a withdrawal for up to 6 wk of thyroid replacement. It was recently shown that even 14 d of L-T4 withdrawal can produce adequate hyperthyrotropinemia (8). The discontinuation of thyroid replacement therapy is not recommended before the age of 3 yr because it is estimated that the main brain development processes are accomplished during the first 3 yr of life, and during this period, thyroid hormones have a crucial role in brain development (9, 10). We now show that a definitive diagnosis can be established by stimulating the thyroid gland with rhTSH while children continue their thyroid replacement treatment.
rhTSH was recently used in children and teenagers with papillary thyroid cancer and in adult patients with congenital hypothyroidism (11, 12). The results in this study can lead to some useful recommendations on the test performance in this age group. Scintigraphy can be usefully performed 24 h after a second rhTSH dose; results in our study are identical to the results attained after up to 6 wk of withdrawal of thyroid replacement.
The present pilot is mostly a proof of a concept in eight children, two for each of four diagnoses. Any statistical analysis is this group of subjects is obviously of limited meaning. rhTSH pharmacokinetics varied markedly between the patients, and no correlation was found between peak TSH levels (Cmax) and the age, sex, or body mass index of the patient. The dose of rhTSH used in this study was based on results obtained in adult studies, adjusting for body surface area. Cmax in our patients was twice as high as those of adult patients, suggesting different metabolism and clearance of TSH in children. Indeed, the t1/2 of the children was significantly shorter than previously reported for adults (13). It turns out that children require a smaller dose; additional clinical studies are needed to adjust the appropriate dose in children.
In the six patients with normal TSH receptor, a small but significant decrease in fT4 levels was noted after each rhTSH injection, whereas in the two patients with TSH receptor defect, fT4 levels did not decrease. Although these results were obtained in a small number of subjects, it might suggest a TSH effect on deiodinase II enzyme, in agreement with in vitro experiments (14, 15, 16). However, additional studies are needed to support this idea.
It should be emphasized that this report is mostly a proof of a concept, and the use of rhTSH is not necessary in the majority of congenital hypothyroidism cases. The use of rhTSH is effective, and no safety issues were encountered. Scintigraphy after rhTSH will diagnose sublingual thyroid and show the presence of a thyroid gland in iodide organification defect. The latter will also respond to rhTSH by a marked elevation of Tg levels. The diagnosis of thyroid agenesis, hypoplasia, and various genetic forms will be assisted by quantification of the Tg response to rhTSH.
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Acknowledgments
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rhTSH (Thyrogen) was a donation by Dr. A. Oved from Genzyme, Israel.
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Footnotes
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Presented at the annual meeting of the European Society for Pediatric Endocrinology (ESPE), 2005.
Disclosure Summary: D.T., L.E., Z.S.O., and Z.H. have nothing to declare.
First Published Online February 6, 2007
Abbreviations: fT4, Free T4; rh, recombinant human; Tg, thyroglobulin; tT3, total T3.
Received September 29, 2006.
Accepted January 26, 2007.
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Abstract
Introduction
