Recombinant human TSH to avoid l-thyroxine withdrawal in congenital hypothyroidism

Topic: RhTSH & CONGENITAL HYPOTHYROIDISM

Title: Recombinant thyrotropin in the diagnosis of congenital hypothyroidism.

Authors: Tiosano D, Even L, Orr ZS, & Hochberg Z

Reference: Journal of Clinical Endocrinology & Metabolism, 92: 1424-1437, 2007

Summary

Background

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.

Purpose

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.

Patients

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 re-evaluated while on thyroid replacement therapy.

Methods

Patients received 0.6 mg/m 2 rhTSH (by im injection) on two consecutive days.

Results

RhTSH pharmacokinetics, maximal concentration, t 1/2, and area under the curve in children were different as compared with adults. In the patients with intact TSH receptors, free T 4 levels decreased after the first and the second injection of rhTSH (P = 0.014 & P = 0.015, 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.

Commentary

The development of recombinant human TSH (rhTSH) has revolutionized the follow up of adults with thyroid cancer by providing a means to evaluate for the presence of residual and metastatic thyroid tissue without the need to interrupt thyroid suppressive therapy. The use of rhTSH in childhood and adolescence, on the other hand, is only beginning to be explored. Babies with congenital hypothyroidism would seem to be obvious candidates for this approach. Affected infants are commonly seen by the consulting pediatric endocrinologist only after thyroid replacement has been initiated and, because of the critical importance of thyroid hormone on brain development, therapy is usually continued until 3 years of age before therapy is stopped temporarily in order to make a definitive etiological diagnosis. In the present proof of principal study, the possibility that rhTSH might make it possible to make an etiological diagnosis in babies with congenital hypothyroidism without the need to interrupt thyroid hormone treatment is explored.

Eight patients with congenital hypothyroidism of different etiologies, ranging in age from 5-15 yrs were treated with 2 injections of rhTSH 24 hours apart, using a dose of 0.6 mg/m 2 (extrapolated from adult studies). Scintigraphy and thyroid function studies were performed at 48 hours and compared with results after thyroid hormone withdrawal. Scintigraphy results were identical after both methods and the drug was well tolerated. A somewhat surprising result was that the both the free T 4 and free T 3 concentrations appeared to decrease in several of the patients after rhTSH stimulation.

Before these results can be applied to babies, a number of issues remain to be clarified. As is so often the case, the present study demonstrates once again that children are not merely -little adults-. The peak TSH level (C max ) was twice that reported in adults treated with a similar rhTSH dose, and the t 1/2 was significantly shorter, consistent with previous evidence that the metabolism and clearance of TSH is different in children than in adults. Whether a smaller rhTSH dose will be similarly effective and whether a second injection is even necessary remain to be explored.

The present pilot study suggests that rhTSH may be a useful tool in the etiological evaluation of children with CH. How safe and effective it will prove to be in infancy and to what extent this study will stimulate novel approaches to other thyroid diseases in infancy and childhood remains to be seen.

( Summary and commentary prepared by Rosalind Brown )

Present summary & commentary are related to the Chapter N- 15 of TDM