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It has to be emphasized that the process of spontaneous deterioration of thyroid function, that may occur over time in the children with HT-related SH, may be very slow and not predictable in the single case [ 19 ]. Therefore, although surveillance is mandatory in all these cases, it might be necessary a long time to infer whether L-T4 treatment should be implemented or not [ 20 ].

Thus, an elevated TSH at HT diagnosis could be considered as the best predictor for a thyroid function deterioration from SH to overt hypothyroidism, as already suggested by other studies concerning patients with SH and no underlying AITDs [ 32 , 33 ]. Finally, another factor which might exert a negative impact on the long-term evolution of SH is the association with either TS or DS, two chromosomopathies that may be linked with an increased risk of thyroid status deterioration over time [ 25 , 26 , 34 ].

Such a presentation pattern of HT, that is also called Hashitoxicosis Htx , is not very common in the pediatric age, although Htx is generally reported as the second commonest cause of hyperthyroidism in childhood, after GD [ 35 ]. This condition is believed to result from unregulated release of stored thyroid hormones, during inflammatory-mediated destruction of thyroid [ 36 ].


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Presenting symptoms are very similar to those of GD and differential diagnosis between these two conditions may be challenging, if only based on clinical and biochemical findings [ 36 , 37 ]. Nevertheless, thyrotropin receptor autoantibodies, which are accepted to be one of GD hallmarks [ 36 ], are generally absent in the children with Htx [ 37 ]. According to the few available reports on the natural history of Htx in pediatric age [ 36 , 37 ], the hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses [ 37 ].

Management of children with Htx requires only a prolonged clinical and biochemical follow-up, but pharmacological treatment may be occasionally needed only in few selected cases; non-pharmacological therapies are never required [ 37 ]. The children with a more severe Htx course and a longer duration of the hyperthyroid phase have been reported to exhibit higher thyroid autoantibodies at Htx diagnosis [ 37 ]. Nevertheless, such a finding needs to be confirmed by further reports.

Subclinical hyperthyroidism is defined as a serum TSH concentration below the lower limit of the reference range, when FT4 levels are within their reference ranges [ 38 ]. The natural history of HT-related subclinical hyperthyroidism has been so far investigated in only few children [ 39 ]. On the basis of those findings, it was argued that, at least in childhood, the frequency with which HT-related subclinical hyperthyroidism risks progressing to overt hyperthyroidism should be considered very low, irrespectively of both TSH and FT4 serum concentrations at HT diagnosis [ 39 ].

According to other reports, the risk of progression to frank hyperthyroidism in the patients with this biochemical condition is distinctly higher, particularly in the cases with undetectable TSH levels at entry [ 40 — 42 ]. However, it has to be considered that, in those reports, natural history of subclinical hyperthyroidism was investigated in elderly patients [ 40 — 42 ], as against as in the study by Aversa et al.

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According to the results of the only available pediatric study on the natural history of subclinical hyperthyroidism, the evolution of this condition over time does not seem to differ from that observed in the children with Htx, at least in terms of duration of TSH suppression periods. These findings suggest that Htx and HT-related subclinical hyperthyroidism might be simply different stages along the same continuum [ 39 ]. A picture of overt hypothyroidism may be observed, at diagnosis of HT, in Nevertheless, the natural history of frank hypothyroidism in the children with HT has never been investigated to now, since in these cases a replacement treatment is always initiated immediately after diagnosis [ 15 ].

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Treatment of overt thyroid failure, in fact, is always mandatory and urgent, especially in very young infants, who are also exposed to the risk of a permanent impairment of neuropsychological development, if not treated early [ 43 ]. However, the long-term evolution of thyroid function in the children with HT and overt hypothyroidism might be postulated to be not very far from the one historically reported by Rallison et al. Finally, when we consider the very different biochemical patterns of thyroid function which may characterize HT presentation in children and adolescents, we should take into account a possible role of environmental factors, such as iodine status.

In fact, a hypothyroid presentation pattern may be observed more frequently in iodine deficient areas, whilst a hyperthyroid presentation picture may be found more often in areas where iodine intake is elevated [ 45 , 46 ]. It has to be clarified, however, that all the patients of our cohort with either overt or subclinical hyperthyroidism at HT presentation exhibited an optimal iodine intake [ 37 , 39 ].

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. FDL wrote the paper; GC and RG have been involved in revising the manuscript for important intellectual outcome; GS and GZ have given substantial contributions to conception and design; MV has given substantial contribution to acquisition, analysis and interpretation of data; TA and MW have been involved in drafting the manuscript and looking for the most suitable references.

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All authors read and approved the final manuscript. Each Author listed on the manuscript has seen and approved the submission of the present version of the manuscript and takes full responsibility for the manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Giuseppe Crisafulli, Email: ti. Romina Gallizzi, Email: ti. Tommaso Aversa, Email: ti. Giuseppina Salzano, Email: ti. Mariella Valenzise, Email: ti. Malgorzata Wasniewska, Email: ti. Giuseppina Zirilli, Email: moc. National Center for Biotechnology Information , U.

Journal List Ital J Pediatr v. Ital J Pediatr. Published online Feb 7.

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Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Dec 5; Accepted Feb 2. This article has been cited by other articles in PMC. Conclusions 1 a deterioration of thyroid status over time may be observed especially in the children presenting with SH, but also in those presenting with euthyroidism; 2 a definitive resolution of the hyperthyroid phase is generally observed in those presenting with either overt or subclinical hyperthyroidism.

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Keywords: Hashitoxicosis, Overt hyperthyroidism, Overt hypothyroidism, Subclinical hyperthyroidism, Subclinical hypothyroidism, Thyroid status natural course. Authors Nos. Open in a separate window. Each topic is treated by an eminent expert in the field, ensuring consistently high quality. Thyroid Diseases in Childhood will be an important source of information for endocrinologists, pediatricians, oncologists, and gynecologists, as well as other professionalsinterested in this topic.

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