Aina Scatti Regàs*, Ricord Pujol Borrell, Roser Ferrer Costa, Elsa Puerto Carranza and Maria Clemente Leon

Department of Paediatrics, Vall d'Hebron University Hospital, Spain

*Corresponding Author: Aina Scatti Regàs, Department of Paediatrics, Vall d'Hebron University Hospital, Spain.

Received: October 06, 2020; Published: January 22, 2021

Citation: Aina Scatti Regàs., et al. “Graves' Disease with Negative Autoantibodies against the TSH Receptor: 5 Cases”. Acta Scientific Paediatrics 4.2 (2021): 20-24.

Abstract

The diagnosis of GD is based on the detection of suppressed plasma TSH and TRAb [4]. However, there are patients in whom TRAb are not detected despite of having a highly suggestive clinic, hormonal profile and imaging tests. We describe 5 pediatric cases of this still little studied and understood clinical situation. The diagnosis of GD is based on the detection of suppressed plasma TSH and TRAb [4]. However, there are patients in whom TRAb are not detected despite of having a highly suggestive clinic, hormonal profile and imaging tests. We describe 5 pediatric cases of this still little studied and understood clinical situation.

Keywords: Graves Disease (GD); Thyroid Stimulating Hormone Receptor (TSHR); Anti-thyroid

Introduction

Graves disease (GD) is the leading cause of hyperthyroidism in childhood. It is an autoimmune disease with production of autoantibodies directed to the thyroid stimulating hormone receptor (TSHR) and progressive infiltration of the thyroid by T and B lymphocytes [1].

There are three types of antibodies that bind to TSHR (TRAb): stimulants (TSAb); blockers (TBAb), and the so-called “neutrals” [1]. Its detection can be carried out by immunoassays, with a sensitivity of up to 98% in third-generation ones [1,2], or by biological tests, which detect functional activity, being even more sensitive [1-3].

 The diagnosis of GD is based on the detection of suppressed plasma TSH and TRAb [4]. However, there are patients in whom TRAb are not detected despite of having a highly suggestive clinic, hormonal profile and imaging tests [3]. We describe 5 pediatric cases of this still little studied and understood clinical situation.

Case Report

Case 1: Pubertal patient with a personal and family history of autoimmune disease who presents with clinical hyperthyroidism with suppressed TSH and free T4 in the upper limit of normality in successive laboratory controls in the two subsequent months. Increased anti-TPO and anti-TG antibodies, as well as ultrasound compatible with thyroiditis. Currently controlled with anti-thyroid treatment.

Case 2: 14-year-old adolescent who consulted for initial symptoms of hypothyroidism: asthenia, malaise, drowsiness, abdominal pain, constipation and anorexia. In the laboratory test, suppressed TSH with initially normal free T4, evolving within a month to more characteristic symptoms of hyperthyroidism: palpitations, agitation, insomnia, palpebral retraction, with increased goiter and elevated free T4.

Case 3: A 10-year-old girl with hyperthyroidism symptoms and biochemistry. In the evolution, stands out thyroid hypofunction with low doses of methimazole. Therefore, after 1.5 years it was suspended, observing relapse and finally receiving radioiodine. The TRAbs were slightly positive for the first generation techniques three years after the onset of the clinic and were subsequently clearly positive with the second generation immunoassays.

Case 4: New born with transient neonatal hyperthyroidism. His mother had a history of thyroidectomized GD due to papillary carcinoma. TRAbs by second generation immunoassays were negative in both the mother and the child.

Case 5: Patient with early-onset and persistent hyperthyroidism, with a family history of hyperthyroidism and negative TRAb. Genetic study to detect TSHR activating mutations was negative. Received radioiodine as definitive treatment.

Discussion

Although we have few studies in the pediatric population, it seems that patients with hyperthyroidism compatible with GD but with undetectable levels of TRAb tend to have clinically and biochemically less severe thyrotoxicosis [3]. In this sense, our findings are consistent with previous studies: none of the 5 cases presented ophthalmopathy or pretibial myxedema, and FT4 levels at diagnosis were not extremely high.

In cases 2 and 3, with a very silent evolution, we could consider the coexistence of TSAb and TBAb during the evolution of the disease. Recent studies have demonstrated the coexistence and changes in the proportions of TSAb and TBAb in the same patient, which occur mainly during pregnancy and in up to 10% of patients with GD treated with antithyroid drugs [4]. Owing to this reason and its greater sensitivity, some authors recommend using biological tests to diagnose cases in which a low level of autoantibodies is expected, such as in pregnant women or in neonatal hyperthyroidism [2].

In a patient with hyperthyroidism and negative TRAb, we must make the differential diagnosis with the thyrotoxic phase of Hashimoto’s thyroiditis (compatible ultrasound and antibodies, with a FT4 that will decrease in a few weeks). Despite being very rare (only 4.5% of patients with hyperthyroidism, diffuse goiter and negative TRAb [5]), in cases of early-onset hyperthyroidism with a family history and poor response to anti-thyroid treatment (case 5) , we must consider activating mutations of the TSHR. Other causes of thyrotoxicosis can be ruled out by anamnesis, physical examination, and ultrasound.

Having ruled out other diseases, one hypothesis to explain why TRAbs are negative is that the sensitivity of the assays is too low to capture low antibody concentrations. Another possible explanation is that TRAb production is limited to the thyroid gland, without reaching the systemic circulation. This hypothesis is based on the fact that lymphocytes isolated from the thyroid gland of a patient with autoimmune thyroiditis without plasma thyroid autoantibodies have shown that can produce anti-thyroid autoantibodies [3,6].

Conclusion

In conclusion, in the presence of a TRAb negative hyperthyroidism, Graves’ disease cannot be ruled out. It is important to consider this clinical situation to start anti-thyroid treatment as early as possible.

Bibliography

1. Stożek K., et al. “Functional TSH receptor antibodies in children with autoimmune thyroid diseases”. Autoimmunity2 (2018): 62-68.
2. Diana T., et al. “Clinical relevance of thyroid-stimulating autoantibodies in pediatric Graves’ disease—a multicenter study”. The Journal of Clinical Endocrinology and Metabolism 5 (2014): 1648-1655.
3. Vos XG., et al. “Frequency and characteristics of TBII-seronegative patients in a population with untreated Graves’ hyperthyroidism: a prospective study”. Clinical Endocrinology (Oxf). 69.2 (2008): 311-317.
4. McLachlan SM and Rapoport B. “Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa”. Thyroid 23 (2013): 14-24.
5. Kiefer FW., et al. “Fetal/neonatal thyrotoxicosis in a newborn from a hypothyroid woman with Hashimoto’s thyroiditis”. The Journal of Clinical Endocrinology and Metabolism 102 (2017): 6-9.
6. Armengol MP., et al. “Thyroid Autoimmune Disease: Demonstration of Thyroid Antigen-Specific B Cells and Recombination-Activating Gene Expression in Chemokine- Containing Active Intrathyroidal Germinal Centers”. American Journal of Pathology 159 (2011): 861-873.

Copyright: © 2021 Aina Scatti Regàs., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.