Background: Graves disease (GD) is an autoimmune disease caused by antibodies directed to the TSH receptor (TRAb), which can be activating (TSAb), neutral, or blocking (TBAb). This balance determines the final clinical result. Typically TSAbs dominate, resulting in hyperthyroidism. Rarely, TBAbs prevail and result in hypothyroidism (1). The TRAb assay routinely used in the clinic does not allow to differentiate between stimulating or blocking characteristics.
Case: A 28-year old female was initially referred to the thyroid outpatient clinic because of hyperthyroidism caused by typical GD. She was treated with block-replacement therapy for 36 months because of persistently high TRAb titers. Six weeks after drug cessation she developed an overt hypothyroidism. Further analysis showed highly blocking properties of the TRAbs. Levothyroxine (LT4) substitution was initiated, and her thyroid function tests remained stable over the following months under a LT4 dose similar to athyreotic patients. Two years later she became spontaneously pregnant, after which the functional TRAb status was monitored meticulously and LT4 substitution in first instance was increased to ensure adequate fetal LT4 supply in the first trimester. During the course of the pregnancy, TRAbs remained high and blocking, so the maternal LT4 dose was kept high. The fetal development was normal, without evidence for fetal hypothyroidism (including absence of a fetal goiter) and thus without need for intra-amniotic LT4 treatment. A healthy newborn (male) was delivered on term. In the postpartum period the newborn developed transient mild hypothyroidism and was treated with LT4 substitution until disappearance of the maternal TRAbs. The maternal functional TRAb status remained unchanged in the postpartum period. Four years later a second pregnancy and postpartum followed an identical course.
Discussion: GD dominated by TBAb is believed to be a very rare entity in the spectrum of autoimmune thyroid diseases. Although its treatment is rather straightforward (LT4 substitution), the challenge and message of this case is the safety of a pregnancy. Because TBAb, like TSAb, can readily transfer transplacentally, fetal hypothyroidism could develop (2) which if left untreated can cause severe and irreversible impairment in neurodevelopment. In utero, the clinical endpoint of high maternal TBAb is comparable with a status of congenital thyroid dysgenesis. The best treatment is to provide adequate maternal LT4 in order to ensure sufficient transfer to the fetus (3) along with intensive follow-up by an experienced gynecologist. The true challenge was however the evolution of the TRAb status, as pregnancy itself represents a state of physiologic immune modulation, which could potentially lead to an altered quantitative and qualitative maternal TRAb status. In that respect, in the best case scenario the patient could also have evolved towards a state of remission of her GD during pregnancy (as in the case of the majority of classical cases) with less (or no) need for LT4. However, in the worst case scenario an immune shift could have occurred towards high and dominating TSAbs, resulting in maternal and fetal hyperthyroidism, which would have been far more challenging with respect to medical treatment (4, 5). Because GD with TBAb is a rare disease, it is of utmost importance to detect the cases, especially women in childbearing age. This case shows the added value of functional analysis of TRAbs before and during pregnancy along with intensive clinical multidisciplinary follow-up (endocrinologist, gynaecologist, pediatrician). This case highlights that TRAb screening is indicated in every women with a history of GD, especially women under LT4 substitution (either after radioiodine treatment or thyroidectomy or a spontaneous evolution towards hypothyroidism). In case of high TRAb titers differentiation between stimulating and blocking antibodies is of added value in pregnancy counselling and clinical management during pregnancy. Although there is still a long way to go, recent breakthroughs have drawn more attention to this condition that could be more prevalent than currently known.
1. Smith TJ, Hegedüs L. Graves disease. N Engl J Med. 2016 Oct 20;375(16):15521565.
2. Brown RS, Alter CA, Sadeghi-Nejad A. Severe unsuspected maternal hypothyroidism discovered after the diagnosis of thyrotropin receptor-blocking antibody-induced congenital hypothyroidism in the neonate: failure to recognize and implications to the fetus. Horm Res Paediatr. 2015;83(2):1325.
3. Polak M, Van Vliet G. Therapeutic approach of fetal thyroid disorders. Horm Res Paediatr. 2010;74(1):15.
4. Dierickx I, Decallonne B, Billen J et al. Severe fetal and neonatal hyperthyroidism years after surgical treatment of maternal Graves disease. J Obstet Gynaecol. 2014;34(2):11722.
5. Léger J. Management of fetal and neonatal Graves disease. Horm Res Paediatr. 2017;87(1):16.