TSH Receptor Blocking Antibodies Research Articles

Thyroid function in mothers of hypothyroid newborns

Objective: To assess etiologic significance of maternal autoimmune thyroid disease on incidence of transient congenital hypothyroidism in newborns. Methods: Thyroid function was assessed in 259 mothers of hypothyroid newborns from the Quebec newborn screening program between 1984 and 1996. Maternal blood samples were taken routinely at the time of follow-up serum sampling of the infants, for measurements of free thyroxine, TSH, and antimicrosomal autoantibodies. Thyroid scans were conducted to characterize the type of thyroid dysfunction in affected infants. Results were compared with similar data from a control population of 1773 pregnant women recruited from Quebec City between 1991 and 1992. These samples were collected at routine second-trimester prenatal screenings. Results: The mothers of congenitally hypothyroid infants had higher prevalence of suppressed serum TSH concentrations compared with the control population (6.1% versus 2.9%, P = .01), higher prevalence of increased serum TSH levels (7.0% versus 0.9%, P < .001), and similar prevalence of positive antimicrosomal antibodies (11.6% versus 12.1%, P = .90). The prevalence of transient congenital hypothyroidism in the study population of hypothyroid infants was 27%, which is significantly greater than the 15% observed in our overall population of 523 congenitally hypothyroid infants studied between 1974 and 1996 ( P = .04). Antimicrosomal antibodies were demonstrable in ten (77%) of 13 mothers of infants with transient congenital hypothyroidism, and antimicrosomal antibodies or abnormal serum TSH levels in 13 of 13 (100%). Conclusion: These results indicate that most, if not all, cases of transient congenital hypothyroidism were attributable to maternal autoimmune thyroid disease, and presumably to maternal TSH receptor-blocking antibody. They suggest that maternal autoimmune thyroid disease is associated with much higher prevalence of transient congenital hypothyroidism than suspected. Because of the 20% prevalence of autoimmune thyroid disease and thyroid dysfunction in the mothers of congenitally hypothyroid infants, we recommend thyroid assessment of such women, if this information is not available.

Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies.

To determine the incidence of transient congenital hypothyroidism due to TSH receptor-blocking antibodies, we screened dried blood specimens obtained from 788 neonates identified as having possible congenital hypothyroidism (from a total population of 1,614,166 babies) and 121 controls. A RRA was used. The potency of blood spot TSH binding inhibitory activity was compared with the severity of congenital hypothyroidism to assess the possible etiological relationship. Maternal serum was studied to confirm the presence of blocking antibodies by both RRA and bioassay. Blood spots obtained from 9 infants contained potent TSH receptor-blocking activity. Samples from 2 additional babies, studied because of clinical suspicion of the disease, were also positive. Long term outcome was known in 8 of the 11 babies, and all had transient disease. Neonates with TSH receptor-blocking activity greater than 132 U/L had a significantly lower T4 level (P < 0.05) and higher TSH (P < 0.005) than those in whom TSH binding-inhibitory activity was less than 132 U/L. All 9 mothers had autoimmune thyroid disease, and 3 had more than 1 affected child. Potent blocking activity was present in 7 maternal serum samples as long as 7 yr after the births of their affected babies. We conclude that measurement of TSH binding-inhibitory activity in dried neonatal blood specimens is a simple and effective method to predict the occurrence of transient congenital hypothyroidism. The incidence of this disorder in North America is 1 in 180,000 normal infants, or approximately 2% of babies with congenital hypothyroidism.

Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies

Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies

Autoimmune Thyroid Disease in Pregnant Women and their Offspring

To present an overview of autoimmune thyroid disease (AITD) that can occur in pregnancy. The major thyroid antibodies that can traverse the maternal-fetal circulation and affect the fetus are summarized, those women at risk of having affected fetuses are identified, and the diagnosis, course, and treatment of AITD in maternal and neonatal patients are discussed. AITD, including Graves' disease and autoimmune thyroiditis, is common in women of childbearing age. Rarely, the fetus can be affected because of transplacental passage of maternal IgG. Of the thyroid autoantibodies found in AITD, only those directed against the thyroid-stimulating hormone (TSH) receptor have been shown to cause fetal thyroid dysfunction. Both transient neonatal hyperthyroidism and hypothyroidism have been described, as has delayed onset of neonatal hyperthyroidism due to the coexistence of stimulating and blocking TSH receptor antibodies. In general, affected infants are those born to mothers with the most potent antibody activity, and the duration of the neonatal thyroid dysfunction is dependent on the antibody titer and the rate of metabolic clearance from the infant's circulation. If fetal hyperthyroidism is suspected, maternal TSH receptor antibodies should be measured during the third trimester of pregnancy. For neonatal hypothyroidism, this measurement in the mother or baby soon after birth will suffice. Screening for the presence of TSH receptor antibodies by radioreceptor assay is the most cost-effective approach. If results are positive, bioassay should be done to determine the nature of the antibody activity. Women at risk of having babies with neonatal hyperthyroidism include those with a history of previous affected infants, with difficult to control thyrotoxicosis, or with a history of Graves' disease and development of hypothyroidism either spontaneously or as a result of thyroid gland ablation. Transient neonatal hypothyroidism due to TSH receptor-blocking antibodies should be suspected in any infant with hypothyroidism born to a mother with AITD (particularly those with previously affected offspring). Treatment of maternal hyperthyroidism must consider both maternal and fetal thyroid status. In general, the lowest dose of antithyroid medication sufficient to produce maternal euthyroidism or slight hyperthyroidism is used. In pregnant women with hypothyroidism, doses of L-thyroxine should be sufficient to normalize maternal thyroid function without regard to the fetus. Identification and treatment of affected infants soon after birth will ensure a normal outcome. Whether inadequately treated maternal hypothyroidism is associated with a permanent intellectual deficit in the offspring is currently unknown.

High prevalence and little change in TSH receptor blocking antibody titres with thyroxine and antithyroid drug therapy in patients with non-goitrous autoimmune thyroiditis.

We have reevaluated the prevalence and pathogenetic importance of TSH receptor blocking antibodies (TRBAb) in autoimmune hypothyroidism, and investigated the changes in TRBAb activities during thyroxine and antithyroid drug treatment. Serum TSH binding inhibitor immunoglobulin (TBII) and thyroid stimulation blocking antibody (TSBAb) were measured serially in all patients with non-goitrous autoimmune thyroiditis (AT) and measured monthly during methimazole treatment in 6 patients. Ninety patients with non-goitrous AT and 95 patients with goitrous AT were entered consecutively into this study. All patients with non-goitrous AT were treated with thyroxine and followed at intervals of 6 months for 2 years initially and then yearly intervals. The duration of follow-up was 1-8 years. Six patients from the TRBAb-positive non-goitrous AT group who were treated with thyroxine were randomly selected and given additional treatments with methimazole (40 mg per day) for 6 months. Serum TBII was measured by a radioreceptor assay, TSBAb by using FRTL-5 cells, and antithyroid peroxidase and antithyroglobulin antibodies by radioimmunoassay. The prevalences of TBII and TSBAb is non-goitrous AT were 47.8 and 58.9%, respectively, which were significantly higher than those in goitrous AT (6.3% for TBII, 10.5% for TSBAb). All but one patient showed persistent TBII and TSBAb activities during the thyroxine treatment for up to 8 years. A high dose of methimazole (40 mg per day) did not affect the titres of TBII and TSBAb in 5 out of 6 patients with non-goitrous AT tested. However, antithyroid peroxidase and antithyroglobulin antibodies activities were significantly decreased during the methimazole treatment. The high prevalence of TSH receptor blocking antibodies (TRBAb) suggests that TRBAb may play a major role in the development of hypothyroidism and thyroid atrophy in the vast majority of patients with non-goitrous autoimmune thyroiditis. Most TRBAb activities are stable for at least 8 years and are now affected by thyroxine and antithyroid drug treatment.

Outcome in three siblings with antibody-mediated transient congenital hypothyroidism

A woman receiving thyroxine substitution therapy for acquired hypothyroidism caused by autoimmune thyroiditis gave birth to three babies who had transient primary hypothyroidism. All three babies had elevated thyrotropin levels on neonatal screening, but one had normal thyroxine values. Thyrotropin receptor–blocking antibodies were present in maternal serum and in the three neonates. Each baby also had a different congenital malformation. The neurodevelopmental outcome of the children appeared related in part to maternal thyroxine levels, which suggests that transplacental transfer of thyroxine may protect the fetal brain. (J P EDIATR 1995;127:275-7)

Detection of thyrotropin binding inhibitory activity in neonatal blood spots.

Recent studies have suggested that maternal TSH receptor-blocking antibodies might be of primary etiological importance in some cases of transient congenital hypothyroidism (CH). Because these antibodies are extremely potent, we evaluated the feasibility of identifying babies at risk by using readily available newborn blood spots. Blood spots obtained from 84 normal babies (group 1) and from 354 infants whose initial T4 was less than the tenth percentile for the assay and whose TSH was 40 mU/L or more (group 2) were studied without knowledge of the diagnosis. Blood was eluted from spots overnight and evaluated for [125I]TSH binding inhibition (TBI) to solubilized porcine thyroid membranes. Four spots obtained from 3 group 2 babies, but none of those from the group 1 infants, exhibited TBI activity greater than 3 SD above the normal mean (33.9%). Four additional hypothyroxinemic infants whose mothers had Graves' disease were also negative. Subsequent follow-up revealed that all 3 positive babies had transient CH, and all 3 mothers had primary myxedema. Potent TBI activity was confirmed in the serum of all 3 mothers and in the 2 babies in whom it was evaluated at birth. We conclude that newborn blood spots can be used to detect potent maternal TBI activity, and that this identifies a baby likely to have transient, rather than permanent, CH. Because of their stability and ease of collection and handling, newborn blood spots should offer a convenient tool for future studies aimed at defining in more detail the incidence and clinical characteristics of this unique syndrome.

A strong association between thyrotropin receptor-blocking antibody- positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans

A strong association between thyrotropin receptor-blocking antibody- positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans

A strong association between thyrotropin receptor-blocking antibody-positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans.

We investigated whether the associations between HLA alleles of patients with autoimmune hypothyroidism varied according to the presence or absence of TSH receptor-blocking antibody (TRBab). We analyzed the HLA-A, -B, -C, and -DR antigens by serotyping and the DQA1 and DQB1 genes using both enzymatic DNA amplification and sequence-specific oligonucleotide hybridizations. The patient population consisted of 47 Korean patients with atrophic autoimmune thyroiditis and 62 patients with goitrous autoimmune thyroiditis. The antigen frequency of HLA-DR8 was significantly increased in 23 atrophic autoimmune thyroiditis patients that were positive for TSH binding inhibitor immunoglobulin (TBII) compared to 136 controls [52% vs. 16%; chi 2 = 13.1; Pc (corrected P value) = 0.003]. This relative risk was 5.7; the etiological fraction was 0.43. HLA-DQB1*0302 was also increased in patients with TBII-positive atrophic autoimmune thyroiditis (24% vs. 7%; chi 2 = 11.2; Pc = 0.012; relative risk = 4.4; etiological fraction = 0.19). No specific DR antigens or DQB1 alleles were increased in either TBII-negative atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis. A significant decrease in the frequency of HLA-DR6 antigen was observed in both TBII-positive atrophic autoimmune thyroiditis (0% vs. 32%; chi 2 = 8.4; Pc = 0.03) and goitrous autoimmune thyroiditis (0% vs. 32%; chi 2 = 23.2; Pc < 0.001) patients. The frequency of the HLA-Cw1 antigen was significantly increased in all patient groups. We conclude that TRBab-positive atrophic autoimmune thyroiditis is immunogenetically different from both goitrous autoimmune thyroiditis and TRBab-negative atrophic autoimmune thyroiditis. It is possible that HLA-DR8 and/or DQB1*0302 may be related to the susceptibility genes involved in the production of TRBab in Koreans.

OUTCOME OF 3 SIBLINGS WITH ANTIBODY-MEDIATED TRANSIENT CONGENITAL HYPOTHYROIDISM

Transient neonatal hypothyroidism due to transplacental transfer of maternal TSH receptor blocking antibodies (TBIIs) is a rare cause of congenital hypothyroidism. A woman with hypothyroidism secondary to Hashimoto's thyroiditis diagnosed and treated since age 15 y delivered three babies at age 21, 23 and 25 y. TBII tilers were very high throughout this period in the mother and in the newborns. All three babies (2 boys, 1 girl) had high TSH on newborn screening (Table in SI units) and were started on thyroxine replacement (8-12 μg/kg) at age 16 d (#1 and 2) and 3 d(#3). Treatment was stopped at age 33 mo in sib #1 and at age 15 mo in sib #2; both have remained euthyroid since. In addition, #1 had artial septal defect, #2 had unilateral renal agenesis, and #3 died at 10 w of a complex cardiac malformation. During pregancy #1, maternal TSH levels were all normal, whereas during pregnancies #2 and #3, they were elevated (8-20 mIU/l). Developmental evaluation of sib #1 at age 4 y showed an IQ of 91 (Mc Carthy test), while sib #2 at age 2 1/2 y had a motor deficit (Bailey scale: motor 72, mental 88). Conclusions: transplacental transfer of TBIIs in this family was associated with 1) transient neonatal hypothyroidism in all children, with normal thyroid size at birth; 2) various congenital malformations in all children; 3) a developmental outcome that appeared related to maternal TSH levels but not to severity of hypothyroidism at diagnosis.

The IgG subclass distribution of TSH receptor blocking antibodies in primary hypothyroidism

TSH receptor stimulating antibodies are restricted to the IgG1 subclass suggesting an oligoclonal origin. We wished to determine whether thyroid stimulation blocking antibodies, which also bind to the TSH receptor but may cause hypothyroidism, are similarly IgG subclass restricted. Sera containing TSH receptor blocking antibody activity were separated into IgG subclasses by negative depletion of all other subclasses on affinity columns of subclass-specific monoclonal antibodies or protein A as appropriate. Eleven patients from two centres were studied. All had autoimmune hypothyroidism and TSH receptor blocking antibodies but no thyroid stimulating antibodies. TSH receptor blocking antibody activity was measured by assessing inhibition of TSH-stimulated cAMP production by human thyroid cells (five Israeli samples) or by the FRTL-5 rat thyroid cell line (six Korean samples). IgG1 was the most important subclass containing TSH receptor blocking antibody activity but complete restriction to this subclass was never seen. Clearly detectable activity was found in the IgG2 subclass in eight patients, in the IgG3 subclass in three patients, and in the IgG4 subclass in six patients. The percentage recovery of activity in the sum of the separated fractions generally corresponded to the activity in whole immunoglobulin, being 117 +/- 66% in the nine patients in whom this could be assessed, although in one of these, the activities in the sum of the fractions was much higher (284%). Unlike thyroid stimulating antibodies, thyroid stimulation blocking antibodies are not subclass restricted and are therefore likely to have a polyclonal origin. The IgG subclass distribution of these blocking antibodies resembles that of thyroglobulin and thyroid peroxidase antibodies.

Thyroid growth immunoglobulins in feline hyperthyroidism.

Feline hyperthyroidism bears a strong clinical and pathologic resemblance to toxic nodular goiter in humans. To evaluate whether the observed thyroid growth might be due to circulating thyroid antibodies, as has been postulated in humans, we studied the effect of purified immunoglobulin (Ig) G preparations on a rat thyroid follicular (FRTL-5) cell line. When compared with control, hyperthyroid cat IgG caused significantly increased [3H]-thymidine (Tdr) incorporation into DNA (p less than 0.02) and stimulated cellular proliferation 15-fold. Stimulation of 3H-Tdr incorporation tended to be biphasic and could be inhibited completely by a potent, specific TSH receptor blocking antibody. Hyperthyroid cat IgG also significantly inhibited 125I-bTSH binding to porcine thyroid membranes, an effect that could be reproduced using electrophoretically pure IgG and normal cat thyroid membranes. Unlike its effect on growth, hyperthyroid cat IgG did not stimulate intracellular cAMP, and there was no correlation between thyroid function in vivo and IgG growth-promoting activity in vitro. These data suggest that elevated titers of thyroid growth IgGs, probably acting through the TSH receptor, are present in feline hyperthyroidism and may play a role in goiter formation. Unlike growth, the thyroid hyperfunction observed is not IgG dependent. Further study of feline hyperthyroidism may contribute important insights into human nodular goiter and into the mediation of thyroid growth in general.

Circulating thyroid antibodies in congenital hypothyroidism.

The role of maternal thyroid antibodies in congenital hypothyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated cAMP production in a rat thyroid cell line, FRTL5. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.

Thyroid Disease and Pregnancy

Thyroid disease is common in younger women and may be a factor in reproductive dysfunction. This probably only applies to severe cases of hyper- or hypothyroidism. Once adequately treated, neither of these disorders significantly impacts on fertility. The key is to recognize and to treat thyroid disorders in the reproductive-age woman before conception. Thyroxine therapy and even antithyroid drug therapy should be continued during pregnancy as necessary. Pregnancy is a euthyroid state that is normally maintained by complex changes in thyroid physiology. The fetal and neonatal hypothalamic-pituitary-thyroid system develops independently, but it may be influenced by thyroid disease in the mother. Early pregnancy is characterized by an increase in maternal T4 secretion stimulated by hCG and an increase in TBG, resulting in the elevated total serum T4 in pregnancy. The debate continues as to whether maternal T4 is important in early or late fetal brain development. If so, the physiologic changes in thyroid hormone secretion and transport in early pregnancy would help to ensure that a sufficient amount of thyroid hormone was available. There is new evidence in human subjects that substantial maternal T4 can cross the placenta during pregnancy, and this may be particularly important when fetal thyroid function is compromised as a result of congenital hypothyroidism. Maternal and fetal/neonatal outcomes in pregnancy are adversely affected if severe hypothyroidism is undiagnosed or inadequately treated. Thyroid function tests should be obtained during gestation in women taking T4 and appropriate dose adjustments should be made for TSH levels outside a normal range. The TSH-receptor blocking antibodies from the mother are a recognized cause of congenital hypothyroidism in the fetus and neonate that can be permanent or transient. If neonatal hypothyroidism is detected through neonatal screening programs, and prompt and adequate T4 replacement therapy is instituted as soon as possible following delivery, subsequent growth and development are usually normal. Paradoxically, pregnancy often has a favorable effect on the course of maternal Hashimoto's disease, although there is the risk of relapse postpartum. Pathophysiologic conditions of hCG secretion such as gestational trophoblastic disease and hyperemesis gravidarum may present as thyrotoxicosis in pregnancy, but the main cause of this syndrome is Graves' disease. The mainstay of treatment is antithyroid drugs and either propylthiouracil or methimazole may be used safely. Subtotal thyroidectomy, after medical control, is the alternative treatment, but radioiodine ablation is contraindicated.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of atrophic and goitrous auto-immune thyroiditis in children: Clinical, laboratory and TSH-receptor antibody studies

We studied the clinical features, laboratory and thyroid functions and thyrotropin (TSH)-receptor and thyroid-stimulation antibodies in 21 patients with atrophic auto-immune thyroiditis (AAT) and 48 patients with goitrous auto-immune thyroiditis (GAT) of childhood onset. The clinical features of patient with AAT were cessation of growth and obesity, while asymptomatic enlargement of the thyroid gland was the sole symptom in most patients with GAT. Although the ages at diagnosis were comparable in both groups, the estimated ages at onset were much lower in patients with AAT than in those with GAT. Patients with AAT exhibited more severe hypothyroidism when evaluated by serum thyroxine (T4), tri-iodothyronine (T3), TSH, cholesterol levels and basal metabolic rates. The 24 h 123I-thyroidal uptake was significantly lower in patients with AAT than in those with GAT. None of the 19 patients with AAT possessed TSH-binding inhibitor immunoglobulins (TBII). On the other hand, 3 of the 32 GAT patients tested, possessed weak to potent TBII activities. Three TBII-positive patients with GAT also possessed thyroid-stimulation blocking antibodies. These findings suggest that: 1. Pathogenesis of AAT in children whose onset of hypothyroidism was before puberty is not due to TSH-receptor blocking antibodies, which are often found in patients with AAT of postpubertal onset. 2. AAT in children is considered not to be due to the later stage of GAT. 3. Some patients with GAT possessed TSH-receptor blocking antibodies. The aetiology and pathogenesis of AAT in children have yet to be elucidated.

Maternal Thyroid-Blocking Immunoglobulins in Congenital Hypothyroidism*

We evaluated 24 mothers whose babies had congenital hypothyroidism (CH) for the presence of immunoglobulins (Igs) that inhibited [125I]bovine TSH binding and blocked TSH-induced growth and function of FRTL-5 cells. Results were compared with those from 2 mothers with known primary myxedema (atrophic thyroiditis) whose babies had transient CH and with normal controls. Only 1 prospectively evaluated CH mother had potent TSH binding inhibitory, growth inhibitory, and function inhibitory IgGs. Further study of this discordant mother's serum indicated that she was hypothyroid, probably due to atrophic thyroiditis. Both mothers with known primary myxedema had blocking IgGs. The thyroid growth-blocking activity was verified by cell count, could be absorbed by and eluted from Staphylococcal protein-A, indicating that it was an IgG, and was not an anti-TSH idiotype. Half-maximal inhibition was similar in the three different assays for thyroid-blocking activity, suggesting that TSH binding inhibitory, growth inhibitory, and function inhibitory IgGs in some patients with primary myxedema may be the same antibody population. There was no correlation with the titer of antimicrosomal antibodies. These data suggest that maternal thyroid-blocking IgGs interacting with the TSH receptor do not play a role in most cases of sporadic CH. Determination of TSH binding inhibitory IgGs, but not antimicrosomal antibodies, is a sensitive screening test for the presence of TSH receptor-blocking antibodies.