scholarly journals Coexistence of Autoimmune Hyper- and Hypothyroidism in a Kindred with Reduced Sensitivity to Thyroid Hormone

2020 ◽  
Vol 9 (5) ◽  
pp. 263-268
Author(s):  
Yasmine Abdellaoui ◽  
Dimitra Magkou ◽  
Sofia Bakopoulou ◽  
Ramona Zaharia ◽  
Marie-Laure Raffin-Sanson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Free Triiodothyronine ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Autoimmune Hypothyroidism ◽  
First Time ◽  
Receptor Antibodies

Introduction: Resistance to thyroid hormone beta (RTHβ) is a rare disease with an autosomal dominant transmission. Diagnosis may be challenging especially in patients with hyper- or hypothyroidism. Case Presentation: A 31-year-old male patient with suppressed thyroid-stimulating hormone (TSH), elevated free thyroxine and free triiodothyronine, along with high thyroid receptor antibodies was diagnosed with Graves’ disease. Benzylthiouracil was started. One month later, reduced sensitivity to thyroid hormones was suspected because of persistently high thyroid hormone levels contrasting with high TSH level. Molecular analysis highlighted a 10c.1357C>T p.P453S mutation in the thyroid hormone receptor beta gene (THRB). RTHβ was diagnosed. Several relatives also had RTHβ (the mother, the young son, and 2 out of 3 siblings). Autoimmune hypothyroidism was present in the mother, whereas 2 out of 3 siblings had asymptomatic autoimmunity. Discussion/Conclusion: Both Graves’ disease and autoimmune hypothyroidism were described in patients with RTHβ. We show here for the first time that autoimmune hypo- and hyperthyroidism may coexist in kindred with RTHβ. Seven previously published cases of Graves’ disease and RTHβ were retrieved and analyzed. Treatments and thyroid hormone level targets are discussed as well as the possible link between RTHβ and autoimmune thyroid diseases.

A thyroid hormone receptor β gene polymorphism associated with Graves’ disease

1995 ◽  
Vol 15 (3) ◽  
pp. 267-272 ◽  
Author(s):  
V Tassi ◽  
L Scarnecchia ◽  
A Di Cerbo ◽  
M T Pirro ◽  
R Di Paola ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Thyroid Volume ◽  
Distinct Group ◽  
Control Group ◽  
Graves Disease ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Β Receptor ◽  
Thyroid Hormone Receptor Β

ABSTRACT Autoimmune thyroid diseases (AITDs) are clustered in families, but the nature of this clustering is still poorly understood. One possible approach to the identification of genetic factors interacting with the AITDs is the study of the association between polymorphic markers and AITDs themselves. In the present study we have shown an association between an allele of a HindIII restriction fragment length polymorphism (EAβH) intragenic to c-erbAβ, which codes for the thyroid hormone β receptor, and Graves’ disease. This polymorphism can be detected by PCR followed by digestion with the restriction enzyme HindIII. The allelic frequencies were analysed in a panel of DNAs extracted from a population of individuals affected by thyroid disease and originating from southern Italy. A control group (n=120) from the same area was also analysed. The distribution of EAβH alleles was significantly different (P<0·001) in Graves’ disease (n=94) but not in autoimmune thyroiditis (n=60), as compared with controls. Also the distribution of the EAβH genotypes was significantly different in Graves’ patients (P=0·003), as compared with controls, the homozygous state EAβH+/EAβH+ being more frequent in Graves’ patients than in all the other groups. We did not find any association between EAβH genotypes and clinical parameters in Graves’ patients, including eye signs, thyroid volume and level of TSH-binding inhibiting immunoglobulins. Our data support the idea that Graves’ disease is a genetically distinct group within the AITDs.

scholarly journals Painless destructive thyroiditis in a patient with resistance to thyroid hormone: a case report

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Tomoko Nagamine ◽  
Jaeduk Yoshimura Noh ◽  
Naoya Emoto ◽  
Takahito Kogai ◽  
Akira Hishinuma ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Complete Suppression ◽  
Free Triiodothyronine ◽  
General Physician ◽  
Resistance To Thyroid Hormone ◽  
Tsh Suppression ◽  
Stimulating Hormone

Abstract Background Resistance to thyroid hormone (RTH) usually features a syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH) without suppression of the typical high thyroid hormone levels. However, some patients with RTH show thyroid-stimulating hormone (TSH) suppression due to thyrotoxicosis. We report a case of painless thyroiditis in a patient with RTH that was misdiagnosed as Graves’ disease because of TSH-suppressed thyrotoxicosis. Case presentation A sixteen-year-old boy consulted a local general physician for fatigue. He had a goiter, and biochemical analysis showed TSH < 0.1 μIU/mL, free triiodothyronine (FT3) of 2.70 pg/mL, and free thyroxine (FT4) of 3.6 ng/dL. He was diagnosed with Graves’ disease and was treated with 20 mg thiamazole. One year later, he was referred to the department of endocrinology because of SITSH. He was finally diagnosed with RTH due to the finding of a heterozygous missense mutation (methionine 334 threonine) in the thyroid hormone receptor β gene. Three years after cessation of thiamazole, his hyperthyroxinemia showed marked exacerbation with TSH suppression. We diagnosed him with painless destructive thyroiditis because of low technetium-99 m (Tc-99 m) uptake in the thyroid. Extreme hyperthyroxinemia was ameliorated, with a return to the usual SITSH levels, within 1 month without any treatment. Conclusion The present case demonstrates that diagnosing RTH is difficult when patients show hyperthyroxinemia with complete suppression of TSH to undetectable levels, and the data lead to misdiagnosis of RTH as Graves’ disease. The initial diagnosis is important, and Tc-99 m scintigraphy is useful for the differential diagnosis of thyrotoxicosis accompanying RTH.

Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves’ Disease and Hashimoto’s Hypothyroidism

2020 ◽  
Vol 105 (7) ◽  
pp. e2600-e2608 ◽  
Author(s):  
Qian-Yue Zhang ◽  
Wei Liu ◽  
Lu Li ◽  
Wen-Hua Du ◽  
Chun-Lin Zuo ◽  
...  
Keyword(s):  
Susceptibility Genes ◽  
Graves Disease ◽  
Susceptibility Loci ◽  
Chinese Han ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Genome Wide ◽  
Chinese Cohort ◽  
First Time ◽  
Genome Wide Significance

Abstract Context Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. Objects To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. Design In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. Results We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10–8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. Conclusion Our findings suggested that the pathogenesis of HT and GD was different.

scholarly journals Molecular dynamics approach to the I431V mutational impact on thyroid hormone receptor-beta

BIBECHANA ◽  
2018 ◽  
Vol 16 ◽  
pp. 79-91
Author(s):  
Tika Ram Lamichhane ◽  
Sharma Paudel ◽  
Binod Kumar Yadav ◽  
Hari Prasad Lamichhane
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Point Mutations ◽  
Binding Pocket ◽  
Accessible Surface Area ◽  
Thyroid Stimulating Hormone ◽  
Solvent Accessible Surface Area ◽  
Free Triiodothyronine ◽  
Receptor Beta

The point mutations like I431V on thyroid hormone receptor-beta (THR-β) gene cause resistance to thyroid hormones (RTH) with the clinical diagnosis of elevated free triiodothyronine (T3) and free thyroxin (T4) but not suppressed thyroid stimulating hormone (TSH) on the blood serum. Some ultrasonographic (USG) reports of the patients with RTH show thyroid gland disorder with goiter or nodule(s) or cyst(s) and some USG reports even with RTH are normal. I431V-mutant causes more steric hindrance while binding T3 into THR-β than the native wild type THRT3. The residue on the 431-codon is dynamic in nature showing its flexibility over the course of entry and release of T3-hormone into/from the ligand binding pocket. The more increased solvent accessible surface area of I431V-mutant than that of native I431-residue makes the partial unfolding of the globular THR-β protein. The smaller height of radial distribution function between I431-mutant and T3 shows the decrease in probability of finding the atomic particles nearby T3-hormone in THRT3-MT than in THRT3-WT. The electrostatic interaction energy between native I431 and T3 is negative, but it is positive between I431V and T3. Moreover, the internal energy of I431V-mutant has been found smaller than that of native I431-residue in THRT3 systems.BIBECHANA 16 (2019) 79-91

scholarly journals Monoclonal Antibodies to the Thyrotropin Receptor

2005 ◽  
Vol 12 (2) ◽  
pp. 137-143 ◽  
Author(s):  
Takao Ando ◽  
Terry F. Davies
Keyword(s):  
Thyroid Hormone ◽  
Insect Cells ◽  
Target Antigen ◽  
Graves Disease ◽  
Thyroid Cell ◽  
Thyrotropin Receptor ◽  
Native Conformation ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Major Target

The thyrotropin receptor (TSHR) is a seven transmembrane G-protein linked glycoprotein expressed on the thyroid cell surface and which, under the regulation of TSH, controls the production and secretion of thyroid hormone from the thyroid gland. This membrane protein is also a major target antigen in the autoimmune thyroid diseases. In Graves' disease, autoantibodies to the TSHR (TSHR-Abs) stimulate the TSHR to produce thyroid hormone excessively. In autoimmune thyroid failure, some patients exhibit TSHR-Abs which block TSH action on the receptor. There have been many attempts to generate human stimulating TSHR-mAbs, but to date, only one pathologically relevant human stimulating TSHR-mAb has been isolated. Most mAbs to the TSHR have been derived from rodents immunized with TSHR antigen from bacteria or insect cells. These antigens lacked the native conformation of the TSHR and the resulting mAbs were exclusively blocking or neutral TSHR-mAbs. However, mAbs raised against intact native TSHR antigen have included stimulating mAbs. One such stimulating mAb has demonstrated a number of differences in its regulation of TSHR post-translational processing. These differences are likely to be reflective of TSHR-Abs seen in Graves' disease.

scholarly journals The development of Graves' disease after long-term hypothyroidism due to Hashimoto's disease

2020 ◽  
Vol 66 (5) ◽  
pp. 24-30
Author(s):  
E. A. Panfilova ◽  
L. P. Kruk ◽  
M. P. Isaeva ◽  
P. O. Osmanova ◽  
F. A. Bostanova ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Clinical Case ◽  
Thyroid Volume ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Blocking Antibodies ◽  
Stimulating Hormone

The main autoimmune thyroid diseases are Hashimoto's thyroiditis (HT) and Graves' disease (GD). Despite the significant differences in a pathogenesis and a clinical picture between HT and GD, the literature describes the cases of the conversion of one autoimmune disease to another, which, according to one version, is associated with a change in the balance between the levels of a stimulating and blocking antibodies to the thyroid-stimulating hormone receptor. At the same time, there are more frequent observations of the transition of GD to HT, and much less often describe, on the contrary, the development of GD against the background of HT. The article presents a clinical case of the conversion of HT to GD. A detailed algorithm of the conservative management according to the «block-replace» scheme is described, indicating the results of laboratory and instrumental examination. At the time of describing the clinical case, the result of the treatment can be considered successful. The predictors such as a low level of the thyroid-stimulating hormone receptor and thyroid volume before discontinuation of the thyrostatic therapy suggest a low risk of the recrudescence of GD.According to the authors, the phenomenon of the conversion of one autoimmune thyroid disease to another, in addition to the scientific interest, is important for the practitioners, since a timely change in the diagnostic paradigm can significantly change the treatment strategy and the favorably affect the prognosis of disease, preventing the development of complications.

Hyperthyroidism in an infant of a mother with autoimmune hypothyroidism with positive TSH receptor antibodies

2018 ◽  
Vol 31 (5) ◽  
pp. 577-580 ◽  
Author(s):  
Kriti Joshi ◽  
Margaret Zacharin
Keyword(s):  
Thyroid Function ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Disorder ◽  
Free Triiodothyronine ◽  
Autoimmune Hypothyroidism ◽  
Normal Thyroid Function ◽  
Neonatal Hyperthyroidism ◽  
History Of ◽  
Blocking Antibodies ◽  
Receptor Antibodies

Abstract Background: Neonatal hyperthyroidism is rare, seen in infants of mothers with Graves’ disease (GD), with transplacental transfer of thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs). We describe a neonate with severe hyperthyroidism due to TRAbs, born to a mother with autoimmune hypothyroidism. Case presentation: A baby boy born preterm at 35 weeks had irritability, tachycardia and proptosis after birth. The mother had autoimmune hypothyroidism, from age 10, with thyroxine replacement and normal thyroid function throughout her pregnancy. She had never been thyrotoxic. There was a family history of Hashimoto’s thyroiditis (HT) and GD. The baby’s thyroid function on day 3 demonstrated gross thyrotoxicosis, TSH<0.01 mIU/L (normal range [NR]<10 mIU/L), free thyroxine (FT4)>77 pmol/L (20–35), free triiodothyronine (FT3) 15.4 pmol/L (4.2–8.3) and TRAb 18.4 IU/L (<1.8). The mother’s TRAb was 24.7 IU/L. Thyrotoxicosis required propranolol and carbimazole (CBZ). Thyroid function normalized within 10 days. The baby was weaned off medication by 7 weeks. He remains euthyroid. Conclusions: We postulate that this mother had co-existing destructive thyroiditis and thyroid-stimulating antibodies (TSAbs) and TSHR blocking antibodies (TBAb), rendering her unable to raise a thyrotoxic response to the TSAbs but with predominant TSAb transmission to her infant. Maternal history of any thyroid disorder may increase the risk of transmission to an infant, requiring a careful clinical assessment of the neonate, with important implications for future pregnancies.

General properties of autoimmune thyroid diseases and associated morbidities

2020 ◽  
Vol 33 (4) ◽  
pp. 509-515 ◽  
Author(s):  
Aysel Burcu Palandokenlier Ibili ◽  
Beray Selver Eklioglu ◽  
Mehmet Emre Atabek
Keyword(s):  
Standard Deviation Score ◽  
Invasive Procedure ◽  
Thyroid Stimulating Hormone ◽  
Clinical Findings ◽  
Thyroid Diseases ◽  
Free Triiodothyronine ◽  
Autoimmune Thyroid Diseases ◽  
Autoimmune Thyroid ◽  
Thyroglobulin Antibody

AbstractBackgroundAutoimmune thyroid diseases (ATDs) can be classified into two basic diseases: Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Here, we review the effectiveness of laboratory and imaging methods used for the early diagnosis of ATD and draw attention to methods that may improve screening.MethodsRetrospective data of 142 patients diagnosed with ATD between January 2010 and December 2015 at our paediatric endocrinology clinic were used. Sociodemographic characteristics, clinical findings, treatments and follow-up data of patients were statistically evaluated.ResultsOf the ATD cases, 81% (n = 115) were female. The median age was 12.5 ± 3.5 (range 1–17) years and 91% (n = 129) of patients were in puberty. There was a significant positive correlation between the height (standard deviation score) and follow-up time for patients with HT (r = 0.156, p < 0.01). Thyroglobulin antibody (TgAb) positivity was found in 75% (45/60) of females with a positive maternal ATD history (p = 0.045). Thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) values were significantly altered during the treatment follow-up period in female patients with GD and HT, while only fT4 values were found to be significantly altered in boys with HT.ConclusionAlthough GD and HT have similar mechanisms, they differ in terms of treatment duration and remission and relapse frequencies. Ultrasonography (USG) screening is a non-invasive procedure that is suitable for all patients with ATD. Based on our results, TgAb could be useful in the screening of girls with a history of maternal ATD.

scholarly journals An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone

2021 ◽  
Vol 22 (12) ◽  
pp. 6611
Author(s):  
Kenji Ohba
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Elevated Serum ◽  
Thyroid Stimulating Hormone ◽  
Free Triiodothyronine ◽  
Related Condition ◽  
Important Indicator ◽  
Inappropriate Secretion ◽  
Hpt Axis ◽  
Stimulating Hormone

Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hyperthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Similarly, the term syndrome of IST (SITSH) is widely used in Japan to refer to a closely related condition; however, unlike that for IST, an elevated serum free triiodothyronine concentration is not a requisite criterion for SITSH diagnosis. IST or SITSH is an important indicator of resistance to thyroid hormone β (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor β (TRβ) and TSH-secreting pituitary adenoma. Recent evidence has accumulated for several conditions associated with IST, including RTH without mutations in the TRβ gene (non-TR-RTH), the phenomenon of hysteresis involving the hypothalamus-pituitary-thyroid axis (HPT-axis), methodological interference, and Cushing’s syndrome after surgical resection. However, little information is available on the systematic pathophysiological aspects of IST in previous review articles. This report presents an overview of the recent advances in our understanding of the etiological aspects of IST that are relevant for diagnosis and treatment. Moreover, the report focuses on the potential mechanism of IST caused by hysteresis in the HPT-axis (lagging TSH recovery) in terms of epigenetic regulation.

scholarly journals ThyrotropinomA: Diagnosing a Rare Cause of Hyperthyroidism

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A968-A968
Author(s):  
Monica Bhanot ◽  
Chase Dean Hendrickson
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Equilibrium Dialysis ◽  
Elevated Serum ◽  
Sex Hormone Binding Globulin ◽  
Molar Ratio ◽  
Graves Disease ◽  
Free Triiodothyronine ◽  
Α Subunit ◽  
Free Thyroid Hormones

Abstract Case: The patient is a 40-year-old male who presented for evaluation of hyperthyroidism with symptoms including palpitations, increased bowel movements, anxiety, and worsening tremor. With a family history of Graves’ disease and an ultrasound showing a hyperemic thyroid, there was initial suspicion for Graves’ disease. Although a radioactive iodine thyroid scan showed diffuse uptake that was elevated, 21.4% at 4 hours and 33.1% at 24 hours, lab evaluation appeared inconsistent with Graves’ disease revealing: TSH 1.65 µU/mL (upper limit of normal [ULN] 4.5), free thyroxine (FT4) 1.99 ng/dL (ULN 1.17), free triiodothyronine 6.16 ng/dL (ULN 3.98), thyroid stimulating immunoglobulin 92% (ULN 122), and thyroid receptor antibodies less than 1.0 IU/L (ULN 1.75). Lab results were reproducible with elevated FT4 even by equilibrium dialysis at 3.9 ng/dL (ULN 2.4) and high-normal TSH with serial dilution that ruled out assay interreference. Given these findings, our focus turned to rare causes of hyperthyroidism including thyrotropinoma and thyroid hormone resistance (RTH). Unique to the diagnosis of thyrotropinoma is an elevated serum α subunit in 50-85% of cases (1). Therefore, we obtained an α subunit level which was 0.35 ng/mL (ULN 0.55) with a molar ratio of 2.2 (ULN 2.4). Since the α subunit level was normal, the patient obtained genetic testing for mutations in the thyroid hormone receptor β gene seen in 85% of RTH cases (1). However, no sequence variants were identified. Since initial lab and genetic analyses were undifferentiating, additional tests were obtained including an insulin-like growth-factor 1 level of 209 ng/mL (ULN 237) and prolactin level of 10.1 ng/mL (ULN 20) which can be elevated in 30% of mixed thyrotropinoma cases (1). The first evidence to suggest a thyrotropinoma was a mildly elevated sex-hormone binding globulin at 102 nmol/L (ULN 80). Further evaluation with pituitary magnetic resonance imaging showed a 6-milimeter lesion. Although the pituitary lesion is suggestive of a thyrotropinoma, it is not definitive, as they are present in 20% of RTH cases (1). Therefore, with increased suspicion of a thyrotropinoma, we pursued the more robust T3 suppression test which showed 56% suppression of TSH consistent with a thyrotropinoma. The patient had pituitary surgery with pathology confirming weak immunoreactivity for TSH. Post-operatively, his symptoms improved and free thyroid hormones normalized. Discussion: It is important to distinguish between thyrotropinoma and RTH as the treatment is different with 80% of thyrotropinoma cases achieving euthyroidism after surgery (1). In our case, the diagnosis was initially unclear thus it was important to broaden the lab and genetic evaluation considering the limitations of the studies. One such limitation is the α subunit may not be elevated in microadenomas as occurred in our case. 1. Beck-Peccoz et al. J Endocrinol Invest. 2019; 42:1401-6

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