TSH Receptor Autoantibodies Research Articles

A stimulatory TSH receptor antibody enhances adipogenesis via phosphoinositide 3-kinase activation in orbital preadipocytes from patients with Graves' ophthalmopathy

Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital tissues associated with elevated serum levels of TSH receptor (TSHR) autoantibodies. Because previous studies have demonstrated evidence of adipogenesis within the GO orbit, we sought to determine whether M22, a human monoclonal antibody directed against TSHR, enhances adipogenesis in orbital fibroblasts from patients with GO and, if so, to identify signaling mechanisms involved. GO orbital fibroblast cultures (n=10) were treated for 10 days with bovine TSH (1 or 10·0 U/l) or M22 (1 or 10 ng/ml) in serum-free adipocyte differentiation medium. Some cultures also received a phosphoinositide 3-kinase (PI3K) inhibitor or an inhibitor of cAMP production. In other experiments, confluent cultures (n=8) were treated for between 1 and 30 min with TSH (0·1–10·0 U/l) or M22 (0·1–100 ng/ml) with measurement of cAMP production or levels of phosphorylated AKT (pAKT). We found levels of adiponectin, leptin, and TSHR mRNA to be increased in GO cultures treated for 10 days with either M22 (2·6 mean fold ±0·7; P=0·03) or TSH (13·2±5·8-fold, P=0·048). In other studies, M22 and TSH stimulated cAMP production and pAKT levels in GO cells. Inhibition of PI3K activity during 10 days in culture decreased the levels of M22-stimulated mRNA encoding adiponectin (67±12%; P=0·021), as well as adiponectin and CCAAT/enhancer-binding protein α protein levels. In conclusion, M22 is a pro-adipogenic factor in GO orbital preadipocytes. This antibody appears to act via the PI3K signaling cascade, suggesting that inhibition of PI3K signaling may represent a potential novel therapeutic approach in GO.

Novel chimeric thyroid-stimulating hormone-receptor bioassay for thyroid-stimulating immunoglobulins

Thyroid-stimulating immunoglobulins (TSI) are a functional biomarker of Graves' disease (GD). To develop a novel TSI bioassay, a cell line (MC4-CHO-Luc) was bio-engineered to constitutively express a chimeric TSH receptor (TSHR) and constructed with a cyclic adenosine monophosphate (cAMP)-dependent luciferase reporter gene that enables TSI quantification. Data presented as percentage of specimen-to-reference ratio (SRR%) were obtained from 271 patients with various autoimmune and thyroid diseases and 180 controls. Sensitivity of 96% and specificity of 99% for untreated GD were attained by receiver operating characteristic analysis, area under the curve 0·989, 95% confidence interval 0·969-0·999, P = 0·0001. Precision testing of manufactured reagents of high, medium, low and negative SRR% gave a percentage of coefficient-of-variation of 11·5%, 12·8%, 14·5% and 15·7%, respectively. There was no observed interference by haemoglobin, lipids and bilirubin and no non-specific stimulation by various hormones at and above physiological concentrations. TSI levels from GD patients without (SRR% 406 ± 134, mean ± standard deviation) or under anti-thyroid treatment (173 ± 147) were higher (P < 0·0001) compared with TSI levels of patients with Hashimoto's thyroiditis (51 ± 37), autoimmune diseases without GD (24 ± 10), thyroid nodules (30 ± 26) and controls (35 ± 18). The bioassay showed greater sensitivity when compared with anti-TSHR binding assays. In conclusion, the TSI-Mc4 bioassay measures the functional biomarker accurately in GD with a standardized protocol and could improve substantially the diagnosis of autoimmune diseases involving TSHR autoantibodies.

ORIGINAL ARTICLE: Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample

SummaryObjective Patients who appear to have both stimulating and blocking TSHR autoantibodies in their sera have been described, but the two activities have not been separated and analysed. We now describe the isolation and detailed characterization of a blocking type TSHR monoclonal autoantibody and a stimulating type TSHR monoclonal autoantibody from a single sample of peripheral blood lymphocytes.Design, patients and measurements Two heterohybridoma cell lines secreting TSHR autoantibodies were isolated using standard techniques from the lymphocytes of a patient with hypothyroidism and high levels of TSHR autoantibodies (160 units/l by inhibition of TSH binding). The ability of the two new monoclonal antibodies (MAbs; K1‐18 and K1‐70) to bind to the TSHR and compete with TSH or TSHR antibody binding was analysed. Furthermore, the effects of K1‐18 and K1‐70 on cyclic AMP production in Chinese hamster ovary cells (CHO) cells expressing the TSHR were investigated.Results One MAb (K1‐18) was a strong stimulator of cyclic AMP production in TSHR‐transfected CHO cells and the other (K1‐70) blocked stimulation of the TSHR by TSH, K1‐18, other thyroid‐stimulating MAbs and patient serum stimulating type TSHR autoantibodies. Both K1‐18 (IgG1 kappa) and K1‐70 (IgG1 lambda) bound to the TSHR with high affinity (0·7 × 1010 l/mol and 4 × 1010 l/mol, respectively), and this binding was inhibited by unlabelled K1‐18 and K1‐70, other thyroid‐stimulating MAbs and patient serum TSHR autoantibodies with stimulating or blocking activities. V region gene analysis indicated that K1‐18 and K1‐70 heavy chains used the same V region germline gene but different D and J germline genes as well as having different light chains. Consequently, the two antibodies have evolved separately from different B cell clones.Conclusions This study provides proof that a patient can produce a mixture of blocking and stimulating TSHR autoantibodies at the same time.

The Tale of Radioiodine and Graves' Orbitopathy

Autoimmunity against the thyrotropin receptor (TSH-R) is a key pathogenic element in Graves' disease (GD) and the autoimmune aberration may be modified by antithyroid treatment. An association between radioactive iodine (RAI) therapy for GD and the development or worsening of Graves' orbitopathy (GO) is widely quoted. RAI-associated leakage of thyroid antigen(s) leads to an increased production of TSH-R antibodies that may initiate the eye injury. RAI therapy leads to prolonged worsening of autoimmunity against the TSH-R, and the number of patients entering remission of TSH-R autoimmunity is considerably lower than with other antithyroid therapies. Scientific evidence has indicated that RAI treatment for GD is associated with increased risk of occurrence or progression of GO compared with antithyroid drugs (ATD) and thyroid surgery. The risks of developing new GO or worsening of preexisting GO is around 20% after RAI and around 5% after ATD. The risk of developing severe GO after RAI is around 7%. Smoking, high levels of pretreatment serum triiodothyronine, and post-RAI hypothyroidism are associated with increased risk of GO, whereas a high TSH-R autoantibody titer is an independent risk factor for the progression of GO. In patients with mild preexisting GO, steroid prophylaxis is effective in preventing deterioration of GO. Also, routine use of prophylactic oral steroids with RAI therapy should be considered in GD patients without overt GO, but even more so in those at higher risks of eye complications such as smokers, old men, and those with severe hyperthyroidism or high TSH-R antibody titers. In contrast to ATD, remission of TSH-R autoimmunity after RAI therapy is less common, and RAI for GD is associated with definite increased risk of GO. Oral steroids are beneficial for patients with preexisting GO, particularly smokers.

Identification of Outer Membrane Porin F Protein ofYersinia enterocoliticaRecognized by Antithyrotopin Receptor Antibodies in Graves’ Disease and Determination of Its Epitope Using Mass Spectrometry and Bioinformatics Tools

In addition to genetic susceptibility, Yersinia enterocolitica (YE) infection played an important causative role in the pathogenesis of Graves' disease (GD) through molecular mimicry. However, the specific YE proteins and epitopes recognized by anti-TSH receptor (TSHR) autoantibodies (TRAb) have not been fully clarified, resulting in conflicting results from clinical research. Our aim was to explore the roles of YE in the pathogenesis of GD and identify the YE proteins and epitopes that are similar to the TSHR and are recognized by TRAb. Assays of YE antibodies, TRAb, thyroglobulin antibodies, and thyroid microsomal antibodies as well as cross-absorption and two-way immunodiffusion were performed in patients with GD. Using mass spectrometry and the bioinformatics tools of protein structure modeling and epitope prediction, we identified the YE protein and its epitope, which was recognized by TRAb and was similar to TSHR. Our study demonstrated for the first time that the YE protein outer membrane porin F protein (ompF) shared cross-immunogenicity with a leucine-rich domain of TSHR. The epitope recognized by antihuman TSHR antibody is located within the ompF region of amino acids 190-197, and the polyantibody against ompF protein showed TSAb activity. Our results suggest that YE ompF is involved in the production of TRAb and the pathogenesis of GD through molecular mimicry. These findings are potentially important for understanding the role molecular mimicry plays in the disturbance of immune tolerance and the induction of autoimmunity to the TSHR.

Thyroid function and morphology in subjects with microdeletion of chromosome 22q11 (del(22)(q11))

Monoallelic microdeletion of chromosome 22q11 (22q11DS) is considered to be the commonest human microdeletion syndrome. Abnormalities of thyroid function are sporadically reported in this syndrome, but very few studies have specifically assessed this issue, and thyroid morphology has not been systematically studied. To evaluate the prevalence of abnormalities of thyroid function and morphology in a cohort of paediatric and adult patients with 22q11DS. Thirty patients with 22q11DS (median age 9.7, range 1.5-43.9 years) were studied. In all subjects, serum free-T(3), free-T(4), TSH, thyroperoxidase, thyroglobulin, and TSHr auto-antibodies, as well as thyroid ultrasonographic data, were evaluated and compared with age- and sex-matched healthy control groups, for paediatric and adult patients. Fourteen (46.6%) patients showed thyroid hypoplasia involving the entire gland. In all the patients, the volume of the left lobe of the thyroid was significantly reduced (P < 0.01). Among the subjects with thyroid hypoplasia, 10 out of 14 (71%) showed a concomitant heart malformation, a condition that was present in five (31%) of the subjects with a normal thyroid volume (P < 0.05). Seven (23.3%) cases of subclinical hypothyroidism and one (3.3%) case of overt hypothyroidism were identified. Three (10%) patients were positive for thyroid auto-antibodies. Of the patients with overt and subclinical hypothyroidism, five out of eight (62.5%) patients showed thyroid hypoplasia. This study confirms the presence of alterations of thyroid function in 22q11DS, and also suggests a frequent occurrence of abnormalities in thyroid morphology in these subjects. Patients with 22q11DS should be monitored for thyroid function, and thyroid ultrasound screening should be considered, especially in those patients with changes in thyroid function or congenital heart malformations. The possible relationship between developmental abnormalities in the heart and the thyroid gland should be confirmed.

Concomitant Graves Hyperthyroidism with Thyrotrophin-Secreting Pituitary Adenoma

The relationship of autoimmune thyroid disease and TSH-producing pituitary tumor is rarely found. We report two patients with hyperthyroidism, a 27-year-old man and a 28-year-old woman, who were diagnosed with Graves hyperthyroidism with elevated free thyroxine (FT4), suppressed TSH and positive thyrotropin receptor autoantibodies. After treatment with antithyroid drugs, FT4 did not return to normal, and serum TSH levels were found to be above-normal range. Pituitary tumors were subsequently found via pituitary magnetic resonance imaging (MRI). We suggest that Graves hyperthyroidism concomitant with TSH-producing pituitary tumor be kept in mind, as it may confuse the therapeutic course of hyperthyroidism and make it more complicated.

Reproducibility of Elecsys®Anti-TSHR Test Results in a Lot-to-Lot Comparison

Most recently, a new rapid and fully-automated TSH receptor autoantibody (TRAb) assay has been established. This assay system uses the M22 human monoclonal antibody for competing against the patient's TSH receptor autoantibodies (TRAb) to be detected. The aim of our present study was to compare the reproducibility of TRAb values based on measurements with different TSH receptor preparations in a lot-to-lot comparison. For TRAb values > 2 IU/l the relative differences ranged from -9.0 to +10.0%. The mean difference was 0.28 +/- 8%. For TRAb values around the cutoff for positivity (1.75 IU/l) a higher range of relative differences from -20 up to +15% was obtained. The overall mean of differences was -0.8+/-14%. The data clearly demonstrate that the automated TRAb assay has a high stability in regard to TSH receptor preparations.

Technical Evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies

Technical Evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies

A Stimulatory Thyrotropin Receptor Antibody (M22) and Thyrotropin Increase Interleukin-6 Expression and Secretion in Graves' Orbital Preadipocyte Fibroblasts

Patients with Graves' ophthalmopathy (GO) have circulating autoantibodies directed against the thyrotropin receptor (TSHR) and elevated levels of the proinflammatory cytokine interleukin-6 (IL-6) in both serum and orbital tissues. We hypothesized that these autoantibodies might increase IL-6 expression and secretion in preadipocyte fibroblasts and adipocytes from patients with GO, and thus directly impact the clinical activity of the disease. IL-6 mRNA levels were measured in cultures of GO orbital preadipocytes (n = 3) treated during adipocyte differentiation with a monoclonal stimulatory TSHR antibody (M22; 10 ng/mL), IL-6 (1 ng/mL), or TSH (10 U/L). Additionally, levels of IL-6 protein secretion were assessed after adipocyte differentiation in orbital cultures exposed to TSH or M22 for 24 or 48 hours (n = 8). IL-6 mRNA levels were also measured in orbital adipose tissue specimens from well-characterized GO patients (n = 9) and normal individuals (n = 9). Treatment of GO orbital preadipocyte cultures with IL-6, TSH, or M22 during adipocyte differentiation resulted in increased IL-6 mRNA levels (3.1-fold, 2.9-fold, and 2.7-fold, respectively; p < 0.05). Treatment of orbital cultures with M22 or TSH after adipocyte differentiation enhanced the release of IL-6 protein into the medium at both 24 and 48 hours for TSH (mean 1.9- and 2.3-fold; p = 0.002 and 0.015, respectively) and at 48 hours for M22 (mean 2.0-fold; p = 0.005). In addition, we found mean IL-6 mRNA levels to be significantly increased in GO orbital adipose tissue specimens (10-fold; p < 0.01), primarily attributable to high levels in three of the four patients with clinical activity scores >or=5. Both TSH and M22 increase IL-6 expression in orbital preadipocyte fibroblasts and IL-6 secretion by mature adipocytes. These results suggest that circulating TSHR autoantibodies in GO might play a direct role in the clinical activity of the disease.

Peculiarities of Graves' disease in children and adolescents with Down's syndrome

To compare the presentation and clinical course of Graves' disease (GD) in two pediatric populations consisting of 28 patients with Down's syndrome (DS) and 109 controls without DS respectively. The evolution over time of GD was determined in both groups according to the clinical changes and the variations in TSH, free thyroxine, and TSH receptor autoantibodies serum levels during the entire follow-up. Female prevalence (50 vs 81.6%; chi(2)=12.0, P<0.0005) and average age at GD presentation (9.9+/-4.4 vs 11.5+/-3.5 years, P<0.05) were significantly lower in DS group than in controls. Clinical responsiveness to methimazole therapy was significantly better in DS patients, as demonstrated by both the lower relapse rates after the first cycle withdrawal (7.1 vs 31.2%; chi(2)=7.4, P<0.005) and the higher persistent remission rates after definitive therapy withdrawal (46.4 vs 26.7%; chi(2)=4.1, P<0.05). Moreover, in DS group, no patients needed surgery or radioiodine ablation, whereas non-pharmacological treatment was necessary in 11% of controls (chi(2)=3.8, P<0.05). Antecedents of Hashimoto's thyroiditis (HT) were documented in 21.4% of DS patients and in 3.7% of controls (chi(2)=10.4, P<0.005). Association with other autoimmune diseases was detected in 32.1% of DS cases and in 12.8% of controls (chi(2)=5.94, P<0.025). GD in DS children and adolescents is characterized by several peculiarities: i) earlier presentation; ii) no gender predominance; iii) less severe clinical course; iv) higher frequency of documented HT antecedents; v) more frequent association with other autoimmune diseases.

Diagnosis and discrimination of autoimmune Graves' disease and Hashimoto's disease using thyroid-stimulating hormone receptor-containing recombinant proteoliposomes

Graves' disease (GD) is an autoimmune disease of the thyroid gland caused by autoantibodies against thyroid-stimulating hormone receptor (TSHR). Currently, the diagnostic test for TSHR autoantibodies is based on an indirect competitive binding assay that measures the ability of TSHR autoantibodies to inhibit the binding of thyroid-stimulating hormone (TSH) to TSHR. Here, we have developed a specific and direct diagnostic method for autoantibodies in GD that incorporates immobilized TSHR-containing recombinant proteoliposomes into an enzyme-linked immunosorbent assay (ELISA). To reduce non-specific binding of autoantibodies to recombinant proteoliposomes, we investigated the effect of polyethylene glycol (PEG)-lipid on the binding of commercially available anti-TSHR antibodies (aTSHRAb). The incorporation of PEG-lipids into liposomes decreased non-specific binding, as compared to liposomes that did not contain PEG-lipids, and the addition of blocking reagents further decreased non-specific reactivity. aTSHRAb exhibited higher reactivity towards PEG-modified TSHR recombinant proteoliposomes than PEG-modified liposomes without TSHR (bare liposomes). Importantly, serum autoantibodies from patients with GD, which is associated with hyperthyroidism, exhibited remarkably specific binding to TSHR recombinant proteoliposomes. Serum autoantibodies from patients with Hashimoto's disease (HD), which is associated with hypothyroidism, also reacted specifically with proteoliposomal TSHR. These results suggest that immobilized TSHR recombinant proteoliposomes can serve as a direct diagnostic test for GD and HD. Furthermore, given that there is no competition test currently available for detecting autoantibodies in HD, the combination of TSHR recombinant proteoliposome ELISA and indirect competitive TSHR binding assay might be an effective way to discriminate between GD and HD.

TSH Receptor Antibody (TRAb) Assays Based on the Human Monoclonal Autoantibody M22 are more Sensitive than Bovine TSH Based Assays

Measurements of TSH receptor autoantibodies (TRAb) using assays based on the human monoclonal TSH receptor autoantibody M22 or bovine TSH have been compared in 136 adult patients. They suffered from Graves' disease (GD, n=62), Hashimoto's thyroiditis (HT, n=26), or non-autoimmune hyperthyroidism (NAH, n=48) and were selected on the basis of undetectable, borderline or low TRAb levels (0.6-3 IU/l) as measured by TSH based TRAb assay (Dynotest TRAKhuman from BRAHMS). The time interval between initial diagnosis of GD and TRAb determination was high and ranged from 1 month to 3.5 years (median: 2.3 years). Using the kit manufacturer's cutoff values, 53/62 (85.5%) of the selected group of GD patients were TRAb positive (>0.4 IU/l) by M22 based TRAb ELISA (Medizym TRAb clone, Medipan) and 45/62 (72.6%) were TRAb positive (>1.5 IU/l) by TSH based TRAb assay. In the HT group, 9/26 (34.6%) sera were positive in the M22 based ELISA and all but one of these 9 were positive or borderline in the TSH based assay. ROC plot analysis of the GD group using the NAH group as reference showed that at 95% specificity, the bovine TSH based TRAb assay had a sensitivity of 62.9% (cutoff for positivity=1.64 IU/l) and the M22 based TRAb ELISA a sensitivity of 90.3% (cutoff for positivity=0.32 IU/l). Overall therefore, the M22 based Medizym TRAb clone assay is more sensitive than the bovine TSH based Dynotest TRAK human assay.

Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves’ disease (GD): an international multicentre trial

Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid-stimulating monoclonal antibody (M22) has been established. To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays. Totally 508 Graves' disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated. ROC plot analysis revealed an area under curve of 0.99 (95% CI: 0.99-1.0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut-off level of 1.75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot-derived cut-off of 1.75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor-based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity. Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.

Orbital Lymphoma Masquerading as Thyroid-Associated Orbitopathy

A 70-yr-old woman 1 was referred because of orbital pain, bilateral proptosis, eyelid swelling, inflammatory symptoms, and visual impairment. Her symptoms had begun 2 yr earlier, and a computed tomography (CT) scan of the orbits at the time had shown mild proptosis and enlargement of the left superior rectus muscle. Thyroid function tests revealed mild hypothyroidism with negative thyroid autoantibodies. A diagnosis of thyroid-associated orbitopathy (TAO) was made. The patient had a history of mild chronic lymphocytic leukemia, without lymph node or solid organ involvement. She was treated with L-thyroxine and an 18-month course of low-dose methylprednisolone and azathioprine, with a partial improvement of her eye manifestations. Her eye symptoms recurred, however, when immunosuppressive treatment was withdrawn and consequently she was referred to our department. Physical examination (Fig. 1, upper panel) showed marked, bilateral proptosis, soft tissue inflammation, and mild impairment of ocular movement (1). There was no upper lid retraction. Thyroid function tests were normal on L-thyroxine with negative thyroid autoantibodies, including TSH receptor autoantibodies. A CT scan of the orbits (Fig. 1, upper panel) showed bilateral proptosis, mild enlargement of extraocular muscles, together with a diffuse nodular infiltration of soft tissues, involving the eyelids and the orbital cavity. These features suggested ocular involvement by a neoplastic process, rather than TAO, in which the typical finding is the enlargement of extraocular muscles (rectus inferior medial superior) (2). An orbital biopsy of affected tissue (Fig. 1, lower panel) revealed a dense infiltrate of small B lymphocytes staining positive for CD20, CD5, and bcl-2, therefore supporting the diagnosis of B cell chronic lymphocytic leukemia involving the orbits (3, 4). Treatment with clorambulacil was commenced. Four weeks later, improvement of eye manifestations was evident, and this was sustained at the next follow-up visit 4 months later (Fig. 1, middle panel). Orbital manifestations went into complete remission at the latest follow-up visit (10 months after clorambucil therapy was started). Orbital lymphoma can mimic TAO. In atypical cases of TAO, like those who have no history of Graves’ disease, no TSH receptor antibodies, and absence of upper lid retraction, alternative diagnoses should be considered (5). In these cases, orbital imaging should always be performed. Indeed, the unusual eye muscle involvement

TSH Receptor – Autoantibody Interactions

TSH receptor (TSHR) autoantibodies (TRAbs)activate the TSHR cyclic AMP cascade (stimulating TRAbs) or act as TSHR antagonist (blocking TRAbs), and both types inhibit TSH binding to the TSHR. Isolation of human monoclonal TSHR autoantibodies (stimulating M22 and blocking 5C9) has been a key milestone in studies of the TSHR and TSHR autoimmunity. Comparison of M22 and TSH interactions with the TSHR at the atomic level reveal that M22 heavy and light chains mimic TSH alpha and beta chains, respectively, in the way they bind to the receptor, but the evolutionary forces which have caused this close molecular mimicry are as yet completely unknown. More recently two more human monoclonal antibodies to the TSHR (K1-18 with stimulating and K1-70 with blocking activities) have been isolated from a single blood sample collected from a patient with hypothyroidism who previously presented with hyperthyroidism. K1-18 and K1-70 were derived from different lymphocytes as shown by V region genes analysis. This provides, for the first time, clear proof that a patient can produce both blocking and stimulating TRAbs at the same time. Although it has been postulated that stimulating and blocking TRAbs bind to different regions on the TSHR, our studies showed that antibodies of both types bind well to the TSHR containing only N-terminal amino acids 22-260. Whether TRAbs make contact with other parts of the TSHR in order to produce their biological effects (stimulation or blocking) remains to be elucidated.

Pituitary-Thyroid Feedback in a Patient with a Sporadic Activating Thyrotropin (TSH) Receptor Mutation: Implication That Thyroid-Secreted Factors Other Than Thyroid Hormones Contribute to Serum TSH Levels

Constitutive mutations of the TSH receptor gene are a rare cause of severe congenital hyperthyroidism. Persistent TSH suppression has been described in euthyroid Graves' disease patients treated with antithyroid drugs. An ultrashort negative feedback loop affecting TSH secretion by activating the pituitary TSH receptor with TSH receptor autoantibodies has been suggested as a possible mechanism of TSH suppression in these patients. The aim of the study was to determine whether TSH suppression also occurs in euthyroid treated patients with non-autoimmune hyperthyroidism. We investigated the outcome of pituitary-thyroid feedback in a patient carrying an activating mutation of the TSH-R gene in an observational prospective study. Repeated clinical investigations from birth until the age of 14 yr are presented for the patient on drug treatment and after radical treatment. TSH was consistently undetectable or present at very low concentrations in the serum for several years, although FT(4) and FT(3) concentrations remained mostly in the normal range. Moreover, serum TSH concentrations increased only slightly when serum FT(4) concentrations fell below normal levels. During drug treatment, serum TSH concentrations expressed as a function of serum FT(4) and FT(3) concentrations were significantly lower than those for control or congenital hypothyroid populations. By contrast, after radical treatment, serum TSH levels increased, reaching the normal range, and low serum FT(4) and FT(3) concentrations were associated with appropriate increases in serum TSH concentrations. These data provide insight into the regulation of serum TSH concentrations and suggest an alternative mechanism, in addition to serum thyroid hormone levels, for adjusting TSH secretion.

Bedeutung der TSH-Rezeptor-Antikörper für die Diagnose des Morbus Basedow sowie die Prognoseabschätzung der Schilddrüsenüberfunktion und der endokrinen Orbitopathie

Graves' disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO). To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs. TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.

A Case of Graves' Disease Combined with Hantaan Virus Infection

Graves' disease (GD) is generally presented by thyrotoxicosis with hyperthyroidism, and it is an organ-specific autoimmune disease induced by thyroid-stimulating hormone receptor autoantibodies. However, among diverse etiologies, viral infections have been suggested to trigger or to be involved in the pathogenesis of GD. Hantaan virus infection causing hemorrhagic fever with renal syndrome (HFRS) is common in South Korea and its pathogenesis is suggested to be an immunologic mechanism. We have experienced a patient who was diagnosed as HFRS with thyrotoxicosis. So we herein report the case as GD combined with the hantaan virus infection.

En kvinne med leggødem og arrforandringer

A patient presented with non-pitting lymphoedema of the legs and finger clubbing. A skin biopsy showed epidermal hyperkeratosis and abundant mucinous material (Alcian blue positive) in reticular dermis. Treatment (radioactive iodine) for Grave's disease (with exophthalmus) 20 years ago, raised suspicion of thyroid dermopathy. Together, these three extrathyroidal manifestations of Graves' disease are typical of the EMO syndrome. In addition, the patient had elevated serum concentrations of thyroid-stimulating hormone receptor autoantibodies. Autoimmune mechanisms are involved in the stimulation of fibroblasts and the production of large amounts of mucin. Pretibial myxoedema relates to scars, mechanical factors, and dependent position. Lack of steroid treatment during radioactive iodine therapy and smoking, may have exacerbated the thyroid dermopathy in this case. Awareness of pretibial myxoedema as a late autoimmune manifestation of Graves' disease, may contribute to earlier diagnosis and correct treatment.