Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves’ Orbitopathy

George, Augustine; Diana, Tanja; Längericht, Jan; Kahaly, George J.

doi:10.3389/fendo.2020.629925

Cited by 35 publications

(21 citation statements)

References 43 publications

(51 reference statements)

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“…Both hyper-and hypothyroidism negatively impact GO (35)(36)(37). In line with the expression of the TSHR as autoantigen on orbital target cells (38,39) in patients with GD/GO, high serum concentrations of TSHR-Ab (>five-fold increase) are associated with the presence of GO both in children and adults with GD and Hashimoto's thyroiditis (40)(41)(42)(43). Although neither regularly done in commercial laboratories nor routinely available to the clinician, dilution analysis of serum TSHR-Ab is both predictive for the occurrence of GO (positive and negative predictive values of 100% with a cut-off dilution titer >4) (29), as well as for the response to antithyroid treatment of associated Graves' hyperthyroidism (42,44).…”

Section: Control Of Risk Factorsmentioning

confidence: 91%

“…ATDs and Tx per se do not modify the natural history of mild GO (53,54,168), although RCTs on moderate-to-severe GO are lacking. Long-term ATD treatment is beneficial for GO due to normalization of thyroid function and associated decline of TSHR-Ab serum levels (169), which are a biomarker for GO (43,170). Avoiding iatrogenic hypothyroidism in treating patients with GD/GO (Figures 1-4) is an important principle of medical management.…”

Section: Treatment Of Hyperthyroidism In Patients With Go [Recommendations #28-32]mentioning

confidence: 99%

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The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Bartalena

Kahaly

Baldeschi

et al. 2021

European Journal of Endocrinology

484

497

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Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO, intravenous (iv) glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness and patient choice after extensive counselling, a combination of iv methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 grams (g) of iv methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include: a) a second course of iv methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; c) orbital radiotherapy combined with oral or iv glucocorticoids, d) teprotumumab; e) rituximab and f) tocilizumab. Sight threatening GO is treated with several high single doses of iv methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint and eyelid surgery) is indicated for inactive residual GO manifestations.

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Section: Control Of Risk Factorsmentioning

confidence: 91%

Section: Treatment Of Hyperthyroidism In Patients With Go [Recommendations #28-32]mentioning

confidence: 99%

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Bartalena

Kahaly

Baldeschi

et al. 2021

European Journal of Endocrinology

484

497

View full text Add to dashboard Cite

show abstract

“…Natural aAb levels are commonly determined in AITD as diagnostic markers, which support the diagnosis, correlate to disease severity, and enable the monitoring of treatment success. In Graves’ disease, natural aAb to the TSH-receptor (TSHR-aAb) are causative for the clinical phenotype, as they bind as endocrine active agonists to the TSH-receptor and stimulate hyperthyroidism and thyroid eye disease [ 2 ]. In comparison, natural aAb to another thyroid autoantigen, namely the thyroperoxidase (TPO-aAb), are detectable in both Graves’ disease and Hashimoto’s thyroiditis, where they are associated with cell-mediated cytotoxicity [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto’s Thyroiditis

Sun

Mehl

Renko

et al. 2021

IJMS

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The essential trace element selenium (Se) is needed for the biosynthesis of selenocysteine-containing selenoproteins, including the secreted enzyme glutathione peroxidase 3 (GPX3) and the Se-transporter selenoprotein P (SELENOP). Both are found in blood and thyroid colloid, where they serve protective functions. Serum SELENOP derives mainly from hepatocytes, whereas the kidney contributes most serum GPX3. Studies using transgenic mice indicated that renal GPX3 biosynthesis depends on Se supply by hepatic SELENOP, which is produced in protein variants with varying Se contents. Low Se status is an established risk factor for autoimmune thyroid disease, and thyroid autoimmunity generates novel autoantigens. We hypothesized that natural autoantibodies to SELENOP are prevalent in thyroid patients, impair Se transport, and negatively affect GPX3 biosynthesis. Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto’s thyroiditis as compared with healthy control subjects (6.6% versus 0.3%). Serum samples rich in SELENOP autoantibodies displayed relatively high total Se and SELENOP concentrations in comparison with autoantibody-negative samples ([Se]; 85.3 vs. 77.1 µg/L, p = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, p = 0.001), while GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.

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“…Thyrotropin receptor autoantibodies (TSH-R-Ab) are specific biomarkers of both Graves' disease (GD) and thyroid-associated orbitopathy (TAO) that define their pathogenetic background and clinical phenotype. They represent an indispensable diagnostic tool in the clinical assessment of GD and TAO [1] [2] [3] [4] [5] [6] . TSH-R-Ab express variable biological activity and are accordingly classified as stimulating (TSAb), blocking (TBAb), and neutral antibodies [7] .…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of three thyrotropin receptor antibody assays in thyroid-associated orbitopathy

Matutinović¹,

Diana²,

Beleslin³

et al. 2022

J Med Biochemistry

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Background: Thyrotropin receptor autoantibodies (TSH-R-Ab) are indispensable biomarkers in the laboratory assessment of thyroid-associated orbitopathy (TAO). Clinical sensitivity of three different assays for TSH-R-Ab determination was evaluated in patients with TAO. Methods: 87 consecutive TAO patients were enrolled and their serum samples analyzed in parallel with three assays. An ECLIA competitive binding and a chemiluminescent bridge immunoassay were used to measure total and binding TSH-R-Ab concentration, while their functional activity was determined using a stimulatory TSH-R-Ab (TSAb) cell-based bioassay. Results: Compared to the two binding assays (ECLIA p<0.001, bridge p=0.003), the TSAb bioassay was more sensitive pertaining to the positive detection of TSH-R-Ab in TAO patients. No difference (p=0.057) was noted between the ECLIA and bridge assays regarding sensitivity rate. All patients with active and/or moderate-to-severe TAO tested positive in the TSAb bioassay (100% and 100%, respectively), while the positivity rates for bridge and ECLIA binding assays were 89.7% and 82.1% for active TAO, and 90.2% and 86.3% for severe TAO, respectively. Negative predictive values of the bioassay, bridge, and ECLIA assays were 100%, 75%, and 71%, respectively for active TAO, and 100%, 86%, and 71%, respectively for moderate-to-severe TAO. The superiority of the bioassay was most prominent in euthyroid (ET) TAO. Positivity rates of the TSAb bioassay, bridge and ECLIA binding assays were 89.6%, 75%, and 64.6%, respectively for inactive TAO; 86.1%, 69.4%, and 52.8%, respectively for mild TAO; 87.5%, 62.5%, and 12.5%, respectively for euthyroid TAO. The bridge assay correlated better with the ECLIA binding assay (ρ=0.893, p<0.001), compared to the bioassay (ρ=0.669, p<0.001). Conclusions: In patients with TAO of various activity and severity, the TSAb bioassay demonstrates a superior clinical performance compared to both ECLIA and bridge binding assays.

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Stimulatory Thyrotropin Receptor Antibodies Are a Biomarker for Graves’ Orbitopathy

Cited by 35 publications

References 43 publications

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto’s Thyroiditis

Sensitivity of three thyrotropin receptor antibody assays in thyroid-associated orbitopathy

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