Thyrotrophin receptor antibody characteristics in a woman with long‐standing Hashimoto's who developed Graves' disease and pretibial myxoedema

Context Sequential conversion of H ashimoto's thyroiditis ( HT ) to G raves' disease ( GD ) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long‐standing HT , and infrequent conversion of blocking ( TBA b) to stimulating ( TSA b) thyrotrophin receptor antibody ( TRA b) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor ( TSHR )/ TRA b interactions in detail. Such ‘fingerprinting’ helps determine the behaviour and characteristics of TRA b in longitudinal studies. Patient An 80‐year‐old woman taking thyroxine for long‐standing HT became hyperthyroid. This persisted despite thyroxine withdrawal – free T 3 was 7·3 pmol/l (2·6–5·7) and TSH  < 0·01 mU/l (0·2–4·5) and TRA b highly positive. She had a goitre (ultrasound – HT ), pretibial myxoedema, with mild inactive G raves' orbitopathy. She had RAI treatment and is on thyroxine replacement. Measurements and Results Blood samples at presentation ( A ) and 1 year ( B ) showed high TSA b and TPOA b activity but no TBA b. Experiments involving TSHR mutations confirmed that (i) TRA b had stable characteristics over 1 year; (ii) TSHR mutation R 255 D caused complete inhibition and (iii) R 109 A caused marked reduction of cAMP production by M 22 (TSHR‐stimulating human monoclonal antibody) and A and B; (iv) mutations R 80 A , E 107 A and K 129 A while affecting M 22 had little effect on A and B . Conclusions The reasons for an immunological paradigm shift in this elderly woman remain speculative. We believe that de‐novo TSA b synthesis occurred converting her long‐standing HT to GD although the mechanisms responsible remain unexplained. TRA b analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRA b and M 22 function.