Thyrotrophin receptor antibody characteristics in a woman with long-standing Hashimoto's who developed Graves' disease and pretibial myxoedema.
BACKGROUND
Sequential conversion of Hashimoto's thyroiditis (HT) to Graves' disease (GD) is uncommon. Distinct immune paradigms, paucity of functioning tissue in long-standing HT, and infrequent conversion of blocking (TBAb) to stimulating (TSAb) thyrotrophin receptor antibody (TRAb) may account for this. Molecular and crystal structure analysis helps delineate TSH receptor (TSHR)/TRAb interactions in detail. Such 'fingerprinting' helps determine the behaviour and characteristics of TRAb in longitudinal studies.


METHODS
An 80-year-old woman taking thyroxine for long-standing HT became hyperthyroid. This persisted despite thyroxine withdrawal - free T3 was 7·3 pmol/l (2·6-5·7) and TSH < 0·01 mU/l (0·2-4·5) and TRAb highly positive. She had a goitre (ultrasound - HT), pretibial myxoedema, with mild inactive Graves' orbitopathy. She had RAI treatment and is on thyroxine replacement.


RESULTS
Blood samples at presentation (A) and 1 year (B) showed high TSAb and TPOAb activity but no TBAb. Experiments involving TSHR mutations confirmed that (i) TRAb had stable characteristics over 1 year; (ii) TSHR mutation R255D caused complete inhibition and (iii) R109A caused marked reduction of cAMP production by M22 (TSHR-stimulating human monoclonal antibody) and A and B; (iv) mutations R80A, E107A and K129A while affecting M22 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 TSAb synthesis occurred converting her long-standing HT to GD although the mechanisms responsible remain unexplained. TRAb analysis confirmed stable autoantibody characteristics over 1 year and variable effects of TSHR mutations on TRAb and M22 function.
Section of Diabetes and Endocrinology, Department of Medicine, Caerphilly Miners' Hospital, Caerphilly, UK.
C
C
Kamath
S
S
Young
K
K
Kabelis
J
J
Sanders
M A
MA
Adlan
J
J
Furmaniak
B
B
Rees Smith
L D
LD
Premawardhana
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019138:Antibodies, Blocking / Q000097:blood; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006111:Graves Disease / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D050031:Hashimoto Disease / Q000150:complications* / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood*; D007868:Leg Dermatoses / Q000209:etiology* / Q000276:immunology*; D009154:Mutation; D009230:Myxedema / Q000209:etiology* / Q000276:immunology*; D011989:Receptors, Thyrotropin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000008:administration & dosage; D013997:Time Factors
D019138:Antibodies, Blocking; D018828:Immunoglobulins, Thyroid-Stimulating; D011989:Receptors, Thyrotropin; D011994:Recombinant Proteins; C094372:thyrotropin-binding inhibitory immunoglobulin; D013974:Thyroxine