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

Abstract

CONTEXT:

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.

PATIENT:

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.

MEASUREMENTS AND 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.

• Authors: C Kamath, S Young, K Kabelis, J Sanders, M A Adlan, J Furmaniak, B Rees Smith, L D Premawardhana
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 77 Issue 3 Pg. 465-70 (Sep 2012) ISSN: 1365-2265 [Electronic] England
• PMID: 22891608 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Antibodies, Blocking
• Immunoglobulins, Thyroid-Stimulating
• Receptors, Thyrotropin
• Recombinant Proteins
• thyrotropin-binding inhibitory immunoglobulin
• Thyroxine

Topics

• Aged
• Aged, 80 and over
• Animals
• Antibodies, Blocking (blood)
• CHO Cells
• Cricetinae
• Cricetulus
• Female
• Graves Disease (etiology, genetics, immunology)
• Hashimoto Disease (complications, drug therapy, immunology)
• Humans
• Immunoglobulins, Thyroid-Stimulating (blood)
• Leg Dermatoses (etiology, immunology)
• Mutation
• Myxedema (etiology, immunology)
• Receptors, Thyrotropin (chemistry, genetics, metabolism)
• Recombinant Proteins (chemistry, genetics, metabolism)
• Thyroxine (administration & dosage)
• Time Factors