A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves' orbitopathy.
BACKGROUND
Immunoglobulins stimulating the TSH receptor (TSI) influence thyroid function and likely mediate extrathyroidal manifestations of Graves' disease (GD).


OBJECTIVE
The aim of this study was to assess the clinical relevance of TSI in GD patients with or without Graves' orbitopathy (GO), to correlate the TSI levels with activity/severity of GO, and to compare the sensitivity/specificity of a novel TSI bioassay with TSH receptor (TSH-R) binding methods (TRAb).


METHODS
TSI were tested in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness to TSI of the novel chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R) was compared with the wild-type (wt) TSH-R.


RESULTS
All hyperthyroid GD/GO patients were TSI-positive. TSI were detected in 150 of 155 (97%, Mc4) and 148 of 155 (95%, wt) GO patients, in six of 45 (13%, Mc4) and 20 of 45 (44%, wt) mostly treated GD subjects, and in 0 of 40 (Mc4) and one of 40 (wt) controls. Serum TSI titers were 3- and 8-fold higher in GO vs. GD and control, respectively. All patients with diplopia and optic neuropathy and smokers were TSI-positive. TSI strongly correlated with GO activity (r = 0.87 and r = 0.7; both P < 0.001) and severity (r = 0.87 and r = 0.72; both P < 0.001) in the Mc4 and wt bioassays, respectively. Clinical sensitivity (97 vs. 77%; P < 0.001) and specificity (89 vs. 43%; P < 0.001) of the Mc4/TSI were greater than TRAb in GO. All 11 of 200 (5.5%) TSI-positive/TRAb-negative patients had GO, whereas all seven of 200 (3.5%) TSI-negative/TRAb-positive subjects had GD only.


CONCLUSIONS
The novel Mc4/TSI is a functional indicator of GO activity and severity.
Department of Medicine I, Gutenberg University Medical Center, Mainz 55101, Germany.
S D
SD
Lytton
K A
KA
Ponto
M
M
Kanitz
N
N
Matheis
L D
LD
Kohn
G J
GJ
Kahaly
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D013956:Antithyroid Agents / Q000627:therapeutic use; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery; D049970:Graves Ophthalmopathy / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy / Q000601:surgery; D006801:Humans; D006980:Hyperthyroidism / Q000097:blood / Q000188:drug therapy; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood*; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D008713:Methimazole / Q000627:therapeutic use; D008875:Middle Aged; D051381:Rats; D011989:Receptors, Thyrotropin / Q000378:metabolism; D012016:Reference Values; D012720:Severity of Illness Index; D013965:Thyroidectomy; D055815:Young Adult
D013956:Antithyroid Agents; D018828:Immunoglobulins, Thyroid-Stimulating; D007457:Iodine Radioisotopes; D011989:Receptors, Thyrotropin; D008713:Methimazole