Comparison of TRAb and TSI in different etiologies of thyrotoxicosis
A total of 77 untreated GD patients were enrolled and followed up in our study. And a total of 36 Hashimoto thyroiditis, 17 subacute thyroiditis and 63 healthy control were also enrolled in our study to validate the diagnostic value of TSI. General characteristics of the study population was shown in Table 1. FT3, FT4 was highest and TSH was lowest in patients with untreated GD. TRAb titers and TSI value in participants were shown in Fig. 1. Both TRAb and TSI values were highest in the untreated GD than in healthy controls and patients with Hashimoto thyroiditis and subacute thyroiditis (all P < 0.001). The values of TSI were positive for patients with untreated GD (median SRR, 25% and 75% percentiles: 466.58%, 358.14%-547.60%). TSI values were all negative for patients with Hashimoto thyroiditis (median SRR, 25% and 75% percentiles: 48.68%, 40.12%-65.48%) and subacute thyroiditis (median SRR, 25% and 75% percentiles: 36.4%, 31.00%-45.85%) as well as the healthy control (median SRR, 25% and 75% percentiles: 57.95%, 49.97%-64.98%). TSI values gradually decreased with ATD treatment in GD patients (Fig. 1b and supplemental data). TSI value was (median SRR, 25% and 75% percentiles: 416.98%, 278.66%-543.23%) for GD patients undertreatment and (median SRR, 25% and 75% percentiles: 98.99%, 53.17%-139.86%) for GD patients at the end of treatment. TSI value for GD patients at the end of treatment was significantly lower than untreated GD patients (P < 0.001).
Table 1
Clinical characteristics of the study population
| Healthy Control | Untreated GD | Hashimoto Thyroiditis | Subacute Thyroiditis |
gender(M/F) | 16/47 | 18/59 | 6/30 | 5/12 |
Age(years) | 46.71 ± 13.57 | 41.20 ± 11.94 | 40.00 ± 12.79a | 43.94 ± 7.59 |
FT3(pmol/L) | 4.01(3.71–4.36) bcd | 18.63(12.58–29.31) a | 5.65(4.47–7.69) ab | 6.69(5.79–13.33) a |
FT4(pmol/L) | 12.63(11.85–13.72) bcd | 32.95(27.91–40.41) a | 18.10(15.18–22.34) ab | 26.39(20.88–38.95) a |
TSH(mIU/L) | 1.98(1.18–2.47) bcd | 0.0006(0.0001–0.0016) a | 0.009(0.003–0.7865) ab | 0.004(0.002–0.0255) a |
TPOAb(IU/L) | 0.26(0.09–0.48) b | 356.69(90.61–1000) acd | 167.10(14.44-679.44) abd | 0.60(0.25–2.27) bc |
TgAb(IU/L) | 1.84(1.14–3.13) b | 76.02(18.40-391.20) acd | 51.61(14.17-660.03) ad | 4.29(1.45–21.45) bc |
TRAb(IU/L) | 0.30(0.30–0.30) bcd | 6.64(4.17–12.93) acd | 0.30(0.30–0.88) b | 0.44(0.30–0.54) b |
TSI (SRR%) | 57.95(49.97–64.98) b | 466.58(358.14–547.60) acd | 48.68(40.12–65.48) b | 36.4(31.00-45.85) b |
CV% | 4.21(1.68–7.73) | 3.33(1.49–6.18) | 4.16(2.13–7.69) | 2.35(1.37–6.48) |
TSI: thyroid-stimulating immunoglobulin; SRR: specimen-to reference ratio; CV: coefficient variation; SRR% and CV% were calculated according to the manufacturer’s formula; SRR%= [Average specimen relative light unit (RLU) / average reference control RLU] × 100. CV%= (SD RLU specimen / Average Test RLU) × 100. compared to healthy control, aP<0.05; compared to untreated GD, bP<0.05; compared to Hashimoto thyroiditis, cP<0.05; compared to Subacute thyroiditis, dP<0.05; P value was calculated by Mann-Whitney U test. |
The association of TSI with the risk of relapse in patients with GD
To investigate the association of TSI value with the risk of relapse in patients with GD, 77 patients were continued to follow up till discontinuation of ATD. 77 (18 males and 59 females) GD patients discontinued ATD treatment when serum TRAb was 1.75 IU/L or less for twice in succession and thyroid hormone concentrations were within the normal range. 70 (90.9%) patients were treated with methimazole and 7 (9.1%) patients treated with Propylthiouracil. A total of 21 (27.3%) patients were positive for TSI measurement at the end of treatment and 19 (24.7%) patients showed relapse within 12 months after ATDs discontinuation.
According to clinical fate of patients with GD after withdrawal ATD within 12 months, patients were divided into 2 groups, group without relapse and group with relapse. Their clinical characteristics are summarized in Table 2. Age, thyroid function parameters at the end of treatment, including TSH, FT3, and FT4, showed no significant difference between two groups. In addition, no significant difference was observed in the TRAb level before treatment and at the end of treatment. The average ATDs therapy duration showed no significance difference between patients with relapse and patients with remission (for relapse patients was 15.14 ± 7.56 months and 16.62 ± 5.83 months for patients with remission, P = 0.467). However, TSI level at the end of treatment was significantly higher in relapse group (P = 0.001) but showed no significant difference from the value reported during diagnosis. Of 19 patients with relapse, 13 patients were positive for TSI at the end of treatment and 6 patients were negative for TSI. As shown in Fig. 2a, the relapse rate was significantly higher in the positive TSI group than in the negative TSI group (61.9% [13/21] versus 10.71% [6/56], respectively, P < 0.001]. Based on the cutoff value of SRR 140%, Positive predictive value (PPV) and negative predictive value (NPV) for TSI in the relapse group was 61.9% (13/21) and 89.28% (50/56), respectively. As patients in our study were all TRAb negative (cutoff for TRAb < 1.75 IU/L) upon ATD discontinuation, PPV and NPV for TRAb in the relapse group was 0 (0/77) and 75.32% (58/77), respectively.
Table 2
Clinical data of Graves’ disease patients with or without relapse at the end of treatment
| with relapse | without relapse | P value |
Gender(M/F) | 5/14 | 13/45 | 0.462 |
Age (years) | 41.86 ± 12.61 | 43.50 ± 12.64 | 0.860 |
FT3 (pmol/L) | 4.13(3.98–4.80) | 4.11(3.84–4.46) | 0.211 |
FT4 (pmol/L) | 13.35(12.64–14.85) | 13.31(12.75–14.66) | 0.655 |
TSH (mIU/L) | 1.37(0.45–1.87) | 1.57(1.09–2.18) | 0.127 |
TRAb (IU/L) | 0.70(0.51–0.97) | 0.61(0.38–0.87) | 0.136 |
TRAb at diagnosis (IU/L) | 5.30(3.60-10.13) | 7.06(3.72–16.19) | 0.331 |
TSI (SRR%) | 216.54(112.06-377.04) | 98.99(65.06-128.51) | 0.001 |
TSI at diagnosis (SRR%) | 491.9(369.90-589.70) | 461.55(336.33-549.08) | 0.446 |
CV% | 5.74(2.71–9.46) | 4.70(1.30–7.41) | 0.312 |
Positive TSI (n) | 13 | 8 | < 0.001 |
Negative TSI (n) | 6 | 50 |
Duration of ATD treatment (months) | 15.14 ± 7.56 | 16.62 ± 5.83 | 0.467 |
TSI: thyroid-stimulating immunoglobulin; SRR: specimen-to reference ratio; CV%: coefficient variation; SRR% and CV% were calculated according to the manufacturer’s formula; SRR%= [Average specimen relative light unit (RLU) / average reference control RLU] × 100. CV%= (SD RLU specimen / Average Test RLU) × 100. P value was calculated by Mann-Whitney U test. |
To analyze the longitudinal TSI measurements in patients with relapse or with remission, we plotted TSI values at the time of ATD withdrawal and 1 year after ATD withdrawal (Fig. 2b) and found that TSI values significantly decreased only in remission patients. On the contrary, TSI values increased in patients with relapse.
Logistic regression analysis of quantitative or positive TSI and relapse
After adjustment for age, gender, TRAb at diagnosis, TSI at diagnosis, and TRAb at the end of treatment, the odds ratio (OR) of TSI positivity (SRR > 140%) at the end of treatment for the risk of relapse was 33.271 (95% CI: 4.741-233.458, P < 0.001) and OR of quantitative TSI was 1.009 (95% CI: 1.002–1.015, P = 0.008) (Table 3).
Table 3
Association of TSI measurement with relapse in Graves’ patients treated with anti-thyroid drugs
| OR (95%CI) | P | OR (95%CI) | P |
Age | 0.983(0.921–1.036) | 0.517 | 0.964(0.906–1.026) | 0.252 |
Gender (Male = 1) | 0.397(0.092–1.707) | 0.215 | 0.315(0.062–1.612) | 0.166 |
TSI at diagnosis | 0.999(0.994–1.005) | 0.773 | 0.996(0.989–1.002) | 0.183 |
TRAb at diagnosis | 0.982(0.91–1.059) | 0.636 | 0.966(0.886–1.054) | 0.443 |
TRAb at the end of treatment | 3.029(0.542–16.933) | 0.207 | 3.685(0.574–23.648) | 0.169 |
TSI at the end of treatment | 1.009(1.002–1.015) | 0.008 | / | / |
TSI positivity (SRR > 140%) at the end of treatment | / | / | 33.271(4.741-233.458) | < 0.001 |
TSI: thyroid-stimulating immunoglobulin; SRR: specimen-to reference ratio; OR: odds ratio; 95% CI: 95% confidence interval. |