Changes in Serum TSH Receptor Antibody (TRAb) Values in Patients with Graves Disease after Total or Subtotal Thyroidectomy

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1 Endocrine Journal 2003, 50 (5), Changes in Serum TSH Receptor Antibody (TRAb) Values in Patients with Graves Disease after Total or Subtotal Thyroidectomy YUUKI TAKAMURA, KEIICHI NAKANO, TAKASHI URUNO, YASUHIRO ITO, AKIHIRO MIYA, KAORU KOBAYASHI, TAMOTSU YOKOZAWA, FUMIO MATSUZUKA, KANJI KUMA, AND AKIRA MIYAUCHI Kuma Hospital, Shimoyamate-dori, Chuo-ku, Kobe , Japan Abstract. TSH receptor antibodies (TRAb) are generally regarded as mediators of thyroid stimulation in Graves disease. In addition, a high serum TRAb value during pregnancy is one of the risk factors for intrauterine death, prematurity, and fetal or neonatal hyperthyroidism. Recently, correlations between a high serum TRAb value and endocrine opthalmopathy were also suggested. Surgical resection of the thyroid is usually followed by a reduction of serum TRAb levels in variable degrees. The relation between the extent of the thyroidectomy and the degree of reduction is still controversial. In addition, the changes in the TRAb value after total thyroidectomy (TT) over a long period of time have never been studied. We studied the changes in serum TRAb values after TT and subtotal thyroidectomy (ST) for more than 7 years. Forty-one patients with Graves disease underwent TT, and 99 patients underwent ST. The serum TRAb values and the ratio of the patients who achieved normal values among each group (normalization rates of TRAb) at 3 and 6 months, 1, 3, 5 and 7 years after surgery were compared between the TT group and ST group. The mean preoperative TRAb values were not significantly different between the TT and ST groups, and the mean TRAb values measured 3, 6 and 12 months after surgery were not significantly different between the groups. However, the TRAb values measured 3, 5 and 7 years after surgery were significantly (p<0.05) lower in the TT group than in the ST group (16.7 ± 3.3% vs 28.0 ± 2.6%, 12.6 ± 3.4% vs 29.3 ± 3.8%, 5.6 ± 0.9% vs 25.4 ± 4.1%, respectively). The normalization rates of TRAb were not significantly different between the groups until 1 year after surgery. However, the normalization rates 3, 5 and 7 years after surgery were significantly (p<0.05) higher in the TT group than in the ST group (65.7% vs 42.4%, 77.3% vs 46.7%, 100% vs 59.1%, respectively). The surgical complication rates of TT were similar to ST except for permanent hypoparathyroidism. TT is a treatment option for Graves disease, especially in patients with a high TRAb value who wish to have children or who have Graves opthalmopathy. Key words: Graves disease, Surgery, Total thyroidectomy, TRAb (Endocrine Journal 50: , 2003) Received: March 3, 2003 Accepted: June 10, 2003 Correspondence to: Yuuki TAKAMURA, M.D., Kuma Hospital, Shimoyamate-dori, Chuo-ku, Kobe , Japan GRAVES disease is an autoimmune disease characterized by thyrotoxicosis caused by diffuse hyperplasia and hypersecretion of the thyroid gland, infiltrative opthalmopathy, and localized myxedema. Thyroid hyperplasia and hypersecretion are caused by TSH receptor antibodies (TRAb), which are antibodies to the TSH receptor on the thyroid follicular cell membrane that act in a manner analogous to TSH itself [1, 2]. There are currently three treatment options for Graves disease: surgery, radioiodine ablation, and antithyroid drugs. Surgery and radioiodine reduce the volume of thyroid tissue but are not thought to alter the underlying pathogenic mechanism, except for the possibility of removing intrathyroidal lymphocytes, a source of TRAb [1]. Changes in the serum TRAb value may represent the degree of hyperthyroidism. The continuation of a high (elevated) TRAb value or an increased TRAb value after surgery may cause hyperthyroidism recurrence [3, 4]. In addition,

2 596 TAKAMURA et al. previous studies demonstrated that a high TRAb value is linked to endocrine opthalmopathy [5, 6], or risk for intrauterine death, and fetal or neonatal hyperthyroidism in pregnant women with Graves disease [7 12]. Surgery for Graves disease brings a rapid improvement of hyperthyroidism and is still the treatment of choice if antithyroid drug therapy and radioactive iodine therapy are not feasible [13]. The efficacy and demerits of thyroidectomy were reported by Palit et al. using meta-analysis [14]. There are 2 surgical methods for Graves disease: total thyroidectomy (TT) and subtotal thyroidectomy (ST). ST is usually chosen for Graves disease therapy, but 5 15% of patients have recurrent thyrotoxicosis after surgery [1], which is more likely to occur in patients with high serum TRAb values before surgery [15] and severe eye involvement [5]; such patients should therefore undergo TT rather than ST [1]. Although the surgical outcomes and their relation to serum TRAb values have been demonstrated by several authors [3, 4, 14 24], there have been only a few reports concerning the surgical outcome of TT for Graves disease [5, 25 27]. In addition, the changes in the TRAb value after TT over a long period of time have never been studied. Therefore, in this study, an attempt was made to evaluate the long term changes in the TRAb value after TT, and to compare TT and ST for Graves disease. Patients Patients and Methods Forty-one patients (5 males and 36 females; mean age, 32 years old; range, 13 71) with Graves disease who underwent TT from 1990 to 1998, and 99 patients (19 males and 80 females; mean age, 27 years old; range, 14 51) who underwent ST in 1994 were retrospectively studied. The reasons for surgery are shown in Table 1. The patients who thought TT was more suitable for the reasons summarized in Table 1 and underwent TT during study period, were recruited in this study. The surgery was performed by several surgeons with a similar technique at Kuma Hospital. Most of the patients were prepared prior to surgery with antithyroid drugs and iodide, and less frequently with additional -blockers or corticosteroids. All Table 1. patients were clinically euthyroid at the time of surgery. The mean weight of the resected thyroid was g (range ) in the TT group and the mean weight of the total (resected and remnant) thyroid was 74.8 g (range ) in the ST group, respectively. Following bilateral subtotal thyroidectomy, a portion of the resected gland the same size as the remnant was taken from the thyroid specimen and weighed to estimate the weight of the remnant thyroid. The mean weight of the remnant thyroid was 5.2 g (range ) in the ST group. The blood loss during surgery was not significantly different between the TT group (mean ml) and the ST group (mean ml) but the duration of surgery was significantly longer in the TT group (mean 94.4 min) than in the ST group (mean 67.9 min). (Table 2) No patients needed a blood transfusion in this series. The median follow-up period was 62 months (range ) in the TT group and 70 months (range ) in the ST group. The TRAb values and normalization rates (ratio of patients who achieved normal serum TRAb values) at 3 months, 6 months, 1 year, 3 years, 5 years and 7 years after surgery were compared between the TT and ST groups. The incidence of surgical complications was also compared in the two groups. Determination of TRAb levels Reason for surgery TT ST opthalmopathy 22 0 resistant to antithyroid agents large goiter 4 11 agranulocytosis 3 7 other side effect of agents 1 14 coexistence of tumor 0 1 patient s preference 1 34 total TRAb was measured by radioreceptor assay using Smith s kit (Cosmic Co., UK) according to the manufacturer s instruction. The results were expressed as %, and values of 15% or greater were considered positive for the presence of TRAb.

3 TRAb AFTER TOTAL THYROIDECTOMY FOR GRAVES DISEASE 597 Table 2. Surgical findings TT ST Student s t-test weight of thyroid a g ( ) 74.8 g ( ) p<0.005 remnant weight of thyroid 0 g 5.2 g ( ) preoperative TRAb value b 60.3% ( ) 52.5 % ( ) N.S. duration of surgery 94.4 min (28 155) 67.9 min (35 128) p<0.005 blood loss ml (20 540) (21 864) N.S. a mean value b TRAb<15% was considered W.N.L. Fig. 1. Changes of TRAb value after total thyroidectomy (TT) or subtotal thyroidectomy (ST). Mean ± S.E. Statistical analysis TRAb values were compared between the TT and ST groups by Student s t-test. The normalization rates of TRAb and the postoperative complication rates were compared between the TT and ST groups using chi-square test. A P-value<0.05 was considered significant. Results Changes in serum TRAb values after total or subtotal thyroidectomy The follow-up rates at 3 months, 6 months, 1 year, 3 years, 5 years and 7 years after surgery were 88.6%, 75.0%, 95.7%, 85.7%, 58.6% and 44.3%, respectively (n = 140). Pre- and postoperative TRAb values (3 months, 6 months, 1 year, 3 years, 5 years and 7 years) were compared between the TT and ST groups (Fig. 1). The preoperative TRAb value was not significantly (p = 0.055) different between the TT and ST groups (60.3 ± 3.4% vs ± 2.2%: Mean ± S.E.). TRAb values measured at 1 year after surgery or earlier were not significantly different between the TT and ST groups (38.5 ± 3.6% vs ± 2.6%, 32.8 ± 3.5% vs ± 3.2%, 26.0 ± 3.0% vs ± 2.5%, respectively). However, TRAb values measured at 3 years, 5 years and 7 years after surgery were significantly (p<0.05) lower in the TT group than ST group (16.7 ± 3.3% vs ± 2.6%, 12.6 ± 3.4% vs ± 3.8%, 5.6 ± 0.9% vs ± 4.1%, respectively). Normalization rates of TRAb after surgery A comparison of normalization rates of TRAb after TT and ST is shown in Table 3. Normalization rates at 3 months, 6 months and 1 year after surgery were not

4 598 TAKAMURA et al. Table 3. Comparison of normalization rate (%) between total and subtotal thyroidectomy Table 4. Proportion of patients whose TRAb value decreased to less than 50% after surgery TT ST 2 test 3 months 14.3 (5/35) 21.3 (19/89) N.S. 6 months 19.4 (7/36) 30.4 (21/69) N.S. 1 year 28.2 (11/39) 41.1 (39/95) N.S. 3 years 65.7 (23/35) 42.4 (36/85) p< years 77.3 (17/22) 46.7 (28/60) p< years 100 (18/18) 59.1 (26/44) p<0.005 TT (n = 30) ST (n = 52) 2 test 3 months 60.0 (15/25) 41.9 (18/43) N.S. 6 months 70.4 (19/27) 45.7 (16/35) N.S. 1 year 83.3 (25/30) 60.4 (29/48) p< years 88.5 (23/26) 65.1 (28/43) p< years 94.1 (16/17) 56.7 (17/30) p< years 100 (13/13) 57.1 (12/21) p<0.01 Table 5. Surgical complication rate TT (n = 41) ST (n = 99) 2 test temporary hypoparathyroidism 5 (12.2%) 5 (5.1%) N.S. permanent hypoparathyroidism 2 (4.9%) 0 p<0.05 temporary RLN palsy 1 (2.4 %) 3 (3.0%) N.S. permanent RLN palsy 0 0 ; RLN, recurrent laryngeal nerve significantly different between the TT and ST groups. However, normalization rates at 3 years, 5 years and 7 years after surgery were significantly (p<0.05) higher in the TT group than the ST group. Proportion of patients whose TRAb value decreased to less than 50% after surgery Uncontrolled hyperthyroidism or a high TRAb value during pregnancy may affect normal childbirth [28], and TRAb>50% is thought to be the risk of neonatal hyperthyroidism [29, 30]. The proportion of patients whose TRAb value had decreased to less than 50% after surgery was calculated and is shown in Table 4. Preoperative TRAb values were higher than 50% in 82 patients (30 in the TT group and 52 in the ST group, respectively). The proportion of patients whose TRAb value decreased to less than 50% at 3 and 6 months after surgery was not significantly different between the TT and ST groups (60.0% vs. 41.9%, 70.4% vs. 45.7%, respectively). However, the proportion of patients whose TRAb value decreased to less than 50% at 1, 3, 5 and 7 years after surgery was significantly (p < 0.05) higher in the TT group than the ST group (83.3% vs. 60.4%, 88.5% vs. 65.1%, 94.1% vs. 56.7%, 100% vs. 57.1%, respectively). Surgical complication rates A comparison of the complication rates after TT and ST is shown in Table 5. Temporary hypoparathyroidism occurred in 5 patients in both the TT and ST groups, and there was no significant difference between the TT and ST groups (12.2% vs. 5.1%). Two cases in the TT group and none in the ST group showed permanent hypoparathyroidism. The complication rate of permanent hypoparathyroidism was significantly (p<0.05) higher in the TT group than ST group (4.9% vs. 0%) although the number of patients was small. One and 3 cases showed temporary laryngeal nerve palsy in the TT and ST groups, respectively, and there was no significant difference between the TT and ST groups (2.4% vs. 3.0%). No patients had permanent laryngeal nerve palsy in either group. Discussion TRAb has been noted as an immunological marker or essential cause of Graves disease [31 33]. Therefore, a change in the TRAb value is thought to express the immunologic response to the therapy, with a decrease in TRAb value reflecting immunologic improvement of this disease. Thyroid resection plays

5 TRAb AFTER TOTAL THYROIDECTOMY FOR GRAVES DISEASE 599 an important role in reducing the TRAb value, but other factors, such as extrathyroidal production and the biological activity of TRAb [34], may also be important. Although the changes in the TRAb value after surgery vary among several investigators [17 21, 26], several years are required for normalization of the TRAb value. Mori et al. reported that the normalization rates of TRAb were 34.5% at 1 year and 49.4% at 3 years after ST for Graves disease (n = 87) [4]. We showed that the normalization rates after ST were 41.1% at 1 year and 42.4% at 3 years, which are not discrepant to those previous studies. However, the normalization rates were not further increased at 5 and 7 years after ST (49.1% and 62.5%, respectively). Miccoli et al. reported the superiority of TT in avoiding a worsening of thyroid humoral autoimmunity and relapsed hyperthyroidism compared to ST, but they could not demonstrate a significant difference between TT and ST in the normalization rates of TRAb at 1 2 years after surgery (54.9% and 78.8%, respectively) [26]. In our study, the normalization rates within 1 year after surgery were also not significantly different between TT and ST; however, the normalization rates at 3 years, 5 years and 7 years after surgery were significantly (p<0.01) higher in the TT group than the ST group. It is thus suggested that it takes about 3 years to normalize the TRAb value. Although some reports have noted that the preoperative TRAb value could not predict the long-term outcome of surgically treated patients with Graves disease [15, 16, 35, 36], Sugino et al. demonstrated that the preoperative TRAb value was related to the early recurrence of hyperthyroidism [15], and Mori et al. reported that the higher the preoperative TRAb value, the longer the time required for it to normalize postoperatively [4]. In our study, the TRAb value decreased more rapidly in the TT group than the ST group (data not shown). If the therapeutic purpose of surgical treatment for Graves disease includes rapid reduction of the TRAb value, TT is more appropriate than ST. The treatment of Graves disease complicated by pregnancy is difficult, because the fetal thyroid is influenced by the same stimulatory and inhibitory factors as the maternal thyroid [37]. Uncontrolled hyperthyroidism or a high TRAb value during pregnancy is a risk for low birth weight (<2500 g), prematurity and eclampsia [28]. The transplacental transfer of TSH receptor antibodies may cause intrauterine death or fetal and neonatal hyperthyroidism [7 11]. Mortimer et al. reported that neonatal hyperthyroidism was seen in 8% (4/48) of births in women with active Graves disease, and that maternal TRAb values exceeded 70% at delivery in all 4 births [38]. In addition, TRAb>50% was thought to be a risk factor of neonatal hyperthyroidism [29, 30]. The proportions of patients whose TRAb value decreased to less than 50% were calculated. They were significantly higher in the TT group than the ST group at 1, 3, 5, and 7 years after surgery, and the proportions were up to 70.4% at 6 months and 83.3% at 1 year. A relation between TRAb and endocrine opthalmopathy, and the probability of improving eye involvement by TT, were also reported by several authors [5, 26, 39]. As the number of patients who underwent TT for endocrine opthalmopathy was small (n = 22), we could not evaluate the influence of TT on opthalmopathy in this study. In those patients who underwent ST, 13 (13.1%) cases showed recurrence or persistence of hyperthyroidism, 5 (5.1%) cases showed subclinical hyperthyroidism (low TSH level and normal serum thyroid hormone), 62 (62.6%) cases showed euthyroidism or subclinical hypothyroidism (high TSH level and normal serum thyroid hormone), and 19 (19.2%) cases showed hypothyroidism who required medical treatment (L-thyroxine, mg). These results were similar to the recent meta-analysis by Palit et al. (hyperthyroidism: 7.9%, euthyroidism: 59.7%, hypothyroidism: 25.6%) [14]. The complication rates of temporary laryngeal nerve palsy and temporary hypoparathyroidism after TT (4.4% and 13.3%, respectively) were similar (7.7% and 9.6%, respectively), but the complication rate of permanent hypoparathyroidism after TT (6.7%) was a little higher than that of the meta-analysis (0.9%) though the number in our series was small. In conclusion, TT may be preferable to ST from the viewpoint of reducing the TRAb value, especially for patients with high TRAb who wish to have children.

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