Graves' disease with moderate-severe endocrine ophthalmopathy-long term results of a prospective, randomized study of total or subtotal thyroid resection.

The optimal thyroid surgery to be performed in patients with Graves' disease and concomitant endocrine ophthalmopathy is a matter of debate. We randomly assigned 44 patients with moderate-severe eye signs in a trial of treatment with subtotal, leaving a small (approximately 2 g) thyroid remnant, or total thyroidectomy. At inclusion, the patients had been treated with antithyroid drugs, and corticosteroids been given to 12 (27%). All received postoperative thyroxine supplementation and were followed for 3 years at regular examinations. The eye disease improved in all cases, and throughout the study, the two groups did not differ with regard to subjective and objective eye symptoms and laboratory findings. At the study start, motility disturbances were present in 8 and 11 of the cases in the subtotal and total resection group and proptosis in 16 and 17, respectively. After 3 years, the corresponding data were 3 and 6 cases with motility defects and 16 and 15 cases with proptosis. Thyrotropin (TSH)-receptor antibody levels gradually fell and became nondetectable in 21 (49%). The surgical complication rate (permanent recurrent laryngeal nerve paresis and permanent hypoparathyroidism) was significantly higher in the total thyroidectomy group. The data indicate that in patients with Graves' disease and active endocrine ophthalmopathy, subtotal thyroidectomy, leaving a small thyroid remnant, will reduce the risk of surgical complications but not the beneficial effect of surgery.

Retrospective evaluation of subtotal and total thyroidectomy in Graves' disease with and without endocrine ophthalmopathy.

A retrospective analysis was performed in 173 consecutive patients with Graves' disease (GD) with the principal aim of evaluating the influences of subtotal (N = 157) and total (N = 19) thyroidectomy on postoperative recurrence rates, endocrine ophthalmopathy (EO) and thyrotropin receptor antibody (TSH-R-ab) titres. Postoperatively recurrent disease, identified by increased thyroid hormone levels, occurred in 32 patients (20%) who underwent subtotal resection. These recurrences were associated with over-representation of preoperative EO (p < 0.001) as well as high TSH-R-ab levels postoperatively (p < 0.05-0.01). Subtotal and total resections were followed by an aggravation of preoperative EO in nine (16%) and one (6%), and by a development of EO in two and none of the patients, respectively. Persistently elevated TSH-R-ab titers during thyrostatic therapy became close to normalized in seven (32%) and 15 (88%) of the patients undergoing subtotal or total thyroidectomies, respectively, which illustrates a thyroid tissue dependency of the autoantibody production. Among the total material of 173 patients, altogether 75 cases exhibited persistent or progressive EO and/or TSH-R-ab elevation after more than 1 year of preoperative thyrostatic treatment. In this group, recurrent GD or aggravated EO occurred in 23 (39%) of those operated with subtotal resection and in one (6%) of those undergoing total thyroidectomy (p < 0.05). The results thus indicate that EO, particularly at the time of surgery, and prevailing TSH-R-ab titers are associated with an increased risk of recurrent GD and suggest that patients exhibiting these characteristics should benefit from total rather than subtotal thyroidectomy.

Total thyroidectomy in therapy-resistant Graves' disease.

BACKGROUND: Influences of total thyroidectomy have not been evaluated in patients with severe Graves' disease who might respond less satisfactorily to subtotal thyroid resection. METHODS: Thirty-three patients with Graves' disease underwent total thyroidectomy because of persistent endocrine ophthalmopathy (n = 28) or elevated thyrotrophin receptor antibody titers (n = 25) despite a mean of 2 years of thyrostatic therapy. Moreover, six and four patients had undergone radioiodine treatment and subtotal thyroid resection, respectively. Perioperative findings and complications have been investigated, as have influences on endocrine ophthalmopathy and thyrotrophin receptor antibody titers during a mean of 2.5 postoperative years. RESULTS: Total thyroidectomy substantiated mean thyroid weights of 17 gm, 2.3 hours of operating time, and total blood loss of 264 cc. Vocal cord paralysis and vitamin D-treated hypocalcemia occurred in two and three patients, respectively, and invariably persisted less than 6 months. Normalization of elevated thyrotrophin receptor antibody titers occurred in 86% of patients without radioiodine exposure, and stable or improved signs of endocrine ophthalmopathy were found in 96% of patients examined 6 or more months after the operation. CONCLUSIONS: Total thyroidectomy seems to be a surgically safe procedure in complicated Graves' disease and to provide normalization of therapy-resistant thyrotrophin receptor antibody titers. Because favorable influences might also encompass severe endocrine ophthalmopathy, prospective analysis on its efficiency is warranted.

Analysis of mutations in exon 1 of the human thyrotropin receptor gene: high frequency of the D36H and P52T polymorphic variants.

The aim of the present study was to investigate the N-terminal part (the translated part of exon 1) of the human thyrotropin receptor (TSHR) for the presence of mutations. Patients with Graves' disease (n = 160) and healthy controls (blood donors; n = 140) were screened using single-stranded conformational polymorphism (SSCP) in combination with restriction enzyme digestion for the two previously known mutations in this part of the receptor, viz. D36H and P52T TSHR-variants. We did not find any novel mutation in this region. However, D36H and P52T variants were found both in the TSHR of Graves' patients and in the healthy controls. The overall frequency of the D36H-receptor variant was 5.0% (15/300) and of the P52T-receptor, 7.3% (22/300). There was no major difference in the frequency for either of the TSHR alleles between the 2 groups. Thus, these 2 polymorphic variants of the TSHR seem to occur in a relatively high frequency in the population.

Graves' disease, endocrine ophthalmopathy and smoking.

We have evaluated the association between smoking, Graves' disease and endocrine ophthalmopathy in a case-control study of 208 patients with newly diagnosed Graves' disease and carried out a retrospective survey of 72 patients treated for Graves' disease and admitted to our ward because of endocrine ophthalmopathy. In the prospective study, patients with Graves' disease smoked significantly more than their healthy controls (41% vs 30%, p < 0.01 for current smokers, odds ratio 1.6, 95% confidence interval 1.1-2.3, and p < 0.05 for patients with a history of smoking, odds ratio: 1.4, 95% confidence interval 1.0-1.9). Among the patients with endocrine ophthalmopathy at diagnosis, there were slightly more patients with a history of smoking (p < 0.05, odds ratio 2.1, 95% confidence interval 1.1-3.9), but not more current smokers when compared with the remaining group. The patients with eye problems tended to have a more active disease with higher levels of thyroxine and TSH-receptor antibodies, but no difference was seen in thyrogastric autoantibodies. No effect of smoking on thyroid hormone and autoantibody levels could be detected. In the retrospective survey we found 64%, 71% and 87% smokers among patients with moderate, severe and malignant eye disease, respectively. In summary, the results show that smoking is associated with an increased risk of contracting Graves' disease and that it enhances the severity of the eye disease in cases that develop endocrine ophthalmopathy during the course of treatment.

The postpartum period constitutes an important risk for the development of clinical Graves' disease in young women.

In the present study, 93 consecutive women, 20-40 years of age, referred to our clinic from 1976-85 with Graves' disease, were examined with respect to a possible relation between onset of disease and previous pregnancy. An increased relative risk of 6.5 (3.8-11.0, 95% confidence interval) of developing Graves' disease within one year following delivery was found. After excluding the nulliparous women, almost 2 out of 3 women who developed Graves' disease in the principal child-bearing age of 20-35 years had a postpartum onset, suggesting an important role of immunomodulatory events following delivery for the development of this disease in young women. Future studies will ascertain to which extent the recognition of postpartum Graves' disease has implications on the choice of therapy in this group of women.

Factors influencing the outcome of thyrostatic drug therapy in Graves' disease.

In patients with Graves' disease, thyrostatic drug treatment may induce definitive remission without the need of more aggressive measures such as surgery or radioiodine. Following drug therapy, however, relapses often occur. In the present study, a multivariate analysis of pretreatment variables was performed, in order to identify individuals running a high risk of an unfavourable outcome of thyrostatic drug therapy. We studied 109 consecutive patients with a mean age of 38 years, range 20-70, over a mean follow-up period of 5.3 years after cessation of therapy. The analysis showed that goitre size, age, thyroid hormone levels, HLA-DR 3 haplotype, and TSH receptor antibody levels were of prognostic significance, whereas HLA-B8 haplotype, a lymphocytic infiltrate at fine needle biopsy, thyroglobulin, and microsomal antibodies had no such value. In particular, patients characterized by young age, large goitre and high hormone values were found to be associated with an unfavourable course.

Stressful life events and Graves' disease.

The role of stressful life events in the onset of Graves' disease (toxic diffuse goitre) is controversial. However, the numerous early clinical reports that supported such an association were not adequately controlled and specificity of the diagnosis could be questioned. Later studies have not shown a causal relation, but these studies were small, did not have proper controls, or epidemiological methods were inappropriate. To assess possible associations between life events, heredity, social support, and Graves' disease, we have done a population-based case-control study in a defined area with about 1 million inhabitants. Over 2 years, 208 (95%) of 219 eligible patients with newly-diagnosed Graves' disease and 372 (80%) of all selected matched controls answered an identical mailed questionnaire about marital status, occupation, drinking and smoking habits, physical activity, familial occurrence of thyroid disease, life events, social support, and personality. Compared with controls, patients claimed to have had more negative life events in the 12 months preceding the diagnosis, and negative life-event scores were also significantly higher (odds ratio 6.3, 95% confidence interval 2.7-14.7, for the category with the highest negative score). Individuals who had relatives with thyroid disease (especially first-degree and second-degree relatives) were more likely to have Graves' disease (3.6, 2.2-5.9). Slightly more patients than controls were divorced (1.8, 1.0-3.3) and reported a less frequent intake of alcohol (0.4, 0.2-0.8). When results were adjusted for possible confounding factors in multivariate analyses, risk estimates were almost unchanged. These findings indicate that negative life events and hereditary factors may be risk factors for Graves' disease.