Zi Wei Liu, Liam Masterson, Brian Fish, Piyush Jani, Krishna Chatterjee

Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid-stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients. To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy. We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions. Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion. Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements. We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects. Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease.