Description of the condition
Graves' disease accounts for 50% to 80% of cases of hyperthyroidism and has a population prevalence of 0.5% to 2%. It is more common in women, with a female:male ratio of 5:1 (Genovese 2012; Ponto 2012). Five per cent of patients with Graves' disease develop moderate to severe Graves' ophthalmopathy, with older age groups (40 to 80 years) at higher risk of developing eye signs (Laurberg 2012).
Graves' disease is an autoimmune disease caused by production of auto-antibodies against the thyroid-stimulating hormone (TSH) receptor, which stimulates follicular cell production of thyroid hormone. Symptoms include evidence of hyperthyroidism such as irritability, heat intolerance, weight loss and diarrhoea, and a hypervascular, enlarged thyroid may be found on examination. Extrathyroidal manifestations range from ophthalmopathy, dermopathy (pretibial myxoedema) and acropachy, which distinguish Graves' from other causes of hyperthyroidism (Lalwani 2012).
Hyperthyroid states are associated with significant cardiovascular and respiratory adverse events such as atrial fibrillation, congestive cardiac failure, hypercoagulability and stroke. A recent meta-analysis suggested a 20% increase in mortality in patients diagnosed with hyperthyroidism (Brandt 2011).
Graves' disease may be diagnosed by evidence of extrathyroidal manifestations (ophthalmopathy, acropachy and pretibial myxoedema) on examination and biochemical hyperthyroidism (suppressed TSH, high triiodothyronine (T3), thyroxine (T4) or both). If the diagnosis is uncertain, a radionuclide uptake test may be performed which shows diffusely increased uptake throughout the thyroid. Assays for TSH receptor antibody (TRAb) have 98% sensitivity and 100% specificity for Graves' disease, but their use in clinical practice remains variable (Paunkovic 2007).
Description of the intervention
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; 3) unilateral total and contralateral subtotal thyroidectomy, or Dunhill's operation. In subtotal thyroidectomy techniques, less than 2 to 8 g thyroid remnant is recommended, to reduce the risk of recurrent hyperthyroidism (Chi 2005; Hermann 1998).
Adverse effects of the intervention
Thyroidectomy for benign disease carries significantly less risk than for thyroid malignancies. Two recent large retrospective case series for total thyroidectomy in benign disease (Bellantone 2002; Efremidou 2009) reported the risk of permanent recurrent laryngeal nerve palsy as 0% to 0.4%, and temporary recurrent laryngeal nerve palsy at 1.3%. Temporary hypocalcaemia was seen in 7.3% of patients, and permanent hypocalcaemia was seen in 0.3% to 3.4%. Haemorrhage requiring repeat surgery was reported to be in the region of 0.2% to 1.5%. The trend was for a decrease in complications over recent years, suggesting surgeon experience and case load may be factors in rates of complications. Subtotal thyroidectomy has been reported to give lower rates of temporary recurrent laryngeal nerve palsy and hypocalcaemia, but outcomes are similar in the long term (Barczynski 2011).
How the intervention might work
Total thyroidectomy removes target tissue for the stimulating TSH receptor antibody. It controls hyperthyroidism at the cost of life-long thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and aims to achieve euthyroidism without the need for thyroxine replacement, however a higher rate of recurrent hyperthyroidism is expected.
Graves' ophthalmopathy is thought to be due to common antigens shared between the thyroid and orbit which are both targeted by TSH receptor antibody (TRAb) and a G-protein G2sAb. Total thyroidectomy has been shown to be associated with regression of Graves' opthalmopathy, associated with a concurrent decrease in TRAb and G2sAb post surgery (De Bellis 2012; Leo 2012).
Why it is important to do this review
Thyroidectomy for Graves' disease may be indicated in patients who have persistent hyperthyroidism after a trial of antithyroid medication; when a rapid return to euthyroidism is desired; or when radioactive iodine treatment is contraindicated (e.g. in pregnancy).
In recent years we have seen a resurgence of interest in surgical management of Graves' disease. The American Thyroid Association's Hyperthyroidism Management Guidelines 2010 named surgery as one of three first-line treatments for hyperthyroidism associated with Graves' disease alongside radioactive iodine and antithyroid drugs. In studies conducted in patients who have persistent hyperthyroidism after medical treatment, total thyroidectomy is shown to be more cost effective than radioactive iodine or lifelong antithyroid medication (In 2009; Zanocco 2012). Health-related quality of life after surgical ablation of the thyroid has been shown to be comparable to the general population (Al-Adhami 2012). Morbidity associated with thyroidectomy has been shown to be less than previously thought (Bellantone 2002; Efremidou 2009).
Choice of 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 outcome for patients. A previous meta-analysis on this subject was carried out in 2000 (Palit 2000), which only searched MEDLINE and not any other databases. Since that time, data from several new randomised controlled trials have been published, which demonstrates considerable interest in this topic.
To assess the effects of total thyroidectomy and subtotal thyroidectomy on Graves' disease and Graves' ophthalmopathy.
Criteria for considering studies for this review
Types of studies
Randomised controlled clinical trials.
Types of participants
All patient age groups receiving surgical treatment for Graves' disease.
Our criteria for Graves' disease are clinical examination and suppressed TSH and elevated free T4, free T3, or both. Additional diagnostic tests such as radionuclide uptake and TRAb (TSH receptor antibody)/TBII (thyrotropin binding inhibiting immunoglobulins) are noted where performed, but not considered essential for study inclusion.
Types of interventions
We will consider studies for inclusion where the surgical interventions listed below are compared. We will exclude studies where only one trial arm contains a surgical intervention, or where surgical interventions are compared to medical interventions.
We plan to investigate the following comparisons of intervention versus control/comparator where the same letters indicate direct comparisons.
a) Bilateral subtotal thyroidectomy
b) Unilateral total and contralateral subtotal thyroidectomy
a1) Unilateral total and contralateral subtotal thyroidectomy
a2) Total thyroidectomy
b1) Total thyroidectomy
Types of outcome measures
- Rate of recurrent hyperthyroidism
- Adverse effects (e.g. permanent recurrent laryngeal nerve palsy, permanent hypocalcaemia)
- Regression of Graves' ophthalmopathy
- All-cause mortality
- Postoperative bleeding
- Health-related quality of life
- Health economic outcomes
Timing of outcome measurement
All outcomes must have reported measurements at a minimum of three months follow-up.
Definition of outcome measurement
- Rate of recurrent hyperthyroidism: bio-chemically confirmed elevation of T3/T4 with postoperatively suppressed TSH.
- Regression of Graves' opthalmopathy: a clinically-significant improvement in Graves' ophthalmopathy using a validated scoring system as reported by the authors of the study.
- Health-related quality of life: measured by a validated instrument.
'Summary of findings' table
We will present a 'Summary of findings' table using the following outcomes listed according to priority:
- Rate of recurrent hyperthyroidism
- Permanent recurrent laryngeal nerve palsy
- Permanent hypocalcaemia
- Regression of Graves' ophthalmopathy
- All-cause mortality
- Health-related quality of life
- Health economic outcomes
Search methods for identification of studies
We will search the following sources from inception to the present:
- The Cochrane Library.
We will also search databases of ongoing trials (ClinicalTrials.gov (www.clinicaltrials.gov/), Current Controlled Trials metaRegister (www.controlled-trials.com/), the EU Clinical Trials register (www.clinicaltrialsregister.eu/) and the WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/)).
For detailed search strategies see Appendix 1. We will continuously apply PubMed's 'My NCBI' (National Center for Biotechnology Information) email alert service to identify newly published studies using a basic search strategy (see Appendix 1). Four weeks before we submit the final review draft to the Cochrane Metabolic and Endocrine Disorders Group (CMED) for editorial approval, we will perform an updated search on all specified databases. If we identify new studies for inclusion we will evaluate these and incorporate findings in our review before submission of the final review draft.
If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes. We will place no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in identified studies.
We will send results of electronic searches to the Cochrane Metabolic and Endocrine Disorders Group for databases which are not available at the editorial office.
Searching other resources
We will try to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, (systematic) reviews, meta-analyses and health-technology assessment reports.
Data collection and analysis
Selection of studies
Two review authors (ZWL, LM) will independently scan the abstract, title, or both sections of every record retrieved, to determine the studies to be assessed further. We will investigate all potentially-relevant articles as full text. Where differences in opinion exist, they will be resolved by a third party. If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and we will contact study authors for clarification. We will present an adapted PRISMA (preferred reporting items for systematic reviews and meta-analyses) flow-chart of study selection (Figure 1) (Liberati 2009).
|Figure 1. Study flow diagram.|
Data extraction and management
For studies that fulfil inclusion criteria, two review authors (ZWL, LM) will independently abstract relevant population and intervention characteristics using standard data extraction templates (for details see Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12) with any disagreements to be resolved by discussion, or if required by a third party.
We will provide information including trial identifier about potentially-relevant ongoing studies in the table 'Characteristics of ongoing studies' and in the appendix 'Matrix of study endpoints (protocol/trial documents)'. We will try to find the protocol of each included study, either in databases of ongoing trials, in publications of study designs, or both, and specify data in the appendix 'Matrix of study endpoints (protocol/trial documents)'.
We will send an email to all study authors of included studies to ask whether they are willing to answer questions regarding their trials. We will publish the results of this survey in Appendix 13. Thereafter, we will seek relevant missing information on the trial from the primary author(s) of the article, if required.
Dealing with duplicate publications and companion papers
In the event of duplicate publications, companion papers or multiple reports of a primary study, we will maximise yield of information by collating all available data. In case of doubt the publication reporting the longest follow-up associated with our primary or secondary outcomes will be given priority.
Assessment of risk of bias in included studies
Two review authors (ZWL, LM) will assess the risk of bias of each trial independently. We will resolve possible disagreements by consensus, or with consultation of a third party. In cases of disagreement, the rest of the group will be consulted and a judgement will be made based on consensus.
- Random sequence generation (selection bias).
- Allocation concealment (selection bias).
- Blinding (performance bias and detection bias), separated for blinding of participants and personnel, and blinding of outcome assessment.
- Incomplete outcome data (attrition bias).
- Selective reporting (reporting bias).
- Other bias.
We will assess outcome reporting bias (Kirkham 2010) by integrating the results of 'Examination of outcome reporting bias' (Appendix 8), 'Matrix of study endpoints (protocol/trial documents)' (Appendix 7), and section 'Outcomes (outcomes reported in abstract of publication)' of the 'Characteristics of included studies' table. This analysis will form the basis for the judgement of selective reporting (reporting bias).
We will judge 'Risk of bias' criteria as 'low risk', 'high risk' or 'unclear risk' and evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will present a 'Risk of bias' figure and a 'Risk of bias summary' figure.
We will assess the impact of individual bias domains on study results at endpoint and study levels.
For blinding of participants and personnel (performance bias), detection bias (blinding of outcome assessors) and attrition bias (incomplete outcome data) we intend to evaluate risk of bias separately for subjective and objective outcomes (Hróbjartsson 2013). We will consider the implications of missing outcome data from individual participants.
We define the following endpoints as subjective outcomes:
- Regression of Graves' ophthalmopathy.
- Health-related quality of life.
We define the following outcomes as objective outcomes:
- Rate of recurrent hyperthyroidism.
- Permanent recurrent laryngeal nerve palsy.
- Permanent hypocalcaemia.
- All-cause mortality.
- Health economic outcomes.
Measures of treatment effect
We will express dichotomous data as odds ratios (OR) or risk ratios (RR) with 95% confidence intervals (CI). We will express continuous data as mean differences (MD) with 95% CI.
Unit of analysis issues
We will take into account the level at which randomisation occurred, such as cluster-randomised trials and multiple observations for the same outcome.
Dealing with missing data
We will obtain relevant missing data from authors, if feasible, and carefully evaluate important numerical data such as screened, randomised patients as well as intention-to-treat (ITT), as-treated and per-protocol (PP) populations. We will investigate attrition rates, for example drop-outs, losses to follow-up and withdrawals, and critically appraise issues of missing data and imputation methods (e.g. last observation carried forward (LOCF)).
Assessment of heterogeneity
In the event of substantial clinical or methodological or statistical heterogeneity, we will not report study results as meta-analytically pooled effect estimates.
We will identify heterogeneity by visual inspection of the forest plots and by using a standard Chi
When we find heterogeneity, we will attempt to determine potential reasons for it by examining individual study and subgroup characteristics.
We expect the following characteristics to introduce clinical heterogeneity:
- Previous treatment.
Assessment of reporting biases
If we include 10 studies or more for a given outcome, we will use funnel plots to assess small study effects. Owing to several possible explanations for funnel plot asymmetry, we will interpret results carefully (Sterne 2011).
Unless there is good evidence for homogeneous effects across studies, we will primarily summarise low risk of bias data by means of a random-effects model (Wood 2008). We will interpret random-effects meta-analyses with due consideration of the whole distribution of effects, ideally by presenting a prediction interval (Higgins 2009). A prediction interval specifies a predicted range for the true treatment effect in an individual study (Riley 2011). In addition, we will perform statistical analyses according to the statistical guidelines contained in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b).
Subgroup analysis and investigation of heterogeneity
We will carry out the following subgroup analyses and plan to investigate interaction:
- Age (depending on data).
- Effects of previous treatment.
We will perform sensitivity analyses in order to explore the influence of the following factors on effect sizes:
- Restricting the analysis to published studies.
- Restricting the analysis taking into account risk of bias, as specified at Assessment of risk of bias in included studies.
- Restricting the analysis to very long or large studies to establish how much they dominate the results.
- Restricting the analysis to studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.
We will also test the robustness of the results by repeating the analysis using different measures of effect size (RR, OR etc.) and different statistical models (fixed-effect and random-effects models).
Appendix 1. Search strategies
Appendix 2. Characteristics of included studies table: template
Appendix 3. Description of interventions
Appendix 4. Baseline characteristics (I)
Appendix 5. Baseline characteristics (II)
Appendix 6. Matrix of study endpoints (publications)
Appendix 7. Matrix of study endpoints (protocol/trial documents)
Appendix 8. Examination of outcome reporting bias
Appendix 9. Definition of endpoint measurement
Appendix 10. Adverse events (I)
Appendix 11. Adverse events (II)
Appendix 12. Adverse events (III)
Appendix 13. Survey of authors providing information on trials
Contributions of authors
Zi Wei Liu (ZWL): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.
Liam Masterson (LM): protocol draft, search strategy development, acquiring of trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.
Piyush Jani (PJ): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.
Brian Fish (BF): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.
Krishna Chatterjee (KC): protocol draft, search strategy development, acquiring trial copies, trial selection, data extraction, data analysis, data interpretation, review draft and future review update.
Declarations of interest