Description of the condition
Goitre is an enlargement of the thyroid gland that can be classified as simple diffuse goitre or multinodular goitre. Multinodular goitre is a clinically recognisable enlargement of the thyroid gland characterised by excessive growth of more than one nodule (Medeiros-Neto 2012). Multinodular goitre can be divided into toxic (hyperthyroid) and non-toxic (euthyroid) multinodular goitre based on the thyroid function.
Epidemiology and pathogenesis of non-toxic multinodular goitre
Multinodular goitre is more common in women, with a female-to-male ratio of 4.5 to 1. The incidence of multinodular goitre in an adult UK population was about 15.5% (Tunbridge 1977). In the US Framingham study where iodine intake was high (urinary iodine 246 mg/L), investigators detected multinodular goitre by palpation in only 1% of the examined adults (Vander 1954).
The major cause for multinodular goitre is iodine deficiency and incidence of multinodular goitre is increased in individuals with a history of chronic iodine deficiency (Medeiros-Neto 2012). It is estimated that about 6% of elderly people in a given population, previously suspected to have iodine deficiency, may have visible multinodular goitre (Berghout 1990). Other risk factors may relate to smoking (Laurberg 2004), natural goitrogens (e.g. cassava, millet, babassu coconut, vegetables from the genus Brassica, and soybean) (Doerge 2002; Schröder-van der Elst 2003), autoimmune disorders (e.g. Grave's disease, Hashimoto's thyroiditis) (Pedersen 2001), certain iodine-rich drugs (e.g. amiodarone) (Vagenakis 1975) and environmental agents (e.g. environmental chemicals, coal-derived pollutants, perchlorate) (Braverman 2007; Lindsay 1992). Patients with multinodular goitre often have a family history of goitre and surgical removal of nodules (Bayer 2004).
Clinical manifestations of non-toxic multinodular goitre
Most patients with non-toxic multinodular goitre have few or no symptoms except for those with large goitre. Many patients are referred to hospital for cosmetic reasons or airway compression symptoms. Compression symptoms are more often seen in patients with intrathoracic extensions of the multinodular goitre. Airway compression results in dyspnoea, stridor, cough, and a sensation of shock (Medeiros-Neto 2012). A few patients may have a sudden transient pain with enlargement of a side of the multinodular goitre secondary to haemorrhage.
Diagnosis of non-toxic multinodular goitre
In patients with large goitre, determination of thyroid hormones and imaging techniques are useful to establish the non-toxic nature of the multinodular goitre. The thyroid hormones free thyroxine (fT4), free triiodothyronine (fT3), thyroid stimulating hormone (TSH) and antithyroid peroxidase (anti-TPO) antibodies are frequently measured in the initial evaluation of the patient. Neck palpation is imprecise both for assessment of thyroid morphology and size (weight) determination (Medeiros-Neto 2012). Sonography provides an accurate estimate of the goitre and nodule volume, identifies thyroid nodules and cysts, detects microcalcification, and specifies the degree of echogenicity of the nodule. Diagnosis of non-toxic multinodular goitre is established by clinical signs, normal TSH (euthyroid state), and more than one nodule by sonography. Computed tomography (CT) and magnetic resonance imaging (MRI) are useful for assessing a multinodular goitre that extends to the upper mediastinum and to evaluate the degree of tracheal compression.
Description of the intervention
Treatments for non-toxic multinodular goitre
Treatments for non-toxic multinodular goitre include surgery, levothyroxine suppression therapy, and radioiodine. Surgery efficiently reduces the goitre size but carries a risk of both surgical and anaesthetic complications. Small multinodular goitres were preferentially treated with levothyroxine suppression therapy. However, levothyroxine suppression therapy seems to be on the wane due to its low efficacy and adverse effects (Diehl 2005). This leaves radioiodine therapy as the only non-surgical alternative. Treatments vary in different countries. In the United States, surgery is the preferred treatment for patients with large multinodular goitres (Bonnema 2000; Bonnema 2002). Radioiodine treatment of non-toxic multinodular goitre was introduced in some European countries about 25 years ago (Bonnema 2009; Hegedüs 1988), and thyroidologists in Europe have tended to treat multinodular goitre with radioiodine as an alternative to surgery.
Radioiodine treatment for non-toxic multinodular goitre
Radioactive iodine (131I) is a β-γ emitting radionuclide with a physical half-life of 8.1 days, a principal γ−ray of 364 KeV, a principal β-particle with a maximum energy of 0.61 MeV, an average energy of 0.192 MeV, and a range in tissue of 0.8 mm. Radioiodine is a good choice for those who decline or are not fit for surgery. Fine-needle aspiration biopsy (FNAB) should be performed in multinodular goitres to rule out thyroid malignancy before radioiodine therapy. If a nodule within a multinodular goitre has a cytologic diagnosis of papillary cancer, surgery should be performed. Radioiodine therapy for non-toxic multinodular goitre results in a mean thyroid volume reduction of approximately 40% to 50% one year after treatment (Huysmans 2000; Le Moli 1999; Nygaard 1993; Wesche 2001). However, the individual response to radioiodine is variable mostly because of low iodine uptake by the multinodular goitre. Moreover, for large multinodular goitres, a high radioiodine dose is needed to achieve an adequate radioiodine accumulation in the thyroid nodules. Therefore, large activities of radioiodine are usually required. For this reason, patients treated with radioiodine are often subject to hospitalisation, greater exposure to radiation, and higher treatment costs.
Recombinant human thyrotropin (rhTSH) aided radioiodine treatment for non-toxic multinodular goitre
Recombinant TSH is produced by recombinant DNA technology which is a laboratory method to bring together genetic material from multiple sources. Thyroglobulin levels and radioiodine imaging stimulated by rhTSH were initially used in the diagnosis of metastatic disease of differentiated thyroid cancer instead of thyroid hormone withdrawal. Later, it was found that rhTSH aided iodine-131 thyroid remnant ablation is also as effective as thyroid hormone withdrawal for patients with differentiated thyroid cancer after surgery (Ma 2010). It was suggested that rhTSH might be used to increase radioiodine uptake in the various nodules of the multinodular goitre. rhTSH aided radioiodine therapy for multinodular goitre improves goitre volume reduction, reduces compression and eliminates areas of thyroid autonomy (Ceccarelli 2010). Moreover, it is easier to perform in outpatients, with reduced costs to the public health system, particularly in countries with limited resources and lack of high-volume thyroid surgeons.
Adverse effects of the intervention
Acute adverse effects include local tenderness, airway compression, and cardiac symptoms (rapid heart beat), which is caused by the surge of thyroid hormones in the blood and the goitre volume increase (in the first 48 hours of radioiodine therapy). Glucocorticoids and β-blockers are used to minimise these acute adverse effects (Fast 2009). A number of studies (Ceccarelli 2010; Ceccarelli 2011; Cubas 2009; Fast 2010; Fast 2011; Graf 2011) suggested that these adverse effects are probably dose-dependent and are negligible with lower rhTSH doses.
The most common long-term adverse effect of rhTSH aided radioiodine therapy for non-toxic multinodular goitre is permanent hypothyroidism (one third of patients). In three reported randomised controlled studies, permanent hypothyroidism at one year was reported in 21%, 63%, and 65% of rhTSH treated patients (Bonnema 2007; Hegedüs 1988; Silva 2004).
How the intervention might work
Radioactive iodine uptake by thyroid cells is mediated by a glycoprotein located on the cell membrane: the sodium/iodine (Na+/I-) symporter (NIS). NIS expression, as well as thyroglobulin production, is TSH-dependent. rhTSH is a heterodimeric glycoprotein produced by recombinant DNA technology. It is obtained following transfection of a microorganism with genes encoding human TSH α and β subunits; rhTSH is then purified. The amino acid sequence of rhTSH is identical to that of human pituitary TSH and shares its biochemical properties. It has been shown to stimulate thyroglobulin production and thyroid cell proliferation as well as radioactive iodine uptake by thyroid cells.
rhTSH not only increases radioiodine uptake (Huysmans 2000; Nieuwlaat 2001), but also leads to a more homogeneous distribution of radioiodine in the gland, and to the thyroid cell activation that makes them more radiosensitive (Ceccarelli 2010). These properties may reduce the radioiodine activity required for the treatment of non-toxic multinodular goitre. rhTSH aided radioiodine therapy for non-toxic multinodular goitre reduces goitre size by 35% to 55%, compared with radioiodine alone. rhTSH might be particularly useful in patients with very large goitres and in those with a low baseline thyroid radioiodine uptake.
Why it is important to do this review
We found no systematic review in relation to rhTSH aided radioiodine treatment for non-toxic multinodular goitre. However, there are narrative reviews about rhTSH aided radioiodine treatment for non-toxic multinodular goitre. One review suggested that radioiodine therapy is effective for large non-toxic goitre in elderly patients. Authors also stated that radioiodine therapy for multinodular goitres should be used in patients with co-morbidities or high operative risk, and in patients with special professions (singers, teachers, speakers) or with the wish for a non-invasive treatment modality (Dietlein 2006). The other review reported that rhTSH-stimulated radioiodine therapy of benign non-toxic multinodular goitre is significantly more effective than radioiodine alone but is still an off-label use (Bonnema 2009).
Recombinant TSH can augment the reduction of a nodular goitre size after radioiodine therapy. However, hypothyroidism is a common complication and acute airway compression may be a life-threatening complication. Whether the benefits outweigh the risk is controversial. Therefore, we will evaluate the effects of rhTSH aided radioiodine treatment to help people make informed decisions.