3.3.11 Management of toxic multinodular goitre and toxic adenoma

Toxic adenoma and toxic multinodular goitre represent the clinically important presentations of thyroid autonomy. Thyroid autonomy is a condition where thyrocytes produce thyroid hormones independently of thyrotropin (TSH) and in the absence of TSH-receptor stimulating antibodies (TSAB).

Toxic adenoma (TA) is a clinical term referring to a solitary autonomously functioning thyroid nodule. The autonomous properties of TA are best shown by radio-iodine or ^99mTc imaging. The classic appearance of TA is that of circumscribed increased uptake with suppression of uptake in the surrounding extranodular thyroid tissue (‘hot’ nodule, Fig. 3.3.11.1).

Toxic multinodular goitre (TMNG) is a heterogeneous disorder characterized by the presence of autonomously functioning thyroid nodules in a goitre with or without additional nodules. These additional nodules can show normal or decreased uptake (cold nodules) on scintiscan. TMNG constitutes the most frequent form of thyroid autonomy.

The prevalence of thyroid autonomy is inversely correlated with iodine intake. Thus, thyroid autonomy is a common finding in iodine-deficient areas, where it accounts for up to 60% of cases of thyrotoxicosis (TMNG c.50%; TA c.10%), but is rare (5–10%) in regions with iodine sufficiency (1, 2). Several studies have suggested that TMNG originates from euthyroid goitres and microscopic autonomous foci have been demonstrated in up to 40% of euthyroid goitres in iodine-deficient areas. Moreover, the prevalence of thyroid autonomy correlates with thyroid nodularity and increases with age. Correction of iodine deficiency in a population results in decrease of thyroid autonomy and this has been impressively shown, e.g. in Switzerland where a doubling in iodine salt content resulted in a 73% reduction of TMNG.

Somatic mutations of the G-protein-coupled TSH receptor or less frequently the Gsα-protein subunit (GSP; 5–10%) have been identified in TA and TMNG and represent the predominant molecular cause of thyroid autonomy. These mutations cause constitutive activation of the cAMP pathway, which stimulates thyroid hormone production and thyroid growth (2–4).

Clinical features of thyroid autonomy may be related to hyperthyroidism and/or compression signs due to the nodule and TMNG (4, 5). Clinical presentation of overt hyperthyroidism, defined by suppressed TSH with elevated free thyroxine (T₄) and/or free triiodothyronine (T₃) varies with age. While classic hyperthyroid features such as tremor, sweating, and hyperkinesis can be found in younger patients, thyrotoxicosis is often oligosymptomatic in older people. In this population, atrial fibrillation, congestive heart failure, and anorexia may prevail. Subclinical hyperthyroidism, defined by low or suppressed TSH with normal free T₄ and free T₃ levels, is also more commonly observed in older patients and is more than ‘just’ a low TSH status, since it confers increased risk for atrial fibrillation and in postmenopausal women contributes to reduced bone density (6).

In addition, a history of possible iodine contamination (contrast media, amiodarone) should be obtained. In the European Study Group of Hyperthyroidism, iodine contamination was found in 36.8% of patients from iodine-deficient areas with first diagnosis of hyperthyroidism. Severity of iodine deficiency, autonomous thyroid cell mass, and older age have been proposed as risk factors for the development of iodine-induced hyperthyroidism, which responds less well to antithyroid drug treatment and puts the patient at risk for a life-threatening thyroid storm (7, 8). Alternatively, a patient may present with a lump or disfigurement of the neck, intolerance of tight necklaces, or increase in collar size. Moreover, dysphagia or breathing difficulties due to local oesophageal or tracheal compression may be present, particularly with TMNG.

Unusually, in some patients there may be a family history of thyroid autonomy and a characteristic course of frequent relapses of hyperthyroidism following thyrostatic therapy or partial thyroidectomy. Depending on the age of onset (neonatal to adulthood) these patients may present with a diffusely enlarged goitre or a TMNG. The underlying cause of this condition is an activating germline mutation in the TSH-receptor gene, which can be confirmed through molecular diagnostics from a peripheral blood sample. Patients with an activating TSH-receptor germline mutation require definitive treatment in the form of a total thyroidectomy or an ablative dose of radio-iodine to prevent further relapses. Genetic counselling is also mandatory as the condition is autosomal dominantly inherited (3, 4).

The diagnosis of TA and TMNG is based on clinical examination, thyroid function tests, thyroid ultrasonography, and scintiscanning (4, 5). Examination of the neck will reveal the degree of thyroid enlargement and nodularity of the gland. A history of a recently enlarging nodule and cervical lymph node enlargement should be noted because of the concern for a developing malignancy at this site. In addition, clinical evidence of lymph node enlargement and tracheal deviation and/or compression should be sought. Standard thyroid function tests (TSH, free T₄, and free T₃) will confirm overt or subclinical hyperthyroidism, but depending on the autonomous cell mass, euthyroidism may still prevail. Localization, size, and number of thyroid nodule(s) as well as goitre volume can be determined by ultrasound scanning using a 7.5- or 9-MHz linear scanner. In addition, the presence or absence of cervical lymph node enlargement should be noted. Increased ^99mTc or ¹²³I radionucleotide uptake in the nodule(s) concomitant with a decreased uptake in the surrounding extranodular thyroid tissue is the typical finding on scintiscanning (Fig. 3.3.11.1). If thyroid autonomy is suspected in a patient with a (still) euthyroid nodule, a ‘suppression’ scan can be performed after administration of thyroid hormones (e.g. 75 μg/day l-thyroxine for 2 weeks followed by 150 μg/day for 2 weeks). Thereby nonautonomous tissue will be suppressed and thyroid autonomy unmasked.

Measurement of thyroid autoantibodies is not routinely performed in thyroid autonomy. However, in iodine-deficient areas distinction between Graves’ disease and TMNG can be difficult if extrathyroidal manifestations of autoimmune thyroid disease are absent and ultrasound scanning shows the presence of thyroid nodules (c.27–34%). In this scenario, measurement of TSAB is helpful to establish the correct diagnosis. Urinary iodine excretion can be measured in cases of suspected iodine contamination. CT or MRI are not routinely indicated for diagnosis of thyroid autonomy but may be used for presurgical planning in cases of large and partly intrathoracic TMNG.

The management of patients with thyroid autonomy (TMNG and TA) will to some extent depend on the patient’s age, the severity of hyperthyroidism, the size of the thyroid gland, and concomitant medical illness (4, 5, 9). Antithyroid medication (ATD) is the first-line treatment in all patients with overt hyperthyroidism. Depending on the type of antithyroid drug, an initial dosage of 30 mg/day methimazole, 40–60 mg/day carbimazole, or 3 × 50 mg/day propylthiouracil is recommended. Higher dosages are associated with more frequent adverse effects and will only result in marginally faster resolution of thyrotoxicosis. ATDs are usually combined with β-blockers (preferably nonselective propranolol) for symptom relief, until the patient is euthyroid. A trial of low-dose antithyroid medication (5–10 mg methimazole/day) may be justified in selected patients with symptomatic subclinical hyperthyroidism, i.e. atrial fibrillation; alternatively, β-blocking agents can be used (6). Monitoring of thyroid function and ATD side effects, in particular full blood count and liver function tests, are mandatory.

Due to the underlying molecular defect there is no spontaneous resolution of thyroid autonomy and definitive treatment is indicated once thyroid autonomy becomes clinically manifest. Elderly patients with severe nonthyroidal illness may be an exception to this rule. However, benefits and risks of such long-term ATD have to be considered against the nowadays very low risk of definitive treatment.

Three different ablative treatment options are available for TA and TMNG: thyroid surgery, radio-iodine treatment, and percutaneous ethanol injection. The purpose of thyroid surgery is to cure hyperthyroidism by removing all autonomously functioning thyroid tissue and other macroscopically visible nodular thyroid tissue (5, 10). Thus the extent of surgery will vary depending on preoperative ultrasound findings and intraoperative morphological inspection. For TA, hemithyroidectomy is usually adequate, if no further nodules are detectable, while in the case of TMNG a subtotal, near-total, or total thyroidectomy is performed. The advantages of surgery are a fast ablation of hyperthyroidism and the immediate relief of compression symptoms. The disadvantages of surgery are thyroid-specific side effects, i.e. vocal cord paralysis and permanent hypoparathyroidism, which should be less than 1% with an experienced endocrine surgeon. Clearly, the rate of postoperative hypothyroidism will vary with the extent of thyroid resection, and cases of near-total or total thyroidectomy require the start of efficient thyroid hormone replacement therapy (1.6–1.8 μg/kg body weight l-thyroxine), aiming for a TSH value of approximately 1 mU/l shortly after surgery. Surgery is usually recommended in large TMNG (>100 ml) and is indicated in case of suspicion of thyroid cancer. In addition, surgery is also advocated in patients with overt hyperthyroidism and adverse side effects of ATD, or as an early emergency procedure in patients with thyroid storm (7, 8).

Radio-iodine therapy is also highly effective for ablation of hyperthyroidism and reduction of TA or TMNG volume (5, 9, 11). Different protocols have been suggested for ¹³¹I therapy in benign thyroid disease. Some investigators prefer to administer a standard dose, e.g. 370–740 MBq/thyroid gland, while others apply a certain ¹³¹I activity/g thyroid tissue. The success rate of an individually dosed ¹³¹I therapy has been reported to range between 85% and 100% in TA and reaches up to 90% in TMNG. An average thyroid and/or nodule volume reduction of about 40% can be anticipated. The advantages of radio-iodine therapy are its simple and outpatient-based applicability. The disadvantages are the ‘time to euthyroidism’ period (6 weeks to more than 3 months), during which time ATD has to be continued and thyroid function monitored at 3- to 6-week intervals. Radio-iodine treatment is contraindicated in pregnancy, and contraception is advocated for at least 6 months after receiving ¹³¹I therapy. Population-based studies comprising more than 35 000 patients treated with ¹³¹I have not shown increased risk of thyroid cancer, leukaemia, other malignancies, reproductive abnormalities, or congenital defects in the offspring, so that ¹³¹I therapy can be considered a very safe treatment. Postradio-iodine hypothyroidism in TMNG and TA usually develops insidiously and depends on the extent of TSH suppression before ¹³¹I therapy and the protocol applied. In one study, the incidence of hypothyroidism was 3% at 1 year, 31% at 8 years, and 64% at 24 years follow-up after radio-iodine treatment. These data emphasize the requirement for long-term monitoring of thyroid function in all patients receiving ¹³¹I therapy.

The principle of percutaneous ethanol injection treatment (PEIT) is the induction of a coagulative necrosis of the autonomous tissue by ultrasound-guided injection of 95% ethanol, usually accompanied by thrombosis of small vessels (5, 9). PEIT has been studied predominantly in specialized centres in Italy and has been demonstrated to be a cost-effective treatment of thyroid autonomy with reported overall cure rates of 68–90%. Between 1 and 9 ml ethanol (usually 1 or 2 ml) is injected into the nodule under ultrasound control. Three to eight treatment sessions over 2–4 weeks are required to destroy an average autonomously functioning nodule. The total amount of alcohol delivered is about 1.5 times the nodular volume. The limited follow-up time and lack of evaluation of PEIT in comparison to standard treatment of thyroid autonomy, however, makes this modality an alternative treatment for patients with contraindications to surgery or radio-iodine (e.g. old age, patients on dialysis, severe nonthyroidal illness). Side effects include transient vocal cord paralysis (3% within 1 week to 3 months) and transient thyroid pain (30% at the time of treatment). A summary of the advantages and disadvantages of the different treatment modalities for TA and TMNG is shown in Table 3.3.11.1.

The long-term management of patients with TA and TMNG is directed at the detection and adequate treatment of thyroid dysfunction (TSH level), detection of novel nodular thyroid disease (palpation and ultrasonography), and, in case of surgery, detection and treatment of postsurgical hypoparathyroidism (serum calcium). In case of ¹³¹I therapy, long-term follow-up for development of hypothyroidism is mandatory, e.g. annually. Thyroxine with or without iodine is often administered after thyroid surgery to prevent recurrent goitre/thyroid nodules. Although large randomized trials are lacking to provide definite evidence that postoperative thyroxine administration is beneficial, unless the patient is hypothyroid, this treatment strategy is inferred by studies treating goitre/nodules with l-thyroxine. In addition, in iodine-deficient areas iodine supplementation may be appropriate to prevent further nodular thyroid disease.