Toxic Multinodular Goiter (TMG)

Definition, Etiology, Pathogenesis Top

A toxic multinodular goiter (TMG) (multinodular goiter [MNG] with functional autonomy) is a condition that develops on the background of thyroid nodular hypertrophy and does not have an immunologic basis. It is characterized by the presence of nodules that show autonomous secretion of thyroid hormones independent from the thyroid-stimulating hormone (TSH).

Clinical Features and Natural History Top

Hyperthyroidism usually develops very slowly (presentation of overt disease is usually preceded by subclinical hyperthyroidism [see Thyrotoxicosis]), but it may also occur suddenly after exposure to large doses of iodine, for instance, in iodine contrast media or drugs (amiodarone or certain disinfectants). Enlargement of the goiter or appearance of a nodule are frequently unnoticed by the patient. If the goiter is large, a sensation of neck compression may occur with dyspnea, dysphagia, cough, or all of these.

Diagnosis Top

Diagnostic Tests

1. Hormone tests: Decreased TSH and normal free thyroxine (FT4) and free triiodothyronine (FT3) (subclinical hyperthyroidism) or suppressed TSH with high FT4 levels, FT3 levels, or both (overt hyperthyroidism; see Thyrotoxicosis and Hyperthyroidism).

2. Other laboratory tests: The measurements of serum antibodies to thyroperoxidase (TPOAb) and antibodies to thyroglobulin (TgAb) are not suggested for the workup of patients with low TSH values,Evidence 1Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the unclear accuracy of those tests to indicate the etiology of low thyroid-stimulating hormone. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002 Feb;87(2):489-99. PubMed PMID: 11836274. as they do not definitely indicate etiology (they may also be present in healthy individuals and patients with nonautoimmune thyroid diseases, most frequently in subacute thyroiditis) and can lead to unnecessary tests. A positive antibody to the TSH receptor (TRAb) indicates Graves disease, which can in some cases coexist with toxic nodules (see Thyrotoxicosis and Hyperthyroidism).

3. Molecular imaging studies (see Thyrotoxicosis and Hyperthyroidism):

1) Radioactive iodine uptake (RAIU): The uptake is high (but not as high as in Graves disease) or commonly normal.

2) Thyroid scan (scintigraphy) demonstrates ≥2 areas of increased tracer activity with reduced or suppressed rest of the gland.

4. Thyroid ultrasonography may be used in selected cases to accurately characterize nodules deemed nonfunctioning (cold) if seen on the thyroid scan (autonomously hyperfunctioning [hot] nodules are considered low risk for malignancy and do not need further investigation; see Goiter, Nontoxic Multinodular).

5. Cytology: For autonomously hyperfunctioning (hot) nodules observed on thyroid radionuclide imaging, fine-needle biopsy (FNB) is not suggested due to the low risk of malignancy and increased risk of indeterminate results (see Thyrotoxicosis). For nonfunctioning (cold) nodules the indications for FNB are the same as in nontoxic MNG (see Goiter, Nontoxic Multinodular).

Diagnostic Criteria

Presence of ≥2 discrete regions of increased tracer activity detected on the thyroid scan, especially corresponding to palpable nodules, with concomitant hyperthyroidism (overt or subclinical).

Differential Diagnosis

Other causes of thyrotoxicosis (see Figure 1 in Thyrotoxicosis). Also see Graves Disease; see Toxic Thyroid Nodule.

Treatment Top

1. Pharmacologic treatment: Thionamides (see Thyrotoxicosis) reduce symptoms of hyperthyroidism (they should not be combined with levothyroxine), but their discontinuation invariably results in the recurrence of hyperthyroidism (after a period from several days to several months). Patients who do not want definitive treatment (see below) or have contraindications to radioiodine (RAI) treatment or surgery can be treated with a long-term thionamide (preferably methimazole). Beta-blockers are used as in other cases of hyperthyroidism for symptom management.

2. Definitive treatment is usually recommended, with either surgery (subtotal or total thyroidectomy) or RAI treatment. Treatment modality is individually selected in every patient.

1) RAI treatment: Radiation sensitivity of autonomously functioning nodules is lower than in Graves disease (thus higher doses of RAI are usually required in TMG compared with Graves disease). Nonfunctioning nodules do not respond to treatment and most functioning nodules are only reduced in size and do not disappear; nevertheless, remission of hyperthyroidism is achieved (although repeated RAI treatment is occasionally necessary after 6-12 months) with most patients with TMG becoming euthyroid after RAI treatment, given that RAI accumulates in the hyperfunctioning nodules sparing the remainder of the thyroid gland (unlike in patients with Graves disease, in whom the goal for treatment is to achieve hypothyroidism). RAI treatment is usually selected for patients with small goiters and no features suggestive of malignancy and in patients with contraindications to surgery (see Thyrotoxicosis and Hyperthyroidism). Due to low serum TSH levels, iodine uptake of the normal thyroid parenchyma is inhibited (therefore the risk of developing posttreatment hypothyroidism is low). RAI therapy should be planned for use after withholding of thionamides for 5 to 7 days (if used for hyperthyroid control prior to RAI therapy). Thionamides may be restarted 5 to 7 days after RAI treatment. TSH levels should be monitored periodically after the therapy. Temporary replacement therapy with levothyroxine may be necessary after RAI therapy until the previously suppressed normal thyroid gland recovers.

2) Surgical treatment is required in patients with nodules revealing cytologic or clinical features suggestive of malignancy. It should also be considered in patients with large goiters causing compressive symptoms, particularly if nonfunctioning nodules are present. Coexistence of primary hyperparathyroidism is also a possible indication for surgery. Surgery is usually possible after achieving euthyroidism; methimazole is stopped on the day of surgery, while the beta-blocker dose is decreased gradually to taper and discontinue within a few days after surgery. After thyroidectomy, start L-T4 substitution and monitor TSH for dose adjustment. Serum calcium and parathyroid hormone (PTH) levels should be checked and followed given the risk of permanent or transient hypoparathyroidism.

Prognosis Top

Untreated TMG increases the risk of arrhythmias, other cardiovascular complications, bone loss, and thyroid storm (see Thyrotoxicosis and Hyperthyroidism). The risk of malignancy in nonfunctioning nodules is the same as in other forms of nodular goiter (see Goiter, Nontoxic Multinodular).