Diffuse toxic goiter: treatment and control of thyrotoxicosis

Diffuse toxic goiter, also known as Graves' disease, is the most common cause of persistent thyrotoxicosis in adults. Treatment is aimed at controlling excess thyroid hormones, relieving symptoms, and achieving sustained remission. Three basic strategies are equally valid: antithyroid drugs, radioactive iodine therapy, and thyroidectomy. The choice of treatment depends on the patient's clinical profile, associated risk factors, ocular manifestations, pregnancy plans, goiter size, resource availability, and patient preference. [1]

Initial care always includes symptom control with beta-blockers to reduce tachycardia, tremor, and anxiety, especially at the beginning of treatment, when transient hormonal fluctuations are possible during specific therapy. In cases of severe thyrotoxic symptoms, beta-blockers are prescribed immediately, concurrently with the initiation of antithyroid drugs or preparation for radioactive iodine or surgery. This improves treatment tolerability and reduces the risk of cardiac complications. [2]

Antithyroid drugs are considered first-line therapy in many countries. European guidelines recommend methimazole or its prodrug carbimazole, while propylthiouracil is reserved for the first trimester of pregnancy and for cases of methimazole intolerance. The typical course lasts approximately 12-18 months, followed by an attempt to wean off the drug. Regular laboratory monitoring is important to avoid both undertreatment and oversuppression. [3]

Radioactive iodine is an effective definitive treatment, particularly for relapses after treatment, drug intolerance, surgical inability, and in patients who prefer a definitive solution. Ocular pathology is a critical issue: radioactive iodine can trigger reactivation of ophthalmopathy in high-risk patients, so prophylaxis with systemic glucocorticoids is recommended for these patients. Surgery shows the best results for large goiters, nodular changes, severe ophthalmopathy, and in pregnant women in the second trimester when conservative treatment is ineffective. [4]

Treatment focuses on the choice of tactics, doses and nuances

Antithyroid drugs

Methimazole is the drug of choice for most adults due to its ease of administration and improved safety profile compared to propylthiouracil. There are two dosing strategies: titration of methimazole based on hormone levels and a block-and-replace regimen, in which levothyroxine is added to a fixed dose of methimazole to maintain euthyroidism. Titration is more commonly used in practice, as it is associated with fewer side effects and easier dose adjustments. Free thyroxine and triiodothyronine levels are monitored every 4 weeks at the start, with subsequent intervals being increased once levels stabilize. [5]

The course of treatment typically lasts 12-18 months, after which, if hormone levels have stabilized and thyroid-stimulating hormone receptor antibody levels have decreased, discontinuation of the drug can be attempted. Factors that reduce the likelihood of remission include a large goiter, high thyroid-stimulating hormone receptor antibody titers, smoking, and young age. In such cases, it is advisable to discuss the risk of relapse and alternative strategies, including radioactive iodine or surgery, in advance. [6]

In recent years, data have been published on the benefits of extended low-dose methimazole therapy. A randomized trial showed that cumulative methimazole use for 60-120 months significantly reduced the relapse rate compared with stopping treatment after 18-24 months, with a comparable safety profile with regular monitoring. For some patients unwilling or with contraindications to definitive treatment, long-term low-dose therapy is becoming a viable option. The decision is made individually, taking into account tolerability and adherence. [7]

Safety requires special attention. Rare but serious reactions include agranulocytosis and cholestatic liver injury with methimazole, and the risk of severe drug-induced hepatitis with propylthiouracil. Patients are instructed to immediately discontinue use and obtain a complete blood count if they experience sudden fever or sore throat, and to report right upper quadrant pain, dark urine, and itching. Blood and liver function tests are performed before initiating therapy and when symptoms appear, with subsequent periodic monitoring determined by the clinician. Propylthiouracil is preferred during the first trimester of pregnancy, with a switch to methimazole in the second trimester. [8]

Radioactive iodine

Radioactive iodine provides a high cure rate due to the targeted destruction of thyrocytes. Preparation involves achieving euthyroidism with methimazole in patients with severe thyrotoxic symptoms or cardiovascular risk, after which the drug is temporarily discontinued according to protocol. Important contraindications include pregnancy, lactation, and severe active ophthalmopathy. Patients at risk for ophthalmopathy are recommended to receive glucocorticoid prophylaxis, which reduces the likelihood of ocular symptoms recurring after radioactive iodine therapy. [9]

Prednisolone is administered at an individualized dose and for a limited period, beginning on the day of radioactive iodine administration. Current guidelines and updated regional recommendations confirm the efficacy and safety of this prophylaxis, particularly in smokers, patients with severe thyrotoxicosis, and individuals with high titers of stimulating antibodies. Patients are informed in advance that the target outcome is often controlled hypothyroidism, which is then fully compensated with levothyroxine. [10]

Following radioactive iodine therapy, hormone levels are monitored every 4-6 weeks during the first few months to ensure early detection of hypothyroidism and prompt initiation of levothyroxine. A short-term increase in symptoms may occur during treatment, which is managed with beta-blockers. Long-term outcomes are favorable with proper hypothyroidism management, and the risk of recurrence of thyrotoxicosis is low. [11]

Surgical treatment

Total thyroidectomy is indicated for large goiters with compressive symptoms, suspected nodular pathology, severe ophthalmopathy, relapses after medications or radioactive iodine, and when the patient desires the fastest and most definitive solution. Preoperative preparation includes achieving euthyroidism with antithyroid drugs and the use of short-term iodine solutions during the preoperative period to reduce blood flow to the gland. The surgery is performed by an experienced team due to the risks of hypoparathyroidism and recurrent laryngeal nerve palsy, which are minimized by the surgeon's skill. [12]

Following total thyroidectomy, levothyroxine is prescribed for life, with individualized dosage adjustments and monitoring every 6-8 weeks. With proper technique and monitoring, quality of life is comparable to the general population. Surgery is the preferred option for patients for whom radiation exposure or long-term medication is undesirable. [13]

Special situations

Pregnancy requires a different approach. In the first trimester, propylthiouracil is preferred due to its lower risk of embryopathies, followed by a switch to methimazole in the second trimester. Radioactive iodine is contraindicated, and surgery in the second trimester is considered in cases of severe, resistant pregnancy or drug intolerance. The goal is to maintain hormone levels at the upper limit of normal with the lowest effective doses and regular monitoring. [14]

Ocular manifestations of Graves' disease are managed according to separate guidelines. For mild active ophthalmopathy, smoking cessation, topical measures, and selenium supplementation in those with selenium deficiency are recommended. For moderate to severe ophthalmopathy, intravenous glucocorticoids are often combined with sodium mycophenolate, according to the EUGOGO consensus. Treatment for thyrotoxicosis is discussed with an ophthalmologist, and steroid prophylaxis is used in patients at risk of ocular activation with radioactive iodine. [15]

Finally, long-term follow-up is essential with any chosen method. After discontinuing methimazole in the classic course, monitoring is performed more frequently in the first year due to the risk of relapse, and then clinically. With prolonged low-dose methimazole therapy, regular contact is maintained, assessing tolerability and safety. After radioactive iodine and surgery, monitoring is aimed at maintaining stable hypothyroidism. Personalized decisions and shared choice with the patient increase adherence and improve outcomes. [16]