Treatment of Graves' Disease in Adults

*Mauricio Alvarez Andrade and Lorena Pabón Duarte*

#### **Abstract**

Graves' Disease is an autoimmune disease, with a genetic susceptibility, activated by environmental factors like stress, iodine excess, infections, pregnancy and smoking. It is caused by thyroid stimulating immunoglobulin (TSI) or thyroid stimulating antibody (TSAb) and is the most common cause of hyperthyroidism with an incidence of 21 per 100,000 per year. Treatment of Graves' Disease includes antithyroid drugs such as methimazole and propylthiouracil, radioactive iodine therapy and thyroidectomy. Methimazole, an antithyroid drug that belongs to the thioamides class, is usually the first line of treatment due to lower risk of hepatotoxicity compared to propylthiouracil. Radioactive iodine therapy is reserved for those patients who do not respond to antithyroid drugs or have contraindication or adverse effects generated by antithyroid drugs, and thyroid surgery is an option in people with thyroid nodular disease with suspected malignancy or large goiters such as predictors of poor response to antithyroid drugs and radioactive iodine therapy. Multiple factors influence the management of patients with Graves' Disease including patient and physician preferences, access to medical services and patients features such as age, complications and comorbidities.

**Keywords:** Hyperthyroidism, Graves' Disease, antithyroid agents, methimazole, propylthiouracil, thyroidectomy

#### **1. Introduction**

Graves' Disease is the most common cause of hyperthyroidism with an incidence of 21 per 100,000 per year [1], with a F:M ratio ranging from 3 to 5:1 [2–4]. The usual age of presentation ranges from 20 to 50 years old.

Graves' Disease is an autoimmune disease, with a genetic susceptibility, activated by environmental factors like stress, iodine excess, infections, pregnancy and smoking. It is caused by thyroid stimulating immunoglobulin (TSI) or thyroid stimulating antibody (TSAb). TSI stimulate follicular thyroid cells by binding to the thyroid stimulating hormone (TSH) receptor on the thyroid cell membrane to produce the thyroid hormone synthesis and liberation as well as gland growth, with consequent hyperthyroidism and bocio [1, 5].

Graves' Disease produces varied symptoms such as sweating, insomnia, weight loss, anxiety, muscle weakness, loss of libido. Clinical signs include tachycardia, systolic hypertension, heart failure, atrial fibrillation, tremors, hyperkinesia, hyperreflexia, hot skin, palmar erythema, onycholysis, alopecia, goiter and impaired mental status. Among the most characteristic signs of the disease are thyroid orbitopathy and the infrequent pretibial myxedema. Orbitopathy is characterized by proptosis, palpebral retraction, chemosis, and periorbital edema [1, 5].

Treatment of Graves' Disease includes antithyroid drugs such as methimazole and propylthiuracil, radioactive iodine therapy and thyroidectomy. Methimazole, an antithyroid drug that belongs to thionamides class, usually is the first line of treatment due to lower risk of hepatotoxicity compared to propylthiuracil. Radioactive iodine therapy is reserved for those patients who do not respond to antithyroid drugs or have contraindication or adverse effects generated by antithyroid drugs, and thyroid surgery is an option in people with thyroid nodular disease with suspected malignancy or large goiters such as predictors of poor response to antithyroid drugs and radioactive iodine therapy [5–9].

Multiple factors influence the management of patients with Graves' Disease including patient and physician preferences, access to medical services and patients features such as age, complications and comorbidities.

## **2. Antithyroid drugs**

#### **2.1 Methimazole**

Methimazole, an antithyroid drug that belongs to the thionamide class, with few exceptions is usually the first line of treatment due to the lower risk of hepatotoxicity compared to propylthiuracil [10, 11].

The mechanism of action of methimazole is to block the production of thyroid hormone by interfering with the iodination of tyrosine residues of thyroglobulin by inhibiting the enzyme thyroid peroxidase and then the synthesis of thyroxine and triiodothyronine. Furthermore, methimazole inhibits iodine oxidation and the binding of iodotyrosyl residues [10, 11].

The route of administration of methimazole is oral. The starting dose depends on the severity of the disease, in most cases it varies between 20 to 40 mg per day, with titration every 4 to 8 weeks and variable maintenance doses and a maximum dose of 60 to 80 mg. does not require dose adjustment except in patients with severe hepatic impairment [10, 11]. The recommended starting dose in mild cases is 15 mg per day and moderate to severe cases 30 mg per day.

Although methimazole has a half-life of less than 6 hours, the half-life has been shown to be greater than 6 hours in follicular cells [12, 13], and the effectiveness of administering it in a single daily dose in usual doses is effective [14–17].

In patients with thyroid storm, higher doses are required, with a starting dose of 60 to 80 mg per day with the dose divided every 4 to .8 hours, with a maximum dose of 120 mg [18].

Serious adverse effects of methimazole include agranulocytosis, hepatotoxicity, and teratogenicity. Agranulocytosis usually occurs in the first months of treatment but can occur at any time during treatment, it is characterized by an absolute granulocyte count less than 500 per ml, fever and sore throat, so it should be indicated to the patient attend the emergency room in case of these symptoms. Treatment consists of stopping methimazole if the granulocyte count is less than 1000 per ml and antibiotic treatment. Agranulocytosis due to methimazole predicts the risk of agranulocytosis due to propylthiuracil, therefore the use of propylthiuracil should also be avoided in these patients. Methimazole hepatotoxicity can occur at any dose, is characterized by cholestasis and slowly recovers after discontinuation of the drug [19–21].

The teratogenicity of methimazole occurs by free crossing the placenta, especially in the first trimester, the effects include aplasia cutis, umbilical malformations, facial dysmorphism, esophageal and choanal atresia as well as craniofacial malformations. For this reason, the use of propylthiuracil in the first trimester of pregnancy is preferred [19–21].
