Graves Disease Treatment & Management

Treatment involves alleviation of symptoms and correction of the thyrotoxic state. Adrenergic hyperfunction is treated with beta-adrenergic blockade. Correcting the high thyroid hormone levels can be achieved with antithyroid medications that block the synthesis of thyroid hormones or by treatment with radioactive iodine.

Radioactive iodine

The most commonly used therapy for Graves disease is radioactive iodine. Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of TSI. Information and guidelines are as follows:

• Many physicians in the United States prefer to use radioactive iodine as first-line therapy, especially in younger patients, because of the high relapse rate (>50%) associated with antithyroid therapy.
• Radioiodine treatment can be performed in an outpatient setting.
• The usual dose ranges from 5-15 mCi, determined either by using various formulas that take into account the estimated thyroid weight and radioiodine uptake or by using fixed dosages of iodine I 131; detailed kinetic studies of¹³¹ I are not essential and do not lead to better treatment results. A fixed dose of 7 mCi has been advocated by some researchers as the first empirical dose in the treatment of hyperthyroidism. In general, higher dosages are required for patients who have large goiters, have low radioiodine uptake, or who have been pretreated with antithyroid drugs.
• Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiopharmaceutical.^[34] In one study, withholding antithyroid drugs for just over 2 weeks before radioiodine treatment resulted in the lowest failure rate. Pretreatment with thioanmides reduces the cure rate of radioiodine therapy in hyperthyroid diseases.^[35]
• Thyroid function test results generally improve within 6-8 weeks of therapy, but this can be highly variable.
• With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2-3 months after administration.
• Following up with the patient and monitoring thyroid function monthly or as the clinical condition dictates is important.
• When patients become hypothyroid, they require lifelong replacement with thyroid hormone.
• The possibility exists that radioactive iodine can precipitate thyroid storm by releasing thyroid hormones. This risk is higher in elderly and debilitated patients. This problem can be addressed by pretherapy administration with antithyroidal medication such as propylthiouracil (PTU) or methimazole, but antithyroid medication also may decrease the effectiveness of radioiodine, as discussed above.
• If thyroid function does not normalize within 6-12 months of treatment, a second course at a similar or higher dose can be given. Third courses are rarely needed.
• Hypothyroidism may ensue in the first year in up to 90% of patients given higher doses of radioiodine.
• Approximately one third of patients develop transient hypothyroidism. Unless a patient is highly symptomatic, thyroxine replacement may be withheld if hypothyroidism occurs within the first 2 months of therapy. If it persists for longer than 2 months, permanent hypothyroidism is likely and replacement with T4 should be initiated.
• Radiation thyroiditis is rare, but it may occur and exacerbate thyrotoxicosis.
• Long-term follow-up is mandatory for all patients.
• One concern with the use of radioiodine in persons with Graves disease is its controversial potential for exacerbating existing Graves ophthalmopathy. However, the presence of ophthalmopathy should not influence the choice of therapy for hyperthyroidism. If possible in patients with mild progressive ophthalmopathy, institute a course of steroids (prednisone up to 1 mg/kg) for 2-3 months, tapering a few days before radioiodine therapy. For those with no obvious ophthalmopathy, the chances of exacerbation are much lower. In patients with severe Graves ophthalmopathy, treatment of hyperthyroidism and ophthalmopathy should proceed concurrently and independently of each other.
• The absolute contraindication for radioiodine is pregnancy. No evidence of germ-line mutations has been demonstrated from gonadal exposure. The incidence of birth defects or abnormal pregnancies has not increased after radioiodine treatments.^[36] After radioiodine therapy, germinal epithelium and Leydig cell function may change marginally, which may have some clinical significance in male patients with preexisting fertility impairment.^[37]
• Because it is known that low-dose thyroid radiation exposure in children increases the risk of thyroid cancer later in life, larger doses of¹³¹ I are recommended for children.^[38] If patients are aged 6-10 years, ablative doses of¹³¹ I (100-150 mCi/g of thyroid tissue) may be used to prevent the survival of thyroid cells that may be transformed later into malignant cells.

Graves ophthalmopathy

Graves ophthalmopathy can be divided into 2 clinical phases: the inflammatory stage and the fibrotic stage. The inflammatory stage is marked by edema and deposition of glycosaminoglycan in the extraocular muscles. This results in the clinical manifestations of orbital swelling, stare, diplopia, periorbital edema, and at times, pain. The fibrotic stage is a convalescent phase and may result in further diplopia and lid retraction. It improves spontaneously in 64% of patients.

Approximately 10-20% of patients have gradual progression of disease over many years, followed by clinical stability. Approximately 2-5% have progressive worsening of the disease, with visual impairment in some.

Correction of both hyperthyroidism and hypothyroidism is important for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may exacerbate preexisting ophthalmopathy but can be prevented by glucocorticoids. In the long term, thyroid ablation may be beneficial for ophthalmopathy because of the decrease in antigens shared by the thyroid and the orbit in the autoimmune reactions. In general, treatment of hyperthyroidism is associated with an improvement of ophthalmopathy, but hypothyroidism must be avoided because it worsens ophthalmopathy.^{[39, 40, 41]}

For mild-to-moderate ophthalmopathy, local therapeutic measures (eg, artificial tears and ointments, sunglasses, eye patches, nocturnal taping of the eyes, prisms, elevating the head at night) can control symptoms and signs.

If the disease is active, the mainstays of therapy are (1) high-dose glucocorticoids,^[42] (2) orbital radiotherapy, (3) both, or (4) orbital decompression. For severe or progressive disease, glucocorticoids at 40 mg/d (usual dose) may be tried. The drug should be continued until evidence of improvement and disease stability is observed. The dosage is then tapered over 4-12 weeks. High-dose pulse glucocorticoid therapy has also been used with good results.

A study by Liao and Huang evaluated the correlation of retrobulbar volume change, resected orbital fat volume, and proptosis reduction after surgical decompression in patients with Graves ophthalmopathy.^[43] Decompression by resecting orbital fat was found to reduce proptosis in patients with disfiguring Graves ophthalmopathy.

If no response to therapy occurs in the inflammatory phase, orbital radiotherapy with or without steroids may be tried. Orbital radiotherapy does not increase the risk for radiation-induced tumors, cataract, and retinopathy, except in patients with diabetes with possible or definite retinopathy.^[44] Diuretics have a limited effect on the edema caused by venous engorgement of the orbit.

Gamma knife surgery has been attempted with success in a limited number of patients, but further studies are needed to validate this approach.

Surgical management is generally performed in the fibrotic phase, when the patient is euthyroid. See Surgical Care.

Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Studies with octreotide LAR (long-acting, repeatable) show conflicting or marginal therapeutic benefit for patients with Graves ophthalmopathy.^{[45, 46, 47]} Infliximab, an anti-tumour necrosis factor alpha (TNF-α) antibody, has been reported to successfully treat a case of sight-threatening Graves ophthalmopathy.^[48] Rituximab, anti-CD20 monoclonal antibody, may transiently deplete B-lymphocytes and potentially suppress the active inflammatory phase of Graves ophthalmopathy.^[49] A multicentered prospective pilot study suggests that periocular injection of triamcinolone may reduce diplopia and the size of extraocular muscles in patients with Graves ophthalmopathy of recent onset.^[50] In a prospective randomized trial, pentoxifylline improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy.^[51]

Pretibial myxedema

Some degree of pretibial (localized dermopathy) myxedema is observed in 5-10% of patients, with 1-2% having cosmetically significant lesions. Affected patients tend to have more severe ophthalmopathy than those who are not affected.

It usually manifests as elevated, firm, nonpitting, localized thickening over the lateral aspect of the lower leg, with bilateral involvement. It also may involve the upper extremities.

Milder cases do not require therapy other than treatment of the thyrotoxicosis.

Therapy with topical steroids applied under an occlusive plastic dressing film (eg, Saran Wrap) for 3-10 weeks has been helpful. In severe cases, pulse glucocorticoid therapy may be tried.

Acropachy

Clubbing of fingers with osteoarthropathy, including periosteal new bone formation, may occur. This almost always occurs in association with ophthalmopathy and dermopathy. No therapy has been proven to be effective.

Indications and outcomes are as follows:

• Thyroidectomy is no longer the recommended first-line therapy for hyperthyroid Graves disease. However, a retrospective cohort study^[52] showed that one-third of all patients electing surgery as definitive management did so without a specific indication, and the patient satisfaction with the decision for surgery as definitive management of Graves disease was high. Surgery is a safe alternative therapeutic option in patients who are noncompliant with or cannot tolerate antithyroid drugs, have moderate-to-severe ophthalmopathy, have large goiters, or refuse or cannot undergo radioiodine therapy.
• Thyroidectomy may be appropriate in the presence of a thyroid nodule that is suggestive of carcinoma.
• In certain cases (eg, in pregnant patients with severe hyperthyroidism), thyroidectomy may be indicated because radioactive iodine and antithyroid medications may be contraindicated.
• It generally is reserved for patients with large goiters with or without compressive symptoms.
• It also may be indicated in patients who refuse radioiodine as definitive therapy or in those in whom the use of antithyroid drugs and/or radioiodine does not control hyperthyroidism.
• Surgery provides rapid treatment of Graves disease and permanent cure of hyperthyroidism in most patients, and it has "negligible mortality and acceptable morbidity" by experienced surgeons.^[53]

Procedures and preparations are as follows:

• Preoperative preparation to render the patient euthyroid is essential in order to prevent thyrotoxic crisis (thyroid storm). The hyperthyroid state can be rapidly corrected using a combination of iopanoic acid, dexamethasone, beta-blockers, and thionamides.^[54]
• This can be accomplished with the use of antithyroid drugs for approximately 6 weeks, with or without concomitant beta-blockade.
• Most surgeons administer iodine (as Lugol solution or saturated solution of potassium iodide to provide ≥30 mg of iodine/d) for 10 days before surgery to decrease thyroid gland vascularity, the rate of blood flow, and intraoperative blood loss during thyroidectomy.^[55]
• With experienced surgeons, vocal cord paralysis due to superior or recurrent laryngeal nerve injury and hypoparathyroidism are rare adverse events, occurring in less than 1% of patients.
• Subtotal thyroidectomy is usually used with the intention of leaving enough thyroid remnants behind to avoid hypothyroidism.
• Importantly, keep in mind that the risk of recurrent hyperthyroidism potentially increases with larger remnant sizes. However, many studies have shown that the size of the remnant is not the only determinant of the risk of recurrence.
• Iodine uptake and immunologic activity (eg, level of TSI) are just 2 of the other factors that influence the risk of recurrent hyperthyroidism.
• If the goal of surgery is to avoid recurrent hyperthyroidism, near-total thyroidectomy has been advocated as the procedure of choice.
• Regardless of the extent of surgery, all patients require long-term follow-up.

Ophthalmopathy is as follows:

• Near-total thyroidectomy has little, if any, effect on the course of ophthalmopathy.
• If ophthalmopathy is severe but inactive, orbital decompression may be performed. Reducing proptosis and decompressing the optic nerve can be achieved by transantral orbital decompression. A study by Alsuhaibani et al found that the change in the volume of the medial rectus muscle may help explain the variability in the proptosis reduction following orbital decompression.^[56]
• The major adverse effect is postoperative diplopia, which may necessitate a second surgery on the extraocular muscles to correct the problem.
• Rehabilitative (extraocular muscle or eyelid) surgery is often needed. Eyelid surgery (eg, severance of the Müller muscle, scleral or palatal graft insertion) can be performed to improve exposure keratitis.

Consultation with an endocrinologist may be necessary for the management and regulation of thyroid hormone levels in atypical presentations, as follows:

• Graves disease in pregnancy
• Neonatal Graves disease management
• Graves disease complicated by a nodular thyroid gland unresponsive to usual medical therapy or in older adults

Consultation with an ophthalmologist may be needed in the following situations:

• Unilateral or bilateral proptosis
• Workup of other etiologies for eye findings besides Graves disease
• Follow-up of visual acuity, corneal disease prevention, and eye muscle function

Consultation with a dermatologist may be needed in patients with localized myxedema that is unresponsive to topical corticosteroids.

The amount of iodine in the diet can influence the hormone synthesis activity in the thyroid gland.

Iodine-containing food has different effects on thyroid uptake of¹³¹ I and technetium Tc 99m. Iodine-rich food decreases¹³¹ I uptake but increases^99m Tc in most patients. However, the diagnostic value of a radioiodine uptake test to differentiate Graves disease and silent thyroiditis is not affected by dietary iodine intake.^[57] Iodine restriction before a radioiodine uptake test is unnecessary.

Dietary iodine intake may influence the remission rate after antithyroid drug therapy. This is based on the observation that the outcome of antithyroid therapy in the older literature showed lower remission rates than it did in later studies and that the average dietary iodine content has been decreasing over the years. However, a direct causal relationship has not been established by clinical trials.

Given the high-output state of the heart, strenuous exercise may be detrimental. The patient should be advised to avoid severe fatigue from exercise. Patients can use their pulse as a guide to activity.