Graves Disease Treatment & Management
- Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
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.
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 of 131 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.  In one study, withholding antithyroid drugs for just over 2 weeks before radioiodine treatment resulted in the lowest failure rate. Pretreatment with thioamides reduces the cure rate of radioiodine therapy in hyperthyroid diseases. 
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.  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. 
Because it is known that low-dose thyroid radiation exposure in children increases the risk of thyroid cancer later in life, larger doses of 131 I are recommended for children.  If patients are aged 6-10 years, ablative doses of 131 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. In a national database analysis, Graves disease patients had increased risk of developing malignancies (especially in the first 3 y of diagnosis) compared with controls, especially for breast and thyroid cancer.  Detection bias because of Graves disease diagnosis could be a factor for this epidemiological association.
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. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels may be mechanistically involved in Graves ophthalmopathy. Serum VEGF and b-FGF levels were higher in patients with Graves ophthalmopathy than in patients without, and they correlated with ophthalmopathy clinical activity scores.
In a longitudinal cohort of 8404 adults with newly diagnosed Graves disease, 740 (8.8%) developed ophthalmopathy. Graves ophthalmopathy 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.
Radioactive iodine therapy for Graves disease is a risk factor for Graves ophthalmopathy. Cholesterol-lowering drugs of the hydroxymethylglutarate-coenzyme A reductase inhibitor class were associated with a reduced risk of ophthalmopathy. Ethnic factors are also important for Graves ophthalmopathy after radioactive iodine treatment; Japanese patients are less prone to Graves ophthalmopathy after radioactive iodine.
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. However, Japanese patients may not respond well to prophylactic use of low-dose glucocorticosteroids. No beneficial effect of glucocorticoid prophylaxis was found in patients without preexisting clinical evidence of ophthalmopathy. 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.[51, 52, 53]
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, (2) orbital radiotherapy, (3) both, or (4) orbital decompression. A meta-analysis has shown that a 3-month course of prednisone (0.4-0.5 mg/kg) reduced the progression of preexisting mild-to-moderate ophthalmopathy.
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 but may be associated with a slightly increased risk of acute liver damage.
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. 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 did not increase the risk for radiation-induced tumors or retinopathy, except in patients with diabetes with possible or definite retinopathy. Low-dose radiation from various sources (even if not aimed at the eyes) is linked to cataracts, which may be detected only after long term follow-up. A meta-analysis found better outcome with combining steroids with radiotherapy compared with steroid therapy alone. However, quality-of-life scores were not different between the 2 groups. 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.
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.[60, 61, 62] Infliximab, an anti-tumour necrosis factor alpha (TNF-α) antibody, has been reported to successfully treat a case of sight-threatening Graves ophthalmopathy. Rituximab, anti-CD20 monoclonal antibody, may transiently deplete B-lymphocytes and potentially suppress the active inflammatory phase of Graves ophthalmopathy. However, clinical data concerning rituximab are still conflicting and controversial.[65, 66] 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. In a prospective randomized trial, pentoxifylline improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy.
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.
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.
With the exception of thyroid storm, Graves disease generally is managed in an outpatient setting.
On occasion, patients may present with thyrotoxic heart disease, including congestive heart failure, atrial fibrillation, or other tachyarrhythmia, which requires inpatient management. Prompt recognition of thyrotoxicosis is required for optimal therapy. In certain cases, the patient may have to be admitted to the intensive care unit or critical care unit. Appropriate subspecialty consultations (eg, endocrinologist, cardiologist) are needed. Once patients' conditions are stabilized, they can be transferred to a regular room or discharged from the hospital.
In certain cases (ie, noncompliant patients, those who develop severe reactions to antithyroid drugs), radioiodine ablation therapy may be given in an inpatient setting.
Indications and outcomes are as follows:
Thyroidectomy is not the recommended first-line therapy for hyperthyroid Graves disease in the United States. However, a retrospective cohort study  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. Also, surgical treatment has been found to be more effective than radioiodine therapy to achieve cure and reduce recurrence. 
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. 
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 thioamides. 
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. 
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. 
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 increases99m 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. 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.
In addition, the use of antithyroid drug therapy for more than 2 years is a good predictor of Graves disease. In pediatric patients with Graves disease, no difference was noted in remission rates between methimazole and PTU, while minor adverse effects were significantly increased in patients receiving PTU doses of 7.5 mg/kg or higher.
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.
Agranulocytosis is an idiosyncratic reaction to antithyroid drugs. The role of serial CBC counts to predict who will develop this serious adverse reaction is not well established.
In contrast to patients with Graves disease, preoperative iodine treatment should not be given to patients with toxic nodular goiters because it can exacerbate hyperthyroidism.
Prevention is difficult because of the lack of knowledge regarding the pathogenesis of this condition.
Hyperthyroidism represents a continuum of thyroid dysfunction. In the case of thyroid storm, decompensated patients with hyperthyroidism should be cared for in an institution with personnel familiar with this disease.
All patients should receive long-term follow-up, regardless of the mode of therapy (ie, surgery, radioiodine, antithyroid drugs).
Close follow-up visits with monitoring of examination findings, thyroid hormone levels, and thyrotropin levels are required.
If the patient is on antithyroidal medication (eg, thioamides), liver function tests and CBC counts with differentials should be monitored based on the clinical situation.
Examination of the eyes should be a routine part of follow-up of these patients, given the lack of predictability of ophthalmopathy.
Smoking cessation techniques should be continued.
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