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Treatment

Medical Care

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.

A study by Yasuda et al of pediatric patients with Graves disease found that a greater incidence and variety of adverse events occurred in those on a high dose of the antithyroid drug methimazole (0.7 or more mg/kg/day) than in those on a low dose (< 0.7 mg/kg/day), with the frequencies of adverse events being 50% and 20%, respectively. However, neutropenia and rash were found to manifest independently of dose.^[55]

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-131 (¹³¹I); detailed kinetic studies of ¹³¹I 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.^[56]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.^[57]
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.
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.^[58]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.^[59]
Long-term side effects are observed mainly in pediatric Graves disease patients treated with radioactive iodine doses administered to achieve euthyroidism.^[60]Low-dose thyroid radiation therapy in children with Graves disease increases the risk for thyroid cancer later in life, because it can leave behind thyroid cells with gene mutations that may eventually transform to become malignant.^[61]In patients aged 6-10 years, ablative doses of¹³¹I (100-150 mCi/g of thyroid tissue) may be used. In a national database analysis, Graves disease patients had increased risk for developing malignancies, especially breast and thyroid cancer, compared with controls, particularly within the first 3 years of diagnosis.^[62]Detection bias because of Graves disease diagnosis could be a factor for this epidemiologic association. Exactly what the risk for cancer from radioactive iodine therapy itself is in patients with Graves disease remains a subject of controversy.^[63]

Graves ophthalmopathy

Graves ophthalmopathy can be divided into two 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.

In a longitudinal cohort of 8404 adults with newly diagnosed Graves disease, 740 (8.8%) developed ophthalmopathy.^[64]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, while cholesterol-lowering drugs of the hydroxymethylglutarate-coenzyme A reductase inhibitor (statin) class have been associated with a reduced risk of ophthalmopathy.^{[64, 65]} For example, a randomized clinical trial showed that the addition of oral atorvastatin to intravenous (IV) pulse glucocorticoid therapy can improve clinical outcomes in patients with moderate to severe Graves ophthalmopathy.^[66]Ethnic factors are also important for Graves ophthalmopathy after radioactive iodine treatment; Japanese patients are less prone to Graves ophthalmopathy after radioactive iodine.^[67]

Smoking is a risk factor for Graves ophthalmopathy, and smoking cessation is advised.

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.^[67]No beneficial effect of glucocorticoid prophylaxis was found in patients without preexisting clinical evidence of ophthalmopathy.^[68]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.^{[69, 70, 71]}

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.

For severe or progressive disease, high-dose pulse IV methylprednisolone (cumulative dose of 4.5 g in 12 weekly infusions) may be used as a first-line treatment. Mycophenolate mofetil (a potent, selective, noncompetitive, and reversible inhibitor of inosine-5'-monophosphate dehydrogenase) can suppress the immune system by depleting guanosine and deoxyguanosine nucleotides in T and B cells. Real-world, retrospective data support mycophenolate as an effective and safe second-line agent for moderate, severe, or sight-threatening Graves ophthalmopathy, to maintain remission after first-line IV glucocorticoid therapy.^[72] The 2021 European Group on Graves’ Orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ ophthalmopathy recommend high-dose pulse IV methylprednisolone combined with mycophenolate as first-line treatment, or alternatively, a higher cumulative dose (7.5 g) of pulse IV methylprednisolone monotherapy for the most severe cases.^[73]

Second-line treatments for moderate to severe and active Graves ophthalmopathy include the following^[73]:

High–cumulative-dose (7.5 g) pulse IV methylprednisolone - The treatment starts with 0.75 g IV methylprednisolone once weekly x6, followed by 0.5 g once weekly x6
Oral prednisone/prednisolone in combination with either cyclosporine or azathioprine - Glucocorticoids at prednisone equivalent 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; a meta-analysis showed that a 3-month course of prednisone (0.4-0.5 mg/kg) reduced the progression of preexisting mild to moderate ophthalmopathy ^[68]
Combination of orbital radiotherapy and oral or IV glucocorticoids - This is an effective second-line treatment for moderate to severe and active disease, especially when diplopia or extraocular movement defects are present; a meta-analysis found that combining steroids with radiotherapy produced better outcomes than did steroid therapy alone; ^[74] a study by Wakelkamp et al found that orbital radiotherapy did not increase the risk for radiation-induced tumors or retinopathy (except in patients with diabetes, in whom a greater risk for possible or definite retinopathy was reported); ^[75] 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 ^[76]
Teprotumumab - Teprotumumab (an inhibitory IGF1 receptor monoclonal antibody) was approved by the US Food and Drug Administration (FDA) for Graves ophthalmopathy in 2020, with patients who received teprotumumab having shown a better response (over placebo) with regard to reduction in clinical activity score and the severity of proptosis; teprotumumab (10 mg/kg initial dose, then 20 mg/kg) is given intravenously every 3 weeks. ^[77]
Rituximab - An anti-CD20 monoclonal antibody, rituximab may transiently deplete B lymphocytes and may suppress the active inflammatory phase of Graves ophthalmopathy; ^[78] however, clinical data concerning rituximab are still conflicting and controversial; ^{[79, 80]} a prospective, multicentered pilot study suggested that periocular injection of triamcinolone may reduce diplopia and the size of extraocular muscles in patients with Graves ophthalmopathy of recent onset; ^[81]
Pentoxifylline - In a prospective, randomized trial, pentoxifylline, a hemorrheologic agent, improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy ^[82]
Tocilizumab - A monoclonal antibody against IL-6, tocilizumab can be used as a second-line therapy in the setting of glucocorticoid resistance

Sight-threatening Graves ophthalmopathy with optic nerve compression is treated immediately with pulse dosing of high-dose methylprednisolone (typically 0.5-1 g IV daily for 3 consecutive days). If there is no response within 2 weeks or the response is poor, urgent surgical orbital decompression is indicated. Severe corneal exposure requires urgent medical or surgical management to avoid corneal breakdown.^[73]

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

Infliximab, an anti–tumor necrosis factor alpha (anti-TNF-α) antibody, has reportedly been used to successfully treat a case of sight-threatening Graves ophthalmopathy.^[83]

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.

Inpatient Care

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.

Surgical Care

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^[84]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. In certain Asian health-care systems, thyroidectomy may play a larger role as a first-line treatment for Graves disease.^[85]
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.^[86]
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.^[87]

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.^{[88, 89]} These antithyroid drugs are used 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.^{[90, 91, 92]}
Preparation can also be accomplished using therapeutic plasma exchange, which can quickly and effectively reduce serum thyroid hormones and TSIs; the technique is especially useful for patients who are intolerant of antithyroid drugs.^[93]
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.

A literature review by Zhang et al comparing endoscopic with conventional open thyroidectomy for Graves disease reported that the endoscopic technique offers better cosmetic satisfaction and less blood loss, while open surgery is associated with reduced operation time. Complication rates for the two techniques with regard to transient recurrent laryngeal nerve palsy, recurrent hyperthyroidism, hypothyroidism, and transient hypocalcemia were equivalent.^[94]

Graves ophthalmopathy

Near-total thyroidectomy has little, if any, effect on the course of ophthalmopathy.

Reducing proptosis and decompressing the optic nerve can be achieved using transantral orbital decompression.

If sight-threatening Graves ophthalmopathy with optic nerve compression does not respond to high-dose IV methylprednisolone therapy within 2 weeks, urgent surgical orbital decompression is needed. Recent eyeball subluxation also requires urgent surgery. Severe corneal exposure may need increasingly invasive surgical procedures to avoid corneal breakdown, which would then become a surgical emergency. Non-urgent surgical management is generally performed in the fibrotic phase, when the patient is euthyroid.

A study by Liao and Huang indicated that decompression by resecting orbital fat can decrease proptosis in patients with disfiguring Graves ophthalmopathy.^[95]Rehabilitative surgery, including eyelid surgery (eg, severance of the Müller muscle, scleral or palatal graft insertion) and extraocular muscle surgery, are indicated for inactive residual manifestations of Graves ophthalmopathy or to improve exposure keratitis.

A study by Alsuhaibani et al found that in patients with Graves ophthalmopathy who undergo orbital bony wall decompression, volume change in the medial rectus muscle may help to explain the variability in proptosis reduction.^[96]

The major adverse effect of orbital decompression is postoperative diplopia, which may necessitate a second surgery, on the extraocular muscles, to correct the problem.

Consultations

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.

Diet

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 of ¹³¹I and technetium-99m (^99mTc) . Iodine-rich food decreases ¹³¹I uptake but increases ^99mTc in most patients. However, the diagnostic value of a radioiodine uptake test to differentiate Graves disease from silent thyroiditis is not affected by dietary iodine intake.^[97]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.^[98]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.^[99]

Dietary/nutritional selenium supplementation is generally believed to be beneficial for mild Graves ophthalmopathy, although the real effectiveness of selenium remains controversial.^[100]

Activity

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.

Complications

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

Prevention is difficult because of the lack of knowledge regarding the pathogenesis of this condition.

Long-Term Monitoring

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 TSH 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.

Guidelines

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Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.
Graves disease. Varying degrees of manifestations of Graves ophthalmopathy.

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Author

Sai-Ching Jim Yeung, MD, PhD, FACP Professor of Medicine, Department of Emergency Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center

Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, Endocrine Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Celgene, Inc.<br/>Received research grant from: DepoMed and Bristol-Myer-Squibb.

Coauthor(s)

Mouhammed Amir Habra, MD Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center

Mouhammed Amir Habra, MD is a member of the following medical societies: American College of Physicians, American Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.

Alice Cua Chiu, MD Associate Affiliate, Department of Internal Medicine, Division of Endocrinology, Bayshore Medical Center

Alice Cua Chiu, MD is a member of the following medical societies: American Medical Association, Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Kent Wehmeier, MD Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine

Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American College of Physicians, American Geriatrics Society, Endocrine Society, Gerontological Society of America, Association of Professors of Medicine

Disclosure: Nothing to disclose.