Diffuse Toxic Goiter (Graves Disease) Treatment & Management

Although the natural history of diffuse toxic goiter is to possibly spontaneously remit (and perhaps later relapse), or even progress into hypothyroidism, observation without intervention, even in minimally symptomatic patients, is not recommended. The risk of bone loss and atrial fibrillation occur, especially in older women and men, even in subclinical cases.

The goals of therapy are to resolve hyperthyroid symptoms and to restore the euthyroid state. The long-term quality of life following treatment is the same in patients randomly allocated to each of the three treatment options (antithyroid drugs [ATDs], radioactive iodine ablation, surgery). ^[12]  Each therapeutic choice has advantages and disadvantages, therefore treatment should be individualized. Patient input into the treatment choice is important and must be discussed and considered. 

Adjunctive symptomatic therapy, such as the use of beta blockers, may help alleviate adrenergic symptoms. Nonsurgical therapy occurs in the outpatient setting. Surgical therapy requires first normalization of the hyperthyroid state by medication.

Regardless of the therapy used, long-term follow-up is needed to monitor thyroid status, especially with a high risk of becoming hypothyroid in the near and distant future or a relapse into hyperthyroidism.

Ophthalmopathy runs its own course, independent of the thyroid course. Although generally benign, ophthalmopathy may become symptomatic years after the thyroid status has been rendered normal. 

Hospitalization is rarely necessary for diffuse toxic goiter. Severe disease with cardiac or other organ compensation, or thyroid storm may require more intense and controlled therapy. Complications, such as agranulocytosis, may need specialized hospital care.

Diet and activity

Diet must include caloric intake to meet the energy expenditure of the hypermetabolism. High iodine-containing substances, such as kelp, should be avoided.

Physical activity is limited by the presence of symptoms, until recovery occurs. Usually, shortness of breath on exertion, fatigue, and palpitations are the limiting symptoms.

Consultations

Oculopathy usually requires ophthalmologic consultation, and dermopathy may require dermatologic consultation.

Radioactive iodine ablation

The most commonly used therapy for Graves disease is radioactive iodine. ^[1] Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of thyroid-stimulating immunoglobulin (TSI). 

Oral administration of 131-iodine (I-131) is incorporated into the thyroid follicular cells, and the beta emission results in cell destruction and glandular fibrosis. The effect is seen in 1.5 to 4 months. Off medications, the thyroid hormone levels become normal (requiring continued monitoring), fall below normal (requiring thyroid hormone replacement therapy, likely for life), or remain elevated (requiring another administration of radioiodine). In those becoming euthyroid, there is a 5% chance every year of becoming hypothyroid due to ongoing disease in the gland; occasionally, hyperthyroidism may reoccur. The usual I-131 dose is 6-8 mCi. The dose is adjusted based on the size of the thyroid gland, age of the patient, and severity of the clinical picture. Resistance is increased by age older than 40 years, large goiters, prior therapy with propylthiouracil (PTU), and nodularity (not seen with diffuse toxic goiter). Previous reviews confirmed the safety of the use of radioiodine. ^[13]

Radioiodine therapy is not used in clinically severe hyperthyroidism or thyroid storm until the hyperthyroid state is medically controlled. Because of transplacental transfer and lactation transfer, it is contraindicated in women who are pregnant or breastfeeding. For the theoretical ovarian exposure, conception in treated women is empirically discouraged for 3-6 months.

Radioiodine may be administered to children, if clinically indicated. Long-term safety data in children are not available.

Worsening of the hyperthyroid state may occur after radioiodine therapy due to the release of prestored hormone. Gland tenderness and swelling is uncommon and may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (not aspirin); they rarely require steroid administration.

Radioiodine administration has been associated with worsening or progression of symptomatic ophthalmopathy. Either radioiodine is avoided in very symptomatic individuals, or corticosteroids (prednisone 0.5 mg/kg) are used beginning the day after the radioiodine administration for 1-3 months, or they are administered if any worsening of the ophthalmopathy occurs after radioiodine administration. Cessation of smoking and avoidance of hypothyroidism also help the course of ophthalmopathy.

The return to the euthyroid state, regardless of therapy, is best monitored by serum free thyroxin, or its equivalent, because the pituitary is suppressed and thyroid-stimulating hormone (TSH) secretion may remain low for some time after a normal or hypothyroid state occurs. Relapse from a euthyroid state to hyperthyroidism is first monitored by new suppression of the serum TSH, and often the serum triiodothyronine (T3) then increases above normal before the serum thyroxine (T4) rises above normal.

Antithyroid drugs (ATDs)

The thionamide drugs PTU and methimazole (MMI) inhibit hormonogenesis within the thyroid gland. PTU has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown added clinical significance. Other than in pregnancy and breastfeeding, MMI has advantages over PTU by a longer half-life with once-a-day dosing, and possibly a more rapid return to the euthyroid state. Although rare, agranulocytosis, lupuslike vasculitis, and hepatitis are more commonly associated with PTU than with MMMI. Agranulocytosis occurs in less than 0.1% of cases but is unpredictable; it may occur at any time. Routine monitoring of the white blood cell (WBC) count is not useful. Should any infection occur, such as a sore throat, the WBC count should then be measured. Discontinuation of the drug results in a rise of WBC within a few days.

Hyperthyroidism itself can result in abnormal liver function tests, thus measure a baseline before initiating medication. A rise to three times above normal dictates discontinuation of the drug.

Minor skin itch or rash may be managed by an antihistamine, without discontinuation of the drug. More marked reactions require discontinuation of that drug.

Granulocyte colony-stimulating factor (GCSF) may need to be administered. Skin rash may perhaps be more common with MMI than PTU; the incidence is about 3%, and it usually occurs within the first few weeks of therapy. MMI is the drug of choice. ^[14]

Boxed warning for PTU

As noted above, PTU is indicated for hyperthyroidism due to Graves disease. The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the agency, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as MMI, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred; among the pediatric patients, 1 death and 6 liver transplants occurred. These reports suggest an increased risk for liver toxicity with PTU compared with MMI. Serious liver injury was identified with MMI in five cases (three resulting in death).

FDA criteria for PTU prescription

PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of MMI, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with MMI during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert) ^[15] :

• Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of MMI.

• Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

• For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.

• PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI and no other treatment options are available.

• Counsel patients to promptly contact their healthcare provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Monitor the serum thyroid indices monthly until euthyroid, and then the dose of the drug may be decreased for maintenance. Use the lowest dose needed to maintain the euthyroid state for long-term therapy.

Relapse and remission

Normalization of thyroid function with these drugs must occur for some time, at least 6 months and perhaps for 1-2 years, to maximize the remission rate after drug discontinuation. Despite this, the relapse rate is 50-70%, usually within the first few weeks or months, but occasionally after a few years. Remission is weakly predicted by a short duration of symptoms, age younger than 40 years, minimal enlargement of the thyroid gland, and concomitant presence of Hashimoto thyroiditis.

Relapse after discontinuation of the drug requires a decision regarding radioiodine therapy or surgery for more definitive therapy, or a return to the antithyroid drug. Although general practice is not to use these drugs over the long term, there is no reason why this cannot occur, if that is what the patient chooses.

Pregnancy and breastfeeding

Radioactive iodine is contraindicated during pregnancy and while breastfeeding. ^[16] Pregnancy often has an effect on improving the immunologic disease state during the pregnancy and then often relapses following delivery. PTU is the treatment of choice because it has less placental transfer than MMI. Rare congenital anomalies reported with MMI (eg, aplasia cutis) are even less associated with PTU. Overall, the congenital abnormality rate with these drugs is similar to background normal rate. MMI may be used if a problem exists with PTU.

The goal is to keep the free thyroxine level in the upper part of normal to minimize fetal drug exposure. Monthly monitoring of serum free thyroxine usually allows the dose of PTU to be decreased and often discontinued in the third trimester. Both PTU and MMI may be used in breastfeeding mothers. A small amount of drug does enter the milk, but neonatal thyroid levels generally remain normal. PTU and MMI are not contraindicated in pregnancy or lactation.

See also the 2017 American Thyroid Association guidelines pertaining to the diagnosis and management of thyroid disease in women during pregnancy and the postpartum period, as well as prior to conception. ^[16] Selected recommendations regarding thyrotoxicosis in pregnancy are outlined in this article's Guidelines section Thyrotoxicosis in Pregnancy.

Subtotal thyroidectomy may be considered for diffuse toxic goiter if it is the choice of the patient, during the second trimester of pregnancy, after failure (resistance or intolerance) of drug therapy, or in the setting of poor compliance to drug therapy. The procedure risks are low with experienced surgeons but include anesthetic risks, hemorrhage, hypoparathyroidism, and vocal cord paralysis.

Patients should be made euthyroid prior to surgery to minimize anesthetic risks, cardiovascular/hemodynamic complications, and the risk of thyroid storm. If normalizing with antithyroid drugs is not possible, then beta blockers and potassium iodide 4 drops each day for 10 days will decrease the vascularity of the thyroid gland.

Cessation of smoking has a beneficial effect on the course of ophthalmopathy.

The strong familial nature of diffuse toxic goiter dictates that first-degree relatives, especially siblings and children, be aware of the increased risk of developing this or associated disorders. Routine testing is not recommended, but consideration for this risk is needed with new symptom development.

Associated autoimmune disease in other glands is uncommon but is of increased incidence and may clinically occur at presentation or in the near or distant future. New symptoms dictate consideration for these conditions.