[E] If antithyroid drugs are chosen as initial management of GD, how should the therapy be managed?

ATDs have been employed for six decades (81). The goal of the therapy is to render the patient euthyroid as quickly and safely as possible. These medications do not cure Graves’ hyperthyroidism. However, when given in adequate doses, they are very effective in controlling the hyperthyroidism; when they fail to achieve euthyroidism, the usual cause is nonadherence (82). The treatment might have a beneficial immunosuppressive role, but the major effect is to reduce the production of thyroid hormones and maintain a euthyroid state while awaiting a spontaneous remission.

[E1] Initiation of antithyroid drug therapy for the treatment of GD

    Methimazole should be used in virtually every patient who chooses antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery. 1/++0
    Patients should be informed of side effects of antithyroid drugs and the necessity of informing the physician promptly if they should develop pruritic rash, jaundice, acolic stools or dark urine, arthralgias, abdominal pain, nausea, fatigue, fever, or pharyngitis. Before starting antithyroid drugs and at each subsequent visit, the patient should be alerted to stop the medication immediately and call their physician when there are symptoms suggestive of agranulocytosis or hepatic injury. 1/+00
    Prior to initiating antithyroid drug therapy for GD, we suggest that patients have a baseline complete blood count, including white count with differential, and a liver profile including bilirubin and transaminases. 2/+00

In the United States, MMI and PTU are available, and in some countries, carbimazole, a precursor of MMI, is widely used. MMI and carbimazole, which is rapidly converted to MMI in the serum (10mg of carbimazole is metabolized to approximately 6mg of MMI), work in a virtually identical fashion and will both be referred to as MMI in this text. Both are effective as a single daily dose. At the start of MMI therapy, higher doses are advised (10–20mg daily) to restore euthyroidism, following which the dose can be titrated to a maintenance level (generally 5–10mg daily) (81,83). MMI has the benefit of once-a-day administration and a reduced risk of major side effects compared to PTU. PTU has a shorter duration of action and is usually administered two or three times daily, starting with 50–150mg three times daily, depending on the severity of the hyperthyroidism. As the clinical findings and thyroid function tests return to normal, reduction to a maintenance PTU dose of 50mg two or three times daily is usually possible. Higher doses of antithyroid medication are sometimes administered continuously and combined with L-thyroxine in doses to maintain euthyroid levels (so-called block and replace therapy). However, this approach is not generally recommended, as it has been shown to result in a higher rate of ATD side effects (81,84).

PTU may rarely cause agranulocytosis, whereas low doses of MMI may be less likely to do so (85,86). PTU very infrequently causes antineutrophil cytoplasmic antibody (ANCA)- positive small vessel vasculitis (87,88), with a risk that appears to increase with time as opposed to other adverse effects seen with ATDs that typically occur early in the course of treatment (89,90). PTU can cause fulminant hepatic necrosis that may be fatal; liver transplantation has been necessary in some patients taking PTU (91). It is for this reason that the FDA recently issued a safety alert regarding the use of PTU, noting that 32 (22 adult and 10 pediatric) cases of serious liver injury have been associated with PTU use (92,93).

MMI hepatotoxicity is typically cholestatic, but hepatocellular disease may rarely be seen (94,95). Aplasia cutis of the scalp is rarely found in babies born to mothers taking MMI (96). MMI taken by themother in the first trimester is also associated with a syndrome of MMI embryopathy, including choanal and esophageal atresia (97,98). Arthropathy and a lupus-like syndrome rarely can occur with either MMI or PTU.

Technical remarks: Baseline blood tests to aid in the interpretation of future laboratory values should be considered before initiating antithyroid drug therapy. This is suggested in part because low white cell counts are common in patients with autoimmune diseases and in African Americans, and abnormal liver enzymes are frequently seen in patients with thyrotoxicosis. In addition, a baseline absolute neutrophil count <500/mm3 or liver transaminase enzyme levels elevated more than fivefold the upper limit of normal are contraindications to initiating antithyroid drug therapy. It is advisable to provide information concerning side effects of ATDs to the patient both verbally and in writing to assure their comprehension, and document that this has been done. This information can be found on the UpToDate Web site (99).

[E2] Monitoring of patients taking antithyroid drugs

There is a need for periodic clinical and biochemical evaluation of thyroid status in patients taking ATDs, and it is essential that the patient understand its importance. An assessment of serum free T4 should be obtained about 4 weeks after initiation of therapy, and the dose of medication adjusted accordingly. Serum T3 also may be monitored, since the estimated serum free T4 levels may normalize with persistent elevation of serum T3. Appropriate monitoring intervals are every 4–8 weeks until euthyroid levels are achieved with the minimal dose of medication. Once the patient is euthyroid, biochemical testing and clinical evaluation can be undertaken at intervals of 2–3 months. An assessment of serum free T4 and TSH are required before treatment and at intervals after starting the treatment. Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter to monitor therapy early in the course.

    A differential white blood cell count should be obtained during febrile illness and at the onset of pharyngitis in all patients taking antithyroid medication. Routine monitoring of white blood counts is not recommended. 1/+00

There is no consensus concerning the utility of periodic monitoring of white blood cell counts and liver function tests in predicting early onset of adverse reaction to the medication (100). While routine monitoring of white blood cell counts may detect early agranulocytosis, this practice is not likely to identify cases, as the frequency is quite low (0.2%–0.5%) and the condition sudden in onset. Because patients are typically symptomatic, measuring white blood cell counts during febrile illnesses and at the onset of pharyngitis has been the standard approach to monitoring. In a patient developing agranulocytosis or other serious side effects while taking either MMI or PTU, use of the other medication is absolutely contraindicated owing to risk of cross-reactivity between the two medications (101).

    Liver function and hepatocellular integrity should be assessed in patients taking propylthiouracil who experience pruritic rash, jaundice, light-colored stool or dark urine, joint pain, abdominal pain or bloating, anorexia, nausea, or fatigue. 1/+00

Hyperthyroidism can itself cause mildly abnormal liver function tests, and PTU may cause transient elevations of serum transaminases in up to one-third of patients. Significant elevations to threefold above the upper limit of normal are seen in up to 4% of patients taking PTU (102), a prevalence higher than with MMI. As noted above, PTU can also cause fatal hepatic necrosis, leading to the suggestion by some that patients taking this ATD have routine monitoring of their liver function, especially during the first 6 months of therapy.

It is difficult to distinguish these abnormalities from the effect of persistent thyrotoxicosis unless they are followed prospectively. In patients with improving thyrotoxicosis, a rising alkaline phosphatase with normalization of other liver function does not indicate worsening hepatic toxicity. The onset of PTU-induced hepatotoxicity may be acute, difficult to appreciate clinically, and rapidly progressive. If not recognized, it can lead to liver failure and death (92,103–105). Routine monitoring of liver function in all patients taking antithyroid medication has not been found to prevent severe hepatotoxicity.

Technical remarks: PTU should be discontinued if transaminase levels (either elevated at onset of therapy, found incidentally or measured as clinically indicated) reach 2–3 times the upper limit of normal and fail to improve within 1 week with repeat testing. After discontinuing the drug, liver function tests should be monitored weekly until there is evidence of resolution. If resolution is not evident, prompt referral to a gastroenterologist or hepatologist is warranted. Except in cases of severe PTU-induced hepatotoxicity, MMI can be used to control the thyrotoxicosis without ill effect (106,107).

[E3] Management of allergic reactions

Minor cutaneous reactions may be managed with concurrent antihistamine therapy without stopping the antithyroid drug. Persistent minor side effects of antithyroid medication should be managed by cessation of the medication and changing to radioactive iodine or surgery, or switching to the other antithyroid drug when radioactive iodine or surgery are not options. In the case of a serious allergic reaction, prescribing the alternative drug is not recommended. 1/+00

Minor allergic side effects, such as a limited,minor rash,may occur in up to 5% of patients taking either MMI or PTU (81).

[E4] Duration of antithyroid drug therapy for GD

    If methimazole is chosen as the primary therapy for GD, the medication should be continued for approximately 12–18 months, then tapered or discontinued if the TSH is normal at that time. 1/+++
    Measurement of TRAb levels prior to stopping antithyroid drug therapy is suggested, as it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission. 2/+00
    If a patient with GD becomes hyperthyroid after completing a course of methimazole, consideration should be given to treatment with radioactive iodine or thyroidectomy. Low-dose methimazole treatment for longer than 12–18 months may be considered in patients not in remission who prefer this approach. 2/+00

A patient is considered to be in remission if they have had a normal serum TSH, FT4, and T3 for 1 year after discontinuation of ATD therapy. The remission rate varies considerably between geographical areas. In the United States, about 20%–30% of patients will have a lasting remission after 12–18 months of medication (44). The remission rate appears to be higher in Europe and Japan; a long-term European study indicated a 50%–60% remission rate after 5–6 years of treatment (108). A meta-analysis shows the remission rate in adults is not improved by a course of ATDs longer than 18 months (84). A lower remission rate has been described in men, smokers (especially men), and those with large goiters (≥ 80 g) (109–113). Persistently high levels of TRAb and high thyroid blood flow identified by color Doppler ultrasound are also associated with higher relapse rates (112,114–116), and these patients should be assessed more frequently and at shorter intervals after antithyroid drugs are discontinued. Conversely, patients with mild disease, small goiters, and negative TRAb have a remission rate over 50%, making the use of antithyroid medications potentially more favorable in this group of patients (117).

Technical remarks: When MMI is discontinued, thyroid function testing should continue to be monitored at 1–3- month intervals for 6–12 months to diagnose relapse early. The patient should be counseled to contact the treating physician if symptoms of hyperthyroidism are recognized.