ATDs act by inhibiting oxidation and organic binding of thyroid iodide to impair thyroid hormone production[
9]. MMI is ten- to twenty-fold more potent than PTU and has a longer half-life[
9]. Importantly, these medications do not cure the hyperthyroid state, rather they palliate the condition. Each of these medications is associated with adverse events that must be considered when prescribed. As such, prior to the initiation of ATD therapy, a back-up plan that takes into account the patient’s age and treatment risks, in the event that a toxic reaction occurs, should be considered.
Propylthiouracil hepatotoxicity
In 2008, a number of serious complications associated with PTU therapy in children were brought to public attention by Rivkees[
10‐
12]. PTU-induced liver injury at that time accounted for 15% of liver transplants in the United States[
13]. From 1990 to 2007, 23 PTU-related liver transplants took place, and 30% of the PTU-related transplant recipients were children. Based on prescribing data, the risk of PTU-induced liver failure leading to transplantation was estimated to be 1 in 2,000 children[
2].
Despite a common perception, because PTU-induced liver injury occurs rapidly and is often irreversible, serial monitoring of transaminase levels in a child on PTU, is not viewed to be useful in helping to reduce drug hepatotoxicity risk[
2]. As such, the only way to reduce the risks of PTU-related hepatotoxicity is to avoid the use of the medication.
In 2009, Rivkees and Madison recommended that PTU not be used in children, and that PTU be stopped in all children taking the medication in favor of alternative treatments[
11]. In April, 2010, the US Food and Drug Administration issued a black box regarding the use of PTU stating that PTU should not be used in children[
10], except in special settings, solidifying the notion that the drug should not be used.
Appropriate limited use of propylthiouracil
Although PTU should be avoided clinically, there is a role for its limited use in special circumstances. PTU can be used when neither prompt 131I or surgical treatment are options in a patient who has had a toxic reaction to MMI, and ATD medication is necessary. In this situation, PTU should only be used short-term while plans for 131I or surgery are developed.
When PTU is used, patients and guardians need to be informed of the risk of liver failure and to be alert for signs and symptoms of liver abnormalities. These features include pruritus, jaundice, anorexia, light colored stools, dark urine, and abdominal pain. If these problems occur, the patient should immediately stop the medication, a practitioner contacted, and laboratory tests obtained (white blood cell count, bilirubin, alkaline phosphatase, ALT/AST).
Methimazole
MMI is now the drug-of-choice for GD. Carbimazole, which is a pro-drug that is converted to MMI, can be used in place of MMI in countries where it is available. Although MMI is often prescribed in divided doses over the day, once a day dosing is sufficient[
14] and is associated with better compliance than multiple daily doses[
15]. The typical MMI dose is 0.2 to 0.5 mg/kg per day, and doses can range from 0.1 to 1.0 mg/kg per day[
3,
16‐
20].
MMI is available in 5, 10, and 20 mg tablets. When used in children, the following doses that are fractions of tablets can be used: infants, 1.25 mg per day; 1 to 5 years, 2.5 to 5.0 mg/day; 5 to 10 years, 5 to10 mg/day; and 10 to 18 years, 10 to 20 mg/day. When there is severe hyperthyroidism, one can use double the above doses. Because the hyperthyroid state can be associated with low white cell counts and patients will be treated with a medication that can depress neutrophil levels, it is reasonable to obtain a complete blood count at therapy onset. In addition, we routinely obtain transaminase levels and liver function tests at therapy onset, to assess for premorbid liver disease, as we find that 1% of our patients may have autoimmune hepatitis.
The response to ATDs influencing circulating thyroid hormone levels is not instantaneous, and several months are needed for thyroid hormone levels to normalize[
7,
14]. Thyroid function tests should thus be obtained monthly after therapy onset. After T4 levels become normal, the MMI doses can be cut by half to maintain euthyroidism[
21]. Because TSH levels may take months to normalize, they should not be used to guide changes in medication in early phases of treatment.
Rather than titrating the MMI dose lower when circulating thyroid hormone levels fall, some physicians prefer the block-and-replace approach and add levo-thyroxine while not changing the MMI dose, however, there is a greater risk of adverse events using block and replace vs. dose reduction[
21,
22]. Recognizing that there is a potential dose–response relationship for some MMI-related complications[
23,
24], it is preferable to use the lowest MMI dose that achieves control, rather than using the block and replace approach.
Although MMI is the drug of choice for GD, MMI therapy is not without risks. Minor side effects may affect up to 17% of children[
25]. The most common minor adverse side effects related to MMI are hives, arthralgia, and neutropenia[
25]. Children may also develop major side effects, including Stevens-Johnson syndrome and vasculitis[
25]. MMI adverse events most commonly occur within 6 months of therapy onset[
25]. Yet, 4% of children will develop adverse events 18 months of MMI therapy, highlighting the need for constant vigilance while on treatment.
Agranulocytosis is another potential serious ATD adverse event and occurs in 0.3% of adults taking PTU or MMI[
7,
26]. With MMI, agranulocytosis is dose-dependent and is rare at low doses[
7,
26]. If an individual receiving MMI feels ill, becomes febrile or develops pharyngitis, MMI should be stopped immediately, a practitioner contacted, and a complete blood cell count obtained.
Agranulocytosis typically develops first 3 months of therapy[
7,
26]. Thus, whereas it is tempting to treat with high-doses of ATD therapy at onset, this approach should be avoided. Rather, relatively lower doses of MMI should be employed initially, and symptoms managed with beta-blockers. Furthermore, the time to normalization of thyroid function tests is only modestly different in individuals treated with high vs. low ATD doses[
14].
Although ATDs can be used long-term, reports describe the development of anti-neutrophil-cytoplasmic antibodies (ANCAs), which are associated with vasculitis and may limit prolonged medical therapy of GD[
27‐
29]. In adults up to 15% of individuals treated with PTU, develop ANCAs after 2 years of therapy[
27,
28]. MMI use is also associated with ANCA-positivity conversion, albeit with a lower incidence than with PTU[
27,
28].
In the pediatric population, ANCA-mediated disease has been observed with either PTU or MMI[
30,
31] . Because these antibodies can trigger serious vasculitis events, antithyroid medications should be stopped and definitive therapy considered when ANCA antibodies are detected[
32]. To test for this potential problem it is reasonable to perform annual assessment of ANCAs on children on prolonged ATD therapy, i.e. more than two years.
Duration of therapy
Remission of GD is defined as being biochemically euthyroid or hypothyroid for one year or more after the discontinuation of ATDs. The collective literature indicates that remission rates in children are less than 25% following many years of ATD therapy[
33‐
37] (Table
1).
Table 1
Studies of rates of remission related to antithyroid drug use
Hamburger | 1985 | 262 | 14% | |
Glaser | 1997 | 184 | 24% | |
Glaser | 2008 | 58 | 29% | |
Kaguelidou | 2008 | 154 | 28% | |
Leger | 2012 | 154 | 48% | |
Although prolonged ATD treatment will control biochemical hyperthyroidism, it is not clear that prolonged ATD use increases the likelihood of lasting spontaneous remission[
38]. In a French study of 94 patients, following treatment for 6 or 18 months, remission rates were 42%and 62% respectively, after two years of treatment[
39]. In 52 Spanish patients, following treatment for 12 or 24 months, remission rates were 46% and 54%, respectively, 2 years after cessation of therapy[
40]; at 5-years, the relapse rate was 85%. Another study of 134 French patients found no benefit of 18 vs. 43 months of treatment[
41]. Thus treating beyond 18 months does not increase remission likelihood in adults.
In the pediatric age group, remission rates range from 20 to 30% following ATDs use for two years or more[
18,
35,
36,
42,
43]. More than 25 years ago, Lippe and coworkers estimated that 25% of children go into remission for every two years of treatment[
44]. Of the 63 patients followed on ATDs, 36 (57%) remitted after an average of four years of therapy[
44]. Yet, there were little data to show if the patients who came off ATDs remained in remission[
44].
Other large cohort studies of ATD use for many years[
33,
34] show low remission rates. Of more than 200 children with GD in Minnesota, 25% were in remission after one year; 25% after 2 years; 26% after 4 years; and 15% after 10 years. In addition, 30% of the boys and girls who went into remission had disease recurrence[
33].
When 184 pediatric children in California were followed for up to 4 years, the overall remission rate was 23%[
34]. After one year of ATDs, 10% were in remission; after 2 years, 14% were in remission; after 3 years, 20%) were in remission; and after 4 years, 23% were in remission.
In a study of children in Argentina, 113 patients received ATDs for prolonged periods[
45]. After 10 years of treatment, 33% of patients treated with ATDs went into remission[
45].
Most recently, a study performed in France reported that prolonged drug therapy was associated with 50% remission rates in children[
37]. One-hundred fifty-four children with GD diagnosed between 1997 and 2002 were examined following treatment with carbimazole. The estimated rates of remission were 20%, 37%, 45%, and 49%, after 4, 6, 8, and 10 years of therapy, respectively[
37].
Age-related factors also influence remission likelihood. In a study of 32 prepubertal vs. 68 pubertal children with GD, remission occurred in 17% of prepubertal children treated for 6 years vs. 30% of pubertal children[
42]. In another report with pre- and post-pubertal cohorts, remission occurred in 28% of children[
46], but the time to remission was three-times longer in the pre-pubertal children than pubertal children[
46]. Of note, adverse reactions to ATDs occurred with greater frequency in prepubertal children (71%) than in pubertal (28%) and postpubertal (25%) children[
46].
In addition to puberty, TRAb levels and gland size influence remission rates. The efficacy of ATDs is inversely related to circulating levels of TRAbs. Remission rates of GD in adults are about 15% in patients high TRAb levels at diagnosis, and 50% when the pretreatment levels are normal[
47]. Large glands at presentation are also associated with much lower remission rates than when gland size is normal[
48‐
50].