May 25th, 2013 by AllisonDellinger

Methimazole and Graves' Disease

I discovered last year that I have Graves' Disease, an autoimmune disease that causes overproduction of thyroid hormone. It was pretty frightening to have something I honestly hadn't paid a lot of attention to in class come to life, making my heart race and making exertion difficult. I also hadn't noticed the slow building of anxiety because I'd just started APPEs. Once I started on methimazole, my symptoms resolved pretty quickly. My heart slowed down, my anxiety drifted away, and my weight rose. (Eep!) Having recently gotten news that my thyroid panel is low-normal instead of being crazy-high, I have had Graves' on the brain. Thus my article selection for this week.

This small Japanese study recognizes that American starting doses of methimazole are lower than Japanese starting doses, and so wanted to look at the effect of higher starting doses on Graves' Disease outcomes and adverse effects. (1)

  • Background

The thyroid gland is stimulated by thyroid-stimulating hormone (TSH), released by the pituitary, to combine iodine with tyrosine and form T3 and T4. (2) These hormones regulate body temperature, heart rate, metabolism, breathing, anxiety and emotion, among many other functions. In Graves' Disease, the body begins producing thyroid-stimulating immunoglobulin, that attacks TSH receptors and forces the thyroid to overproduce thyroid hormones. This can cause symptoms such as racing heart, weight loss, diarrhea, anxiety, and in some cases rash and bulging eyes. (3)

Methimazole (MMI) blocks the oxidation of iodine in the thyroid gland. This prevents the formation of new thyroid hormone, though it doesn't affect circulating thyroid hormone. (2) Another drug with a similar mechanism of action, propylthiouracil, is not recommended for use in pediatric patients due to potential adverse effects of liver failure and vasculitis, making methimazole the drug-of-choice. (1)

Why This Study?

The recommended pediatric starting dose in children in America is 0.2-0.5mg/kg/day, with a 50% reduction for a maintenance dose; however, Japanese guidelines recommend 0.5-1mg/kg/day as a starting dose. The authors wanted to see if there what risks and benefits existed with this higher starting dose.

This retrospective study examined data gathered in a previous study comparing methimazole with propylthiouracil. The previous study had divided children into two groups based on their starting dose of MMI with no significant differences between them. This study further divides those doses into low, moderately high and very high to see if a difference can be distinguished.

Funding

Not reported.

  • Design and Methods

Objectives

Efficacy: incidence of and time to normalization of serum free T4 level on initial treatment; remission defined as normalization 1 year post-MMI use.

Safety: Incidence of any adverse reaction for one year after starting MMI, including liver dysfunction (defined as ASH or ALT >60 IU/L;) reduction or change of MMI after adverse reaction and subsequent course; outcomes after three years.

Design

  • 9 facilities in Japan where children & adolescents were treated by pediatric endocrinologists with 5 years clinical experience.
  • Retrospective analysis of patients who met inclusion criteria for safety and efficacy data.
  • Patients divided into three groups: Group A, treated with low daily doses (infants; 1.25mg; 1-5 years old; 2.5-5mg; 5-10 years: 5-10mg; 10-18 years: 10-20mg); Group B, daily doses within 100% higher than above, or 30mg or lower; and Group C, daily doses greater than 100% higher than above or over 30mg.
  • MMI continued for at least 2 years, withdrawn when thyrotropin binding inhibitory immunoglobulin (TBII) negative for 1 year. Relapse checked afterward 2-3 times per year for up to 3 years, and 1-2 times per year afterward.

Inclusion Criteria

  • GD diagnosed according to Japanese Thyroid Association Guildines: At least one of the clinical findings and all four laboratory findings. Clinical Findings 1) Signs of thyrotoxicosis such as tachycardia, weight loss, finger tremor, and sweating. 2) Diffuse enlargement of the thyroid gland. 3) Exopthalmos and/or specific ophthalmopathy. Laboratory Findings 1) Elevation in free T4 or T3. 2) TSH < 0.1 microunit/mL. 3) Positive anti-TSH receptor antibody or thyroid stimulating antibody. 4) Elevated radioactive iodine uptake to thyroid gland.
  • Antithyroid drugs (ATD; MMI, PTU or carbimazole, an MMI prodrug) used as initial treatment.
  • < 16 years of age
  • GD diagnosed between 1983 and 2006.

Exclusion Criteria

  • Inappropriately retained clinical records.
  • Patient switched from MMI to PTU.

Assessment and Monitoring

  • Recorded time to normalization of serum free T4 on initial treatment
  • Incidence of adverse effects for one year post-start of MMI
  • Outcomes over three years post-start of MMI;

Statistics

  • One-way ANOVA to evaluate variance between groups
  • G-test, which is similar to a chi-squared test

  • Results

Enrollment

  • 64 children and adolescents (55 girls, 9 boys)

Baseline Characteristics

  • Group A: 10 female, 1 male; Free T4 (ng/dL) 4.6, ±2.6; Free T3 (pg/mL) 13.5, ±6.5; TBII, (normal <10-15%) 42.3%, ± 32.4
  • Group B: 31 female, 6 male; Free T4 (ng/dL) 6.1, ±2.0; Free T3 (pg/mL) 19.1, ± 6.3; TBII 53.6%, ± 27.0
  • Group C: 14 female, 2 male; Free T4 (ng/dL) 5.9, ±1.7; Free T3 (pg/mL) 20.3, ± 7.6; TBII 53.0%, ±24.9.

Outcomes

  • Time to normalization of T4 after start of MMI: Group A: 1.9 ± 1.5 months; Group B: 1.6 ± 0.9 months; Group C: 1.9 ± 1.5 months. No significant difference between groups.
  • Adverse effects and changes to PTU: No major adverse events such as agranulocytosis, severe liver failure, or vasculitis occurred. Minor adverse events: Group A: 9.1%; Group B: 13.5%; Group C: 62.5% The difference in group C was significant (P < 0.001.) MMI changed to PTU in 0 patients in Group A, 4 in Group B and 2 in Group C.
  • Remission rates after 3 years: Group A: 42.8%, Group B: 20.8%, Group C: 25% with no significant differences between groups.

Author's Conclusions

  • Lower doses of MMI are suitable for mild GD in children.
  • Moderately high doses are suitable for moderate to severe GD in children.
  • Extremely high doses are harmful in children and should not be used.

Strengths and Weaknesses

Strengths

  • Based on real prescribing practices of expert pediatric endocrinologists
  • Long follow-up

Weaknesses

  • No power calculation
  • Unbalanced groups by # subjects, gender, severity of GD
  • No significance given for baseline differences between groups
  • Small study
  • No examination of adherence

Practice Conclusions

It may seem rather self-evident that using doses higher than generally given to adults in children will result in their having more side effects and is a bad idea, but about a third of the patients in this study, those with the most severe GD, did receive such high doses. There was little difference in efficacy, but this is also a very small study. A properly powered study to examine doses of MMI is needed; meanwhile, I think my practical approach would be to start in the low-to-moderate range, depending on the severity of the child's GD, and increase as needed.

  • References

1) Sato H, et al. Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents. Journal of Pediatric Endocrinology and Metabolism, 2012; 25(9-10): 863-867.

2) Methimazole. Lexi-Comp OnlineTM , Lexi-Drugs OnlineTM , Hudson, Ohio: Lexi-Comp, Inc.; May 26, 2013.

3) The Graves' Disease and Thyroid Foundation. About Graves' Disease. Accessed online at http://gdatf.org/about/about-graves-disease/ on May 25, 2013.

4) Guidelines. Japan Thyroid Association. Accessed online at http://www.japanthyroid.jp/en/guidelines.html on May 25, 2013.

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