Skip to main content

Advertisement

Log in

Safety of long-term antithyroid drug treatment? A systematic review

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Continued low-dose MMI treatment for longer than 12–18 months may be considered in patients not in remission. However, ATDs are not free from adverse effects. We undertook a systematic review to clarify safety of long-term ATD treatment. Medline and the Cochrane Library for trials published between 1950 and Nov 2018 were systematically searched. We included original studies containing data for long-term (> 18 months) ATD treatment. Two reviewers independently extracted data from included trials and any disagreement was adjudicated by consensus. Of 615 related articles found, 12 fulfilled the criteria. Six articles had data for adults, five for non-adults and one article had data for both groups. The sample sizes ranged between 20 and 249 individuals, and the mean duration of ATD treatment ranged between 2.1 and 14.2 years. Considering all data from 1660 patients treated with ATD for a mean duration of 5.8 years (around 10,000 patient-years), major complications occurred only in 14 patients: 7 severe agranulocytosis, 5 severe liver damage, one ANCA-associated glomerulonephritis and one vasculitis with small cutaneous ulcerations. Minor complications rates were between 2 and 36%, while more complications were in higher doses and in the children. The most reported AE was cutaneous reaction; the other adverse events were elevated liver enzymes, leukocytopenia, arthritis, arthralgia, myalgia, thrombocytopenia, fever, nausea and oral aphthous. Long-term ATD treatment is safe, especially in low dose and in adults, indicating that it should be considered as an earnest alternative treatment for GD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Mazza E et al (2008) Long-term follow-up of patients with hyperthyroidism due to Graves’ disease treated with methimazole. Comparison of usual treatment schedule with drug discontinuation vs continuous treatment with low methimazole doses: a retrospective study. J Endocrinol Invest 31:866–872

    CAS  PubMed  Google Scholar 

  2. Marino M et al (2014) An update on the medical treatment of Graves’ hyperthyroidism. J Endocrinol Invest 37:1041–1048

    CAS  PubMed  Google Scholar 

  3. Rivkees SA, Dinauer C (2007) An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 92:797–800

    CAS  PubMed  Google Scholar 

  4. Lee JA et al (2007) The optimal treatment for pediatric Graves’ disease is surgery. J Clin Endocrinol Metab 92:801–803

    CAS  PubMed  Google Scholar 

  5. Nakamura H et al (2007) Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 92:2157–2162

    CAS  PubMed  Google Scholar 

  6. Rivkees SA, Szarfman A (2010) Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 95:3260–3267

    CAS  PubMed  Google Scholar 

  7. Brito JP et al (2016) Antithyroid drugs-the most common treatment for Graves’ disease in the United States: a nationwide population-based study. Thyroid 26:1144–1145

    PubMed  Google Scholar 

  8. Ross DS et al (2016) American thyroid association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid 26:1343–1421

    PubMed  Google Scholar 

  9. Wartofsky L et al (1991) Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan and the United States. Thyroid 1:129–135

    CAS  PubMed  Google Scholar 

  10. Burch HB et al (2012) A 2011 survey of clinical practice patterns in the management of Graves’ disease. J Clin Endocrinol Metab 97:4549–4558

    CAS  PubMed  Google Scholar 

  11. Vaidya B et al (2008) Radioiodine treatment for benign thyroid disorders: results of a nationwide survey of UK endocrinologists. Clin Endocrinol (Oxf) 68:814–820

    Google Scholar 

  12. Escobar-Jimenez F et al (2000) Trends in diagnostic and therapeutic criteria in Graves’ disease in the last 10 years. Postgrad Med J 76:340–344

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yamashita S et al (2011) The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. Thyroid 21:577–580

    PubMed  Google Scholar 

  14. Moon JH, Yi KH (2013) The diagnosis and management of hyperthyroidism in Korea: consensus report of the Korean thyroid association. Endocrinol Metab (Seoul) 28:275–279

    Google Scholar 

  15. Anagnostis P et al (2013) Predictors of long-term remission in patients with Graves’ disease: a single center experience. Endocrine 44:448–453

    CAS  PubMed  Google Scholar 

  16. Orgiazzi J (2015) Should protracted treatment with antithyroid drug (ATD) be considered as a routine strategy in patients with graves’ disease who had a relapse after a first course of ATD? Clin Thyroidol 27:302–305

    Google Scholar 

  17. Léger J, Carel JC (2017) Management of endocrine disease: arguments for the prolonged use of antithyroid drugs in children with Graves’ disease. Eur J Endocrinol 177:R59–R67

    PubMed  Google Scholar 

  18. Azizi F, Malboosbaf R (2017) Long-term antithyroid drug treatment: a systematic review and meta-analysis. Thyroid 27:1223–1231

    PubMed  Google Scholar 

  19. Liberati A et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 21:339b2700. https://doi.org/10.1371/journal.pmed.1000100

    Article  Google Scholar 

  20. Wells GA (2001) The Newcastle-Ottawa scale (NOS) for assessing the quality of non randomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  21. Egger M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Centre for Reviews and Dissemination (2009) CRD's guidance for undertaking reviews in healthcare. York Publishing Services. www.york.ac.uk

  23. Yasuda K et al (2017) Relationship between dose of antithyroid drugs and adverse events in pediatric patients with Graves’ disease. Clin Pediatr Endocrinol 26:1–7

    PubMed  PubMed Central  Google Scholar 

  24. Azizi F et al (2012) Long-term continuous methimazole or radioiodine treatment for hyperthyroidism. Arch Iran Med 15:477–484

    CAS  PubMed  Google Scholar 

  25. Le´ger J et al (2012) Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves’ disease: national long-term cohort study. J Clin Endocrinol Metab 97:110–119

    Google Scholar 

  26. Laurberg P et al (2011) Sustained control of Graves’ hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe Graves’ orbitopathy. Thyroid 21:951–956

    CAS  PubMed  Google Scholar 

  27. Sato H et al (2011) Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves’ disease: efficacy and adverse reactions during initial treatment and long-term outcome. J Pediatr Endocrinol Metab 24:257–263

    CAS  PubMed  Google Scholar 

  28. Chen DY et al (2009) Comparison of the long-term efficacy of low dose 131I versus antithyroid drugs in the treatment of hyperthyroidism. Nucl Med Commun 30:160–168

    PubMed  Google Scholar 

  29. Kaguelidou F, French Childhood Graves’ Disease Study Group et al (2008) Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 93:3817–3826

    CAS  PubMed  Google Scholar 

  30. Azizi F et al (2005) Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur J Endocrinol 152:695–701

    CAS  PubMed  Google Scholar 

  31. Barrio R et al (2005) Graves’ disease in children and adolescents: response to long-term treatment. Acta Paediatr 94:1583–1589

    PubMed  Google Scholar 

  32. Mashio Y et al (1997) Treatment of hyperthyroidism with a small single daily dose of methimazole: a prospective long-term follow-up study. Endocr J 44:553–558

    CAS  PubMed  Google Scholar 

  33. Rivkees SA et al (2010) Adverse events associated with methimazole therapy of graves’ disease in children. Int J Pediatr Endocrinol 2010:1–4

    Google Scholar 

  34. Watanabe N et al (2012) Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves’ disease. J Clin Endocrinol Metab 97:E49–53

    CAS  PubMed  Google Scholar 

  35. Wartofsky L (1993) Has the use of antithyroid drugs for Graves’ disease become obsolete? Thyroid 3:335–344

    CAS  PubMed  Google Scholar 

  36. Franklyn JA et al (1991) Long-term follow up of treatment of hyperthyroidism by three different methods. Clin Endocrinol 34:71–76

    CAS  Google Scholar 

  37. Astwood EB (1967) Use of antithyroid drugs. In: Irvine WJ (ed) Hyperthyroidism. Williams & Wilkins, Baltimore, pp 85–98

    Google Scholar 

  38. Abraham P et al (2010) Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev 20:CD003420

    Google Scholar 

  39. Masiello E et al (2018) Antithyroid drug treatment for Graves’ disease: baseline predictive models of relapse after treatment for a patient-tailored management. J Endocrinol Invest 41:1425–1432

    CAS  PubMed  Google Scholar 

  40. Laurberg P (2006) Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism? Eur J Endocrinol 155:783–786

    CAS  PubMed  Google Scholar 

  41. Montani V et al (1998) Regulation of major histocompatibility class II gene expression in FRTL-5 thyrocytes: opposite effects of interferon and methimazole. Endocrinology 139:290–302

    CAS  PubMed  Google Scholar 

  42. Mozes E et al (1998) Spontaneous autoimmune disease in (NZB x NZW) F1 mice is ameliorated by treatment with methimazole. J Clin Immunol 18:106–113

    CAS  PubMed  Google Scholar 

  43. Volpe R (1994) Evidence that the immunosuppressive effects of antithyroid drugs are mediated through actions on the thyroid cell, modulating thyrocyte-immunocyte signaling: a review. Thyroid 4:217–223

    CAS  PubMed  Google Scholar 

  44. Calissendorff J et al (2015) A prospective investigation of graves’ disease and selenium: thyroid hormones, auto-antibodies and self-rated symptoms. Eur Thyroid J 2:93–98

    Google Scholar 

  45. Leo M et al (2017) Effects of selenium on short-term control of hyperthyroidism due to Graves’ disease treated with methimazole: results of a randomized clinical trial. J Endocrinol Invest 40:281–287

    CAS  PubMed  Google Scholar 

  46. Marinò M et al (2017) Selenium in the treatment of thyroid diseases. Eur Thyroid J 2:113–114

    Google Scholar 

  47. Rayman MP (2012) Selenium and human health. Lancet 379:1256–1268

    CAS  PubMed  Google Scholar 

  48. Rotondi M et al (2007) Role of chemokines in endocrine autoimmune diseases. Endocr Rev 28:492–520

    CAS  PubMed  Google Scholar 

  49. Slingerland DW, Burrows BA (1979) Long-term antithyroid treatment in hyperthyroidism. JAMA 242:2408–2410

    CAS  PubMed  Google Scholar 

  50. Lippe BM et al (1987) Hyperthyroidism in children treated with Long term medical therapy: twenty-five percent remission every two years. J Clin Endocrinol Metab 64:1241–1245

    CAS  PubMed  Google Scholar 

  51. Elbers L et al (2011) Outcome of very long-term treatment with antithyroid drugs in Graves’ hyperthyroidism associated with Graves’ orbitopathy. Thyroid 21:279–383

    PubMed  Google Scholar 

  52. Villagelin D et al (2015) Outcomes in relapsed graves’ disease patients following radioiodine or prolonged low dose of methimazole treatment. Thyroid 25:1282–1290

    CAS  PubMed  Google Scholar 

  53. Hieu TT et al (2012) Cancer risk after medical exposure to radioactive iodine in benign thyroid diseases: a meta-analysis. Endocr Relat Cancer 19:645–655

    CAS  PubMed  Google Scholar 

  54. Sato H et al (2012) Higher dose of methimazole causes frequent adverse effects in the management of Graves’ disease in children and adolescents. J Pediatr Endocrinol Metab 25:863–867

    CAS  PubMed  Google Scholar 

  55. Sato S et al (2015) Comparison of efficacy and adverse effects between methimazole 15 mg + inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves’ disease patients with moderate to severe hyperthyroidism. Thyroid 25:43–50

    CAS  PubMed  Google Scholar 

  56. Reinwein D et al (1993) A prospective randomized trial of antithyroid drug dose in Graves’ disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab 76:1516–1521

    CAS  PubMed  Google Scholar 

  57. Takata K et al (2009) Methimazole-induced agranulocytosis in patients with Graves’ disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 19:559–563

    CAS  PubMed  Google Scholar 

  58. Romaldim JH et al (1983) Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves’ hyperthyroidism. J Clin Endocrinol Metab 57:563–570

    Google Scholar 

  59. Wilberg JJ, Nuttall FQ (1972) Methimazole toxicity from high doses. Ann Intern Med 77:414–416

    Google Scholar 

  60. Nakamura H et al (2013) Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 98:4776–4783

    CAS  PubMed  Google Scholar 

  61. Wang MT et al (2014) Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study. Br J Clin Pharmacol 78:619–629

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang J et al (2015) Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China. Thyroid 25:278–283

    CAS  PubMed  Google Scholar 

  63. Ohye H et al (2014) Antithyroid drug treatment for Graves ‘disease in children: a long-term retrospective study at a single institution. Thyroid 24:200–207

    CAS  PubMed  Google Scholar 

  64. Minamitani K et al (2011) A report of three girls with antithyroid drug-induced agranulocytosis; retrospective analysis of 18 cases aged 15 years or younger reported between 1995 and 2009. Clin Pediatr Endocrinol 20:39–46

    PubMed  PubMed Central  Google Scholar 

  65. Tamai H et al (1989) Methimazole-induced agranulocytosis in Japanese patients with Graves’ disease. Clin Endocrinol 30:525–530

    CAS  Google Scholar 

  66. He Y et al (2017) Emphasis on the early diagnosis of antithyroid drug-induced agranulocytosis: retrospective analysis over 16 years at one Chinese center. J Endocrinol Invest 40:733–740

    CAS  PubMed  Google Scholar 

  67. Balavoine AS et al (2015) Antineutrophil cytoplasmic antibody-positive small-vessel vasculitis associated with antithyroid drug therapy: how significant is the clinical problem? Thyroid 25:1273–1281

    CAS  PubMed  Google Scholar 

  68. Abhayaratna S, Somasundaram N (2013) The role of long term use of antithyroid drugs in Graves’ disease. Sri Lanka J Diabetes Endocrinol Metabol 3:41–44

    Google Scholar 

  69. Howard JE (1967) Treatment of thyrotoxicosis. JAMA 202:706–709

    CAS  PubMed  Google Scholar 

  70. Sattler H (1952) Basedow’s disease. In: Marchand GW, Marchland JF (trans-ed). Grune & Stratton Inc, New York, pp 367–403

  71. McLarty DG et al (1973) Remission of thyrotoxicosis during treatment with propranolol. Br Med J 2:332–334

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge Ms. Niloofar Shiva for critical editing of English grammar and syntax of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to F. Azizi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article is a systematic review, so does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Azizi, F., Malboosbaf, R. Safety of long-term antithyroid drug treatment? A systematic review. J Endocrinol Invest 42, 1273–1283 (2019). https://doi.org/10.1007/s40618-019-01054-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-019-01054-1

Keywords

Navigation