Hyperthyroidism in Children Treated with Long Term Medical Therapy: Twenty-Five Percent Remission Every Two Years*
Abstract
We use an antithyroid drug for the treatment of hyperthyroidism due to Graves' disease in children and adolescents for as long as the patients are willing to comply and/or tolerate the drug. In more than 60 patients treated since 1961, the remission rate was 25% in the first 2 yr. This report looks at these same patients again, followed for an additional 5 yr. Survival analysis methods applied to the follow-up data on 63 children confirm our original statistical findings and suggest a continuing remission rate of 25% every 2.1 +/- 0.4 (+/- SE) yr regardless of the duration of previous therapy. The median time to remission was 4.3 +/- 1.5 yr, and 75% of patients are predicted to be in remission in 10.9 +/- 2.3 yr. Of 36 patients who went into remission, defined by their being euthyroid for 1 yr after cessation of therapy, 1 relapsed, and 2 developed spontaneous hypothyroidism; the remainder are euthyroid 1-11.7 yr after therapy was discontinued. Of 14 who switched from medical therapy, 2 of 7 treated surgically and 4 of 7 treated with 131I are hypothyroid. Only 1 patient had a significant adverse reaction to both methimazole and propylthiouracil. While medical therapy may have some direct effect on the autoimmune response in hyperthyroidism, its role in affecting the time to ultimate remission is unknown. These data, however, describe the course of children so treated and allow us to present therapeutic options initially or during treatment based on statistically derived probabilities of outcome.
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Two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment.
“Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (341), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (333,339,342).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [341]
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Ross, D. S., Burch, H. B., Cooper, D. S., Greenlee, M. C., Laurberg, P., Maia, A. L., Rivkees, S. A., Samuels, M., Sosa, J. A., Stan, M. N., et al. (2016) · Thyroid® · doi:10.1089/thy.2016.0229 · Cited by 2,938 · see citing works
“Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (341), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (333,339,342).”
BackgroundBahn, R. S., Burch, H. B., Cooper, D. S., Garber, J. R., Greenlee, M. C., Klein, I., Laurberg, P., McDougall, I. R., Montori, V. M., Rivkees, S. A., et al. (2011) · Endocrine Practice · doi:10.4158/ep.17.3.456 · Cited by 1,098 · see citing works
“Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (220), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (213,216,221).”
BackgroundThe American Thyroid Association and American Association of Clinical Endocrinologists Taskforce on Hyperthyroidism and Other Causes of Thyrotoxicosis, Bahn, R. S., Burch, H. B., Cooper, D. S., Garber, J. R., Greenlee, M. C., Klein, I., Laurberg, P., McDougall, I. R., Montori, V. M., et al. (2011) · Thyroid · doi:10.1089/thy.2010.0417 · Cited by 898 · see citing works
“Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (220), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (213,216,221).”
BackgroundLaurberg, P., Wallin, G., Tallstedt, L., Abraham-Nordling, M., Lundell, G., & Tørring, O. (2008) · European Journal of Endocrinology · doi:10.1530/eje-07-0450 · Cited by 428 · see citing works
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“Pubertal (Tanner 2–4) 58 (38) Postpubertal (Tanner 5) 31 (20) Personal history of autoimmunity and susceptibility factors 22 (14) 154”
BackgroundResultThyrotoxicosis in Prepubertal Children Compared with Pubertal and Postpubertal Patients
Lazar, L., Kalter-Leibovici, O., Pertzelan, A., Weintrob, N., Josefsberg, Z., & Phillip, M. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.10.6922 · Cited by 162 · see citing works
“(7), which reported a remission rate of 25% every 2 yr in children and adolescents, regardless of age.”
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Léger, J., Gelwane, G., Kaguelidou, F., Benmerad, M., Alberti, C., & the French Childhood Graves' Disease Study Group (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1944 · Cited by 144 · see citing works
“09 Remission 15 (68) 53 (40) Definitive treatment 3 (14) 42 (32) Still on ATD treatment 2 (9) 12 (9) Lost to follow-up 2 (9) 25 (19)”
BackgroundResultInfluentialRemission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism?
Laurberg, P. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02295 · Cited by 139 · see citing works
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“Overall, the remission rate after medical therapy of our PUB group (30% treated a mean of 2.8 years achieved at least a 1-year remission) is comparable to the experience of Lippe et al. (8) who reported a remission rate (euthyroid 1 year off therapy) of 25% for every 2 years of therapy.”
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“In a retrospective analysis, Lippe et al. (1987) demontrated that remission rate in 63 children and adolescents treated with ATD (treatment duration range: 0·4– 12·4 years) increased by an additional 25% every two years.”
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Azizi, F., & Malboosbaf, R. (2017) · Thyroid · doi:10.1089/thy.2016.0652 · Cited by 114 · see citing works
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“, 1987 [59] 63 1 1.”
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“On the other hand, some studies have shown that remission rates increase over multiple years of treatment with ATD in children (2,4,17), and it remains uncertain whether the approach to the treatment of GD in adults described above is suitable in pediatric populations (26).”
Predictors of Early Remission of Hyperthyroidism in Children1
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“Previous studies had their limitations but evaluated age, goiter size, decrease in body mass index and severity of biochemical hyperthyroidism at onset, TRAb levels at onset and at the end of treatment, and duration of medical treatment as predictive markers of GD relapse during childhood (23,27,33,34,35,36,37).”
BackgroundLaurberg, P., Berman, D. C., Andersen, S., & Pedersen, I. B. (2011) · Thyroid · doi:10.1089/thy.2011.0039 · Cited by 85 · see citing works
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“Of the 63 patients followed on ATDs, 36 (57 %) remitted after an average of 4 years of therapy [16].”
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Bettendorf, M. (2002) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-002-0905-3 · Cited by 77 · see citing works
“propylthiouracil) is associated with side-effects such as rash, granulocytopenia, arthritis and hepatitis, and a disappointing long-term remission rate as low as 30%‐40% even after prolonged therapy [43, 47, 48 ].”
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“Propylthiouracil and methimazole both have been used in children with Graves’ disease (11).”
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“These studies reveal an incidence of minor adverse events between 1% [13] and 15% [12].”
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“With the watchful-waiting approach, 15–30% of the time a subgroup of pediatric patients will enter remission; however, this may take between 2 and 10 yr to achieve, and 35– 60% of patients may experience a relapse after medications are discontinued (9, 20, 35, 38).”
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Pediatric Graves' Disease: Outcome and Treatment
Gruñeiro-Papendicck, L., Chiesa, A. E., Finkielstain, G. P., & Heinrich, J. J. (2003) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2003.16.9.1249 · Cited by 62 · see citing works
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ResultGraves Disease in Children: Thyroid-Stimulating Hormone Receptor Antibodies as Remission Markers
Gastaldi, R., Poggi, E., Mussa, A., Weber, G., Vigone, M. C., Salerno, M., Delvecchio, M., Peroni, E., Pistorio, A., & Corrias, A. (2014) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2013.12.047 · Cited by 59 · see citing works
“As regards to childhood and adolescence, previous studies suggest that remission occurs only in 20%-30% of those treated with ATD,(6,8-10,12-14) and less than 25% of patients obtain remission within 2 years of ATD therapy.(2,11,15) The likelihood of remission and its determinants with longterm ATD has been estimated b…”
ResultRelapse following antithyroid drug therapy for Graves’ hyperthyroidism
Laurberg, P., Krejbjerg, A., & Andersen, S. L. (2014) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000088 · Cited by 60 · see citing works
“This is especially so in subgroups with a high risk, such as children [9,10] and patients with Graves’ orbitopathy [44,45].”
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Juvenile thyrotoxicosis; can we do better?
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“However, previous reports indicate that a longer duration of minimum dose treatment is associated with a higher remission rate (10, 71, 100, 101).”
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Bandai, S., Okamura, K., Fujikawa, M., Sato, K., Ikenoue, H., & Kitazono, T. (2019) · Endocrine Journal · doi:10.1507/endocrj.ej18-0418 · Cited by 51 · see citing works
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BackgroundInfluentialThe safety and efficacy of antithyroid drugs
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“Longer courses of therapy in children are accompanied by more likelihood of remission [58].”
BackgroundThe Treatment of Graves' Disease in Children
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van Lieshout, J. M., Mooij, C. F., van Trotsenburg, A. S. P., & Zwaveling‐Soonawala, N. (2021) · European Journal of Endocrinology · doi:10.1530/eje-21-0077 · Cited by 46 · see citing works
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ResultPredictors of Early Remission of Hyperthyroidism in Children 384
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“In the last 2 decades, few studies have re-ported high remission rate with long-term ATD treatment (15,16,27,28); one meta-analysis showed that long-term ATD could induce higher remission rates, compared with conventional therapy (39).”
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“Graves’ disease (GD) is a rare disease in childhood and adolescence with only 1–5p of all patients being children. The incidence of juvenile GD ranges from 0.1 in young children to 3.0 in 100,000 in adolescents. Despite the numerous literature about therapy of GD in adults only a few investigations concerning children…”
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“It has been suggested that long-term ATD therapy is effective and safe both in adults (54, 62, 63) and in children and adolescents (42, 63-68).”
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Treatment of juvenile Graves' disease and its ophthalmic complication: the 'European way'
Krassas, G. E. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500407 · Cited by 19 · see citing works
“Vaidya et al. (18) 17 5 0 1 3 8 Barnes et al. (17) 16 14 6 8 1 NR Shiroozu et al. (97) 5 5 0 1.5 1.5 0 Buckingham et al. (94) 7 32 14 7.5 9 6 Hamburger (73) 9 17 6 8 3 5 Lippe et al. ( 95 ) 2 NR 2 NR NR NR Gorton et al. (96) 13 11 4 7 2 11”
InfluentialLong-term outcomes of graves disease in children treated with anti-thyroid drugs
Chiang, Y.-T., Ting, W., Huang, C., Huang, S.-K., Chan, C.-I., Cheng, B.-W., Lin, C., Wu, Y., Hung, C.-M., Li, H., et al. (2020) · Pediatrics & Neonatology · doi:10.1016/j.pedneo.2019.12.009 · Cited by 18 · see citing works
Behavioral assessment of children and adolescents with Graves’ disease: A prospective study
Hamed, S. A., Attiah, F. A., Abdulhamid, S. K., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0248937 · Cited by 18 · see citing works
“7 mg/kg/day which was subsequently titrated to maintain normal thyroid hormone levels based on the results of serum thyroid hormone testing during follow-ups [11].”
MethodAn update on the pharmacological management of hyperthyroidism due to Graves’ disease
Bartalena, L., Tanda, M. L., Bogazzi, F., Piantanida, E., Lai, A., & Martino, E. (2005) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.6.6.851 · Cited by 17 · see citing works
“One study showed that > 75% of children and adolescents treated with thionamides for > 11 years remained in remission [42].”
BackgroundManagement of Thyrotoxicosis in Children and Adolescents: A Turkish Multi-center Experience
Esen, İ., Bayramoğlu, E., Yıldız, M., Aydın, M., Özturan, E. K., Aycan, Z., Bolu, S., Önal, H., Kör, Y., Ökdemir, D., et al. (2019) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2018.2018.0210 · Cited by 17 · see citing works
“These studies have reported that ethnicity, age, pubertal status, BMI (SDS), goiter volume, initial severity (higher fT4 concentration and TRAb levels) and presence of other autoimmune conditions are prognostic factors (14,15,16,31).”
BackgroundBayramoğlu, E., Elmaoğulları, S., Sağsak, E., & Aycan, Z. (2019) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2018-0495 · Cited by 17 · see citing works
Abdi, H., Amouzegar, A., & Azizi, F. (2019) · PubMed Central · doi:10.22037/ijpr.2020.112892.14005 · Cited by 33 · see citing works
Clinical Course of Pediatric and Adolescent Graves' Disease Treated with Radioactive Iodine
Pinto, T. E., Cummings, E. A., Barnes, D., & Salisbury, S. R. (2007) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2007.20.9.973 · Cited by 16 · see citing works
Maladie de basedow chez l'enfant: aspects cliniques et évolutifs
Boiko, J., Léger, J., Raux-Demay, M. C., Cabrol, S., Bouc, Y. L., & Czernichow, P. (1998) · Archives de Pédiatrie · doi:10.1016/s0929-693x(98)80052-3 · Cited by 17 · see citing works
Okamura, K., Bandai, S., Fujikawa, M., Sato, K., Ikenoue, H., & Kitazono, T. (2020) · Intern J Endocrinol Metab · doi:10.5812/ijem.101139 · Cited by 16 · see citing works
“Namely, the patients are advised to continue ATD treatment until GD is no longer present, regardless of the time taken to achieve this end (13, 17, 26-29); however, the issue with this approach is that it is difficult to tell when patients have achieved remission.”
BackgroundAntithyroid drug therapy of Graves’ hyperthyroidism: realistic goals and focus on evidence
Laurberg, P., Andersen, S., & Karmisholt, J. (2006) · Expert Review of Endocrinology & Metabolism · doi:10.1586/17446651.1.1.91 · Cited by 17 · see citing works
Anti-thyroid drugs in pediatric Graves′ disease
John, M., Sundrarajan, R., & Gomadam, S. (2015) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.152766 · Cited by 17 · see citing works
“Lippe et al. [14] MMI and PTU 1.6% Arthritic reaction ( n =1) Lazar et al. 2000 [22] PTU and MMI 35% Major in 5% patients and minor in 30% patients.”
InfluentialThyrotoxicosis in children: treatment and outcome.
Jaruratanasirikul, S., Leethanaporn, K., & Sriplung, H. (2006) · PubMed · Cited by 14 · see citing works
Propylthiouracil-Induced Hepatic Failure and Encephalopathy in a Child
Kirkland, J. L. (1990) · DICP · doi:10.1177/106002809002400505 · Cited by 14 · see citing works
Treatment of hyperthyroidism in young people
Cheetham, T. D., Hughes, I. A., Barnes, N. D., & Wraight, E. P. (1998) · Archives of Disease in Childhood · doi:10.1136/adc.78.3.207 · Cited by 13 · see citing works
“The remission rate of children in the USA is reported to be 25% after each of repeated two year courses of medical treatment,”
BackgroundWang, S.-Y., Wang, C., Tien, K., Chang, C., & Liu, T. (2019) · The Kaohsiung Journal of Medical Sciences · doi:10.1002/kjm2.12167 · Cited by 12 · see citing works
McCormack, S. E., Mitchell, D. M., Woo, M., Levitsky, L. L., Ross, D. S., & Misra, M. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03565.x · Cited by 12 · see citing works
Santos, T. J. D., Martos‐Moreno, G. Á., Muñoz-Calvo, M. T., Pozo, J., Rodríguez‐Artalejo, F., & Argente, J. (2018) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2018-0132 · Cited by 11 · see citing works
Thyrotoxicosis in children: thirty years’experience
Raza, J., Hindmarsh, P., & Brook, C. (1999) · Acta Paediatrica · doi:10.1111/j.1651-2227.1999.tb00185.x · Cited by 11 · see citing works
“The presenting signs and symptoms were in keeping with those reported in the literature (4, 9, 17).”
BackgroundResult
- Authors
- LIPPE, B. M., LANDAW, E. M., & KAPLAN, S. A.
- Affiliations
- University of California, Los Angeles (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1987-06
- Volume
- 64
- Issue
- 6
- Pages
- 1241-1245
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1992904825
- Cited by
- 192
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 15 · 2018: 9 · 2017: 5 · 2016: 3 · 2015: 7 · 2014: 12 · 2013: 3 · 2012: 7
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01am025744-06)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Ophthalmology and Eye Disorders
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- pediatric hyperthyroidism, Graves' disease, antithyroid drug therapy, long-term medical therapy, remission rate, time to remission, hypothyroidism, relapse, methimazole, propylthiouracil, adverse drug reactions, survival analysis, treatment outcome prediction
- MeSH terms
- Child, Female, Graves Disease, Humans, Hyperthyroidism, Male, Methimazole, Propylthiouracil, Statistics as Topic, Time Factors
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