Dissimilar Hepatotoxicity Profiles of Propylthiouracil and Methimazole in Children
Abstract
BACKGROUND: The antithyroid drugs propylthiouracil and methimazole were introduced for clinical use about 60 yr ago and are estimated to be used in more than 6000 children and adolescents per year in the United States. Over the years that these medications have been used, reports of adverse events involving hepatotoxicity have appeared. To date, there has not been a systematic and comparative evaluation of the adverse events associated with antithyroid drug use. OBJECTIVE: Our objective was to assess safety and hepatotoxicity profiles of propylthiouracil and methimazole by age in the U.S. Food and Drug Administration's Adverse Event Reporting System (AERS). DESIGN: We used the multi-item gamma-Poisson shrinker (MGPS) data mining algorithm to analyze more than 40 yr of safety data in AERS. MGPS uses a Bayesian model to calculate adjusted observed to expected ratios [empiric Bayes geometric mean (EBGM) values] for every drug-adverse event combination in AERS, focusing on hepatotoxicity events. RESULTS: MGPS identified higher-than-expected reporting of severe liver injury in pediatric patients treated with propylthiouracil but not with methimazole. Propylthiouracil had a high adjusted reporting ratio for severe liver injury (EBGM 17; 90% confidence interval = 11.5-24.1) in the group less than 17 yr old. The highest EBGM values for methimazole were with mild liver injury in the group 61 yr and older [EBGM 4.8 (3.3-6.8)], which consisted of cholestasis. Vasculitis was also observed for propylthiouracil in children and adolescents, reaching higher EBGM values than hepatotoxicity signals. CONCLUSIONS: MGPS detects higher-than-expected reporting of severe hepatotoxicity and vasculitis in children and adolescents with propylthiouracil but not with methimazole.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The surprising results from Asia, which contrast with other data from the United States, suggest that prior data on MMI-related hepatotoxicity from small case series may need to be reconsidered.
“These surprising results from Asia, which are in contrast to other data from the United States (133,136), suggest that prior data on MMI-related hepatotoxicity from small case series may need to be reconsidered.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [133]
The FDA issued a safety alert in 2010 regarding the use of PTU, and an analysis of FDA Medwatch data concluded that children are more susceptible to hepatotoxic reactions from PTU than are adults.
“It is for this reason that the Food and Drug Administration (FDA) issued a safety alert in 2010 regarding the use of PTU, and an analysis of FDA Medwatch data (133) concluded that children are more susceptible to hepatotoxic reactions from PTU than are adults.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [133]
Children seem to be more likely to develop PTU-related ANCA-positive vasculitis.
“Children seem to be more likely to develop PTU-related ANCA-positive vasculitis (133).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [133]
Cites
Szarfman, A., Machado, S. G., & Neill, R. T. O. (2002) · Drug Safety · doi:10.2165/00002018-200225060-00001 · Cited by 702 · see citing works
Self-citationLiver transplantation for acute liver failure from drug induced liver injury in the United States
Russo, M. W., Galanko, J. A., Shrestha, R., Fried, M. W., & Watkins, P. B. (2004) · Liver Transplantation · doi:10.1002/lt.20204 · Cited by 473 · see citing works
Empirical bayes screening for multi-item associations
DuMouchel, W., & Pregibon, D. (2001) · ACM SIGKDD Conference on Knowledge Discovery and Data Mining (KDD) · doi:10.1145/502512.502526 · Cited by 268 · see citing works
Bahn, R. S., Burch, H. S., Cooper, D. S., Garber, J. R., Greenlee, C. M., Klein, I. L., Laurberg, P., McDougall, I. R., Rivkees, S. A., Ross, D., et al. (2009) · Thyroid · doi:10.1089/thy.2009.0169 · Cited by 223 · see citing works
Self-citationPutting Propylthiouracil in Perspective
Cooper, D. S., & Rivkees, S. A. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0850 · Cited by 212 · see citing works
Self-citationLIPPE, B. M., LANDAW, E. M., & KAPLAN, S. A. (1987) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-64-6-1241 · Cited by 192 · see citing works
Kaguelidou, F., Alberti, C., Castanet, M., Guitteny, M.-A., Czernichow, P., & Léger, J. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0842 · Cited by 173 · see citing works
Management of Hyperthyroidism in Children and Adolescents
HAMBURGER, J. I. (1985) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-60-5-1019 · Cited by 161 · see citing works
van Puijenbroek, E., Diemont, W. L., & van Grootheest, K. (2003) · Drug Safety · doi:10.2165/00002018-200326050-00001 · Cited by 145 · see citing works
Ending Propylthiouracil-Induced Liver Failure in Children
Rivkees, S. A., & Mattison, D. R. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0809750 · Cited by 140 · see citing works
Self-citationPropylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use
Rivkees, S. A., & Mattison, D. R. (2009) · International Journal of Pediatric Endocrinology · doi:10.1155/2009/132041 · Cited by 135 · see citing works
Self-citationMethimazole-Induced Hepatotoxicity
Woeber, K. A. (2002) · Endocrine Practice · doi:10.4158/ep.8.3.222 · Cited by 127 · see citing works
Glaser, N. S., Styne, D. M., & for the Organization of Pediatric Endocrinologists of Northern California Collaborative Graves’ Disease Study Group (2008) · Pediatrics · doi:10.1542/peds.2007-1535 · Cited by 125 · see citing works
Nikolic, B. B., Nikolic, M. M., Andrejević, S., Zorić, S., & Bukilica, M. (2005) · Arthritis Research & Therapy · doi:10.1186/ar1789 · Cited by 124 · see citing works
Predictors of Early Remission of Hyperthyroidism in Children1
Glaser, N. S., & Styne, D. M. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.6.3986 · Cited by 115 · see citing works
Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use
Rivkees, S., & Mattison, D. (2009) · International Journal of Pediatric Endocrinology · doi:10.1186/1687-9856-2009-132041 · Cited by 90 · see citing works
Self-citationSera, N., Ashizawa, K., Ando, T., Abe, Y., Ide, A., Usa, T., Tominaga, T., Ejima, E., Yokoyama, N., & Eguchi, K. (2000) · Thyroid · doi:10.1089/thy.2000.10.595 · Cited by 89 · see citing works
Severe cholestatic jaundice in uncomplicated hyperthyroidism treated with methimazole.
Arab, D. M., Malatjalian, D. A., & Rittmaster, R. S. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.4.7714072 · Cited by 65 · see citing works
Gao, Y., Chen, M., Ye, H., Yu, F., Guo, X.-H., & Zhao, M.-H. (2008) · Rheumatology · doi:10.1093/rheumatology/ken321 · Cited by 64 · see citing works
Methimazole-induced Cholestatic Jaundice
Mikhail, N. E. (2004) · Southern Medical Journal · doi:10.1097/01.smj.0000054690.98272.b1 · Cited by 50 · see citing works
The Treatment of Graves' Disease in Children
Rivkees, S. A. (2006) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2006.19.9.1095 · Cited by 48 · see citing works
Self-citationMethimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis
Schwab, G. P., Wetscher, G. J., Vogl, W., et al. (1996) · Langenbeck s Archives of Surgery · doi:10.1007/bf00571690 · Cited by 38 · see citing works
A Case of Methimazole-Induced Acute Hepatic Failure in A Patient with Chronic Hepatitis B Carrier
Kang, H., Choi, J. D., Jung, I. G., et al. (1990) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.1990.5.1.69 · Cited by 33 · see citing works
Unusual complications of antithyroid drug therapy: four case reports and review of literature.
Baker, B., Shapiro, B., Fig, L. M., Woodbury, D., Sisson, J. C., & Beierwaltes, W. H. (1989) · PubMed · Cited by 27 · see citing works
Delayed cholestatic hepatitis due to methimazole.
Hung, Y. T., Yu, W. K., & Chow, E. J. (1999) · PubMed · Cited by 27 · see citing works
Propylthiouracil-induced cutaneous vasculitis.
Yarman, S., Sandalci, O., Tanakol, R., et al. (1997) · PubMed · Cited by 23 · see citing works
Methimazole-associated cholestatic liver injury: case report and brief literature review.
Schmidt, G., Börsch, G., Km, M., et al. (1986) · PubMed · Cited by 22 · see citing works
Methimazole-induced cholestatic jaundice in an elderly hyperthyroid patient
Ramos-Bonner, L. S., Goldberg, T. H., Moyer, S., et al. (2007) · The American journal of geriatric pharmacotherapy · doi:10.1016/j.amjopharm.2007.10.003 · Cited by 20 · see citing works
Gemma, R., Suzuki, Y., Tanaka, I., et al. (1992) · Internal Medicine · doi:10.2169/internalmedicine.31.377 · Cited by 15 · see citing works
Huang, C., Hsu, T., Chou, H., & Tsay, G. J. (2004) · PubMed · Cited by 11 · see citing works
Predictors of Early Remission of Hyperthyroidism in Children
Draznin, M. B. (1998) · Clinical Pediatrics · doi:10.1177/000992289803700312 · Cited by 7 · see citing works
Cholestasis Induced by Hyperthyroidism after Liver Transplantation
Lersch, C., Seige, M., Natrath, W., et al. (2009) · Digestion · doi:10.1159/000201271 · Cited by 5 · see citing works
Mamianetti, A., Muñoz, A. D., Ronchetti, R., et al. (1995) · PubMed · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
“Experience in the United States is limited.”
BackgroundResultInfluentialSelf-citationThyroid Function and Human Reproductive Health
Krassas, G. E., Poppe, K., & Glinoer, D. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0041 · Cited by 1,223 · see citing works
De Leo, S., Lee, S. Y., & Braverman, L. E. (2016) · The Lancet · doi:10.1016/s0140-6736(16)00278-6 · Cited by 883 · see citing works
Franklyn, J. A., & Boelaert, K. (2012) · The Lancet · doi:10.1016/s0140-6736(11)60782-4 · Cited by 262 · see citing works
Thyroid Disorders in Children and Adolescents: A Review
Hanley, P., Lord, K., & Bauer, A. J. (2016) · JAMA Pediatrics · doi:10.1001/jamapediatrics.2016.0486 · Cited by 237 · see citing works
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
Antithyroid drug‐related hepatotoxicity in hyperthyroidism patients: a population‐based cohort study
Wang, M., Lee, W., Huang, T., Chu, C., & Hsieh, C. (2014) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12336 · Cited by 114 · see citing works
Ohye, H., Minagawa, A., Noh, J. Y., Mukasa, K., Kunii, Y., Watanabe, N., Matsumoto, M., Suzuki, M., Yoshihara, A., Ito, K., et al. (2014) · Thyroid® · doi:10.1089/thy.2012.0612 · Cited by 106 · see citing works
Balavoine, A.-S., Glinoer, D., Dubucquoi, S., & Wémeau, J.-L. (2015) · Thyroid® · doi:10.1089/thy.2014.0603 · Cited by 65 · see citing works
- Authors
- Rivkees, S. A., & Szarfman, A.
- Affiliations
- Yale University (US)
- United States Food and Drug Administration (US)
- Corresponding author
- Rivkees, Scott A.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-07-01
- Volume
- 95
- Issue
- 7
- Pages
- 3260-3267
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2061857583
- Cited by
- 177
- References
- 33
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 9 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 15 · 2015: 18 · 2014: 16 · 2013: 10 · 2012: 9
- FWCI
- 12.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Keywords
- propylthiouracil, methimazole, antithyroid drugs, hepatotoxicity, drug-induced liver injury, drug safety in children, adverse drug reactions, vasculitis, cholestasis, FDA Adverse Event Reporting System, multi-item gamma Poisson shrinker
- MeSH terms
- Adolescent, Age Factors, Algorithms, Child, Female, Humans, Male, Methimazole, Propylthiouracil, Severity of Illness Index, Antithyroid Agents, United States, United States Food and Drug Administration, Databases, Factual, Adverse Drug Reaction Reporting Systems, Chemical and Drug Induced Liver Injury, Data Mining
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
