Correspondence

Ending Propylthiouracil-Induced Liver Failure in Children

N Engl J Med 2009; 360:1574-1575April 9, 2009

Article

To the Editor:

Graves' disease is treated with antithyroid drugs, radioactive iodine, or surgery.1,2 Propylthiouracil and methimazole are widely used in children as first-line therapy.1,2 Over the past 60 years of propylthiouracil and methimazole use, reports of propylthiouracil-related liver failure and death have accumulated.3-5 In contrast, this problem has not been reported with methimazole use in children.3,5

Several observations can be made on the basis of the medical literature, adverse event reports from the Food and Drug Administration (FDA), and extensive data presented at a workshop at the Eunice Kennedy Shriver National Institute of Child Health and Human Development on October 28, 2008, to discuss the safety of propylthiouracil use in children.5 Each year in the United States, 4000 pediatric patients with Graves' disease are treated with antithyroid drugs, with up to 40% receiving propylthiouracil over the past several years.5 Propylthiouracil-induced liver failure may occur in 1 in 2000 to 1 in 4000 treated children, but the number in whom reversible propylthiouracil-induced liver injury develops may be 10 times that range.5 However, the true extent of propylthiouracil-induced liver injury is unknown.5 Routine biochemical surveillance of liver function and hepatocellular integrity is not viewed to be effective in managing the risk of liver failure.5

Although more children received methimazole than propylthiouracil during the periods in which propylthiouracil-induced liver failure has been reported,3,5 there are no reports of liver failure or liver transplantation in association with methimazole use in children.5 There are also fewer and less-serious adverse event reports in the FDA database for methimazole than for propylthiouracil.5

In 2007, more than 9000 prescriptions were written for propylthiouracil for use in children.5 It is estimated that more than 1000 pediatric patients are currently receiving propylthiouracil in the United States.5 It is clear that, at present, there is no good plan for managing the risk of hepatotoxicity in a patient receiving propylthiouracil, other than not using the drug.5 On the basis of recent data,5 we thus estimate that if propylthiouracil use continues at current levels, it is likely that propylthiouracil-induced liver failure requiring transplantation will develop in at least one child over the next few years.

Considering this estimate, we suggest that propylthiouracil should no longer be used as first-line treatment for Graves' disease in children. Alternative treatments should be considered for children who are currently taking propylthiouracil. In this way, it should be possible to end propylthiouracil-induced liver failure in children.

Scott A. Rivkees, M.D.
Yale University School of Medicine, New Haven, CT 06520
scott.rivkees@yale.edu

Donald R. Mattison, M.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892-7510

The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services.

Dr. Rivkees reports serving as an expert witness in endocrine-related legal cases. No other potential conflict of interest relevant to this letter was reported.

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   Eunice Kennedy Shriver National Institute of Child Health and Human Development. Hepatic Toxicity Following Treatment for Pediatric Graves' Disease Meeting: October 28, 2008. Conference proceeding. (Accessed March 10, 2009, at http://bpca.nichd.nih.gov/outreach/index.cfm.)
   

Citing Articles (12)

Citing Articles

1. 1

   Sureka Bollepalli, Susan R. Rose. 2012. Disorders of the Thyroid Gland. , 1307-1319.
   CrossRef

2. 2

   George J. Kahaly, Luigi Bartalena, Laszlo Hegedüs. (2011) The American Thyroid Association/American Association of Clinical Endocrinologists Guidelines for Hyperthyroidism and Other Causes of Thyrotoxicosis: A European Perspective. Thyroid 21:6, 585-591
   CrossRef

3. 3

   Hirokazu Sato, Masanori Minagawa, Nozomu Sasaki, Shigetaka Sugihara, Itsuro Kazukawa, Kanshi Minamitani, Kunio Wataki, Susumu Konda, Hiroaki Inomata, Kazunori Sanayama, Yoichi Kohno. (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. Journal of Pediatric Endocrinology and Metabolism 24:5-6, 257-263
   CrossRef

4. 4

   Rebecca S. Bahn (Chair), Henry B. Burch, David S. Cooper, Jeffrey R. Garber, M. Carol Greenlee, Irwin Klein, Peter Laurberg, I. Ross McDougall, Victor M. Montori, Scott A. Rivkees, Douglas S. Ross, Julie Ann Sosa, Marius N. Stan. (2011) Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 21:6, 593-646
   CrossRef

5. 5

   Jing Liu, Anna Bargren, Sarah Schaefer, Herbert Chen, Rebecca S. Sippel. (2011) Total Thyroidectomy: A Safe and Effective Treatment for Graves’ Disease. Journal of Surgical Research 168:1, 1-4
   CrossRef

6. 6

   Spiros Karras, Themistoklis Tzotzas, Gerasimos E Krassas. (2011) Toxicological considerations for antithyroid drugs in children. Expert Opinion on Drug Metabolism & Toxicology 7:4, 399-410
   CrossRef

7. 7

   Sarantis Livadas, Xenofon Xyrafis, Frangiskos Economou, Georgios Boutzios, Maria Christou, Aristea Zerva, Athanasios Karachalios, Helen Palioura, Sotiria Palimeri, Evanthia Diamanti-Kandarakis. (2010) Liver failure due to antithyroid drugs: report of a case and literature review. Endocrine 38:1, 24-28
   CrossRef

8. 8

   ScottA Rivkees. (2010) 63 Years and 715 Days to the "Boxed Warning": Unmasking of the Propylthiouracil Problem. International Journal of Pediatric Endocrinology 2010:1, 658267
   CrossRef

9. 9

   ScottA Rivkees, Kerry Stephenson, Catherine Dinauer. (2010) Adverse Events Associated with Methimazole Therapy of Graves' Disease in Children. International Journal of Pediatric Endocrinology 2010:1, 176970
   CrossRef

10. 10

    (2009) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 18:11, i-xii
    CrossRef

11. 11

    ScottA Rivkees, DonaldR Mattison. (2009) Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use. International Journal of Pediatric Endocrinology 2009:1, 132041
    CrossRef

12. 12

    Scott A. Rivkees, Donald R. Mattison. (2009) Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use. International Journal of Pediatric Endocrinology 2009, 1-8
    CrossRef