A recent workshop at the NIH was convened to discuss increasing concerns regarding the safety of propylthiouracil (PTU) use in the pediatric Grave's Disease population. Attendees at the workshop included several pediatric endocrinologist thyroid experts, as well as representatives from the National Institutes of Child Health and Disease (NICHD) Obstetric and Pediatric Pharmacology Branch (OPPB) and the United States Food and Drug Administration (FDA). Although data pertaining to the precise frequency of PTU-related adverse events is not available in the absence of a national registry for pediatric Graves' disease, reviews of case reports in the medical literature, adverse event reports to the FDA, data from the Pediatric Acute Liver Failure Network, and liver transplant data from United Network of Organ Sharing (UNOS) on the frequency of hepatocellular damage, liver failure, and fatalities associated with pediatric PTU treatment are alarming. According to data presented at this workshop, approximately 5,000 children are currently treated with anti-thyroid medications. Ten to thirty percent of these children are receiving PTU therapy. The risk of liver failure associated with PTU appears to be higher in children than in adults and was estimated to occur between 1 in 2000 to 1 in 5000 children. Case descriptions suggest that PTU associated liver failure is rapidly progressive and infrequently reversible, and that routine biochemical surveillance of liver enzyme concentrations may be inadequate for early detection of hepatocellular damage and prevention of further injury. Although the risk of PTU-associated liver injury appears to be lower in adults than children, the population of adults treated with PTU is considerably larger than the pediatric population treated with PTU, suggesting that PTU use in the adult population may also require consideration. The alternative anti-thyroid medication, methimazole (MMI), also carries a risk of adverse effects, but MMI use has not been reported to be associated with liver failure in the pediatric population. Both PTU and MMI are associated with similar rates of agranulocytosis (estimated to be approximately 0.3%). In addition, both PTU and MMI are associated with a risk of antineutrophil cytoplasmic antibodies (ANCA) and vasculitis, although the incidence of ANCA-positivity vasculitis appears to be greater with PTU than MMI. Of note, however, MMI use during pregnancy has been found to be associated with an increased risk of minor birth defects, whereas PTU use during pregnancy does not appear to carry this risk. Given the information presented at this workshop, a number of participants recommended that caution be exercised when considering PTU use in the pediatric population, until the incidence of serious adverse events could be more accurately determined, and that physicians prescribing PTU be made aware of the potential for PTU-induced liver failure and other morbidity in the pediatric population. Investigation to more accurately characterize the safety profiles PTU and MMI use in pediatrics was also strongly endorsed. The notes from this workshop have been posted on the NICHD website for access by prescribing physicians. In addition, the LWPES and the Endocrine section of the AAP intend to issue a joint request that both the NICHD and the Pediatric Advisory Committee within the FDA commissioner's office convene committees to consider this matter expediently, to derive definitive recommendations based on exhaustive, evidence-based research. We will update members of the society as these workshops reach their conclusions. |