American Thyroid Association 88th Annual Meeting:

Liver Failure: A Turning Point in Graves' Disease Treatment

With Scott A. Rivkees, and David Cooper, MD

Scott A. Rivkees, MD, professor, and chair of pediatrics at the University of Florida College of Medicine in Gainesville, delivered the Paul Starr Award Lecture— Unmask Safety Signals in Antithyroid Medications—at the 2018 American Thyroid Association (ATA) annual meeting,1 earning this distinction in recognition of his accomplishments in clinical thyroidology.

What began as an incidental mention of a pediatric patient who required a liver transplant following treatment with propylthiouracil (PTU) for Graves’ disease, which piqued Dr. Rivkees' interest and led him to a realization that similar such reports have been accumulating for more than 60 years.  

 

Aiming for Zero Tolerance Goal for Liver Injury in Children with Graves'

As a pediatric endocrinologist, even the loss of one child due to an avoidable treatment irked Dr. Rivkees, particularly given that accounts of liver failure and death were not similarly reported following treatment with methimazole; and, for which side effects, when they arose, were reversible when the medication was stopped.2

He concluded that since pediatric patients who required treatment for Graves’ disease were at higher risk for PTU-associated liver injury than adults, there was no reason for this drug to remain first-line treatment. As such, he began advocating against prescribing PTU to children and urging the selection of the other treatments to manage their hyperthyroidism.

Out of the need to raise his concerns, he submitted a letter to the editor,3 co-authored with Donald R. Mattison, MD, then chief of the National Institute for Child Health and Human Development,3 which appeared in the New England Journal of Medicine in 2009.

“Drawing attention to such unnecessary and avoidable liver damage in children who were receiving treatment for their Graves’ disease, and his presence on the ATA guidelines writing committee on treatment of hyperthyroidism, prompted closer attention to the use of PTU in adults, particularly in pregnant women,“4 said David Cooper, MD, professor of medicine at the Johns Hopkins University School of Medicine and Professor of International Health at the Bloomberg Johns Hopkins School of Public Health, who as session moderator, presented the award to Dr. Rivkees.

In fact, Dr. Rivkees focused attention lead to a clearer understanding of the increased risk of birth defects—albeit rare—in women using the anti-thyroid medications, particularly early in pregnancy, said Dr. Cooper.

Ultimately, the result was a black box warning regarding severe liver injury with propylthiouracil, issued by the Food and Drug Administration (FDA).5

Vigilance Remains Key as No Medication Is Perfect

"Based on FDA data, it is gratifying to see that in 2016, there were about 40,000 pediatric patients who were taking methimazole. Yet, despite evidence of safety signals for liver damage with propylthiouracil, about 200 children continue to receive this medication,” Dr. Rivkees told EndocrineWeb.

Still, PTU remains the fourth most common cause of liver injury with one child annually receiving a liver transplant or medication-associated death.1 Therefore, we need to avoid the use of PTU in children, period, said Dr. Rivkees. "That means any child still taking PTU should be switched immediately." 

“Now that we’re in a methimazole-only era, with rare exceptions, we must remember that methimazole is ‘no angel.’ given that 17% of children taking this drug will experience minor side effects, as well as the more serious agranulocytosis. As such, it’s really important that we mention to families these risks and what to look for,"1 said Dr. Rivkees. "And they should be instructed to stop the medication immediately if any side effects are observed."

“In adults, it is equally important to be forthright with treatment recommendations on prenatal care, pregnancy—both early and later stages—and about the impact on the baby,” said Dr. Rivkees.

Pregnancy terminations remain a concern with methimazole, as does the possibility of teratogenicity, albeit very low. “We must be careful in counseling women since hyperthyroidism is not good for the mom, her pregnancy outcomes, or the baby, and is more difficult to control. Therefore, in women of childbearing age who have hyperthyroidism, achieving good disease control is best accomplished before they get pregnant,” he said.

The published data show that the time to resolution of a hyperthyroid state is really similar whether prescribing high doses or low doses,6 according to Dr. Rivkees. Since the risk of granulocytosis is dose-dependent, the best approach is to use a low dose, especially over the first three months of treatment.

Clinicians Must Actively Advocate for Medication Safety

“In truth, Dr. Rivkees efforts were extraordinary, as ultimately, his determination has led to a sea change in the treatment of Graves’ disease in children, and by extension in all patients,” Dr. Cooper told EndocrineWeb.

This was recognized Nature Reviews Endocrinology,6  in an article reflecting on the past decade that identified the change in Graves’ disease treatment as one of the most significant changes in patient care in the past decade.

 “Since one-third of all newly approved medications are removed from the market, we must remain active, vigilant, and outspoken in response to any concerns that may arise regarding treatment protocols—be it a collection of cases reflecting an unusual or undesirable pattern of side effects or poor response trends,” said Dr. Rivkees.

“Clinical observations of long-term abnormalities require more than personal vigilance, it may necessitate going to the FDA; after all, surveillance programs are only as good as the feedback we provide,” he said.

“It will require persistence, and in my case, it took reaching out to colleagues at the National Institutes of Health to elevate my concerns about safety and the need for data monitoring to help build a credible case,” said Dr. Rivkees. These sentiments were reiterated by Dr. Cooper who said, “without which we would likely still be prescribing PTU as first-line therapy for Graves’ disease.” 

We became aware of the hidden safety problem related to PTU and liver failure and got the word out,3-5,7 Dr. Rivkees said. ”Given that a child a year for a least two to three decades was dying or having a liver transplant, the messaging we offered has worked, and it’s wonderful that the last child to have a Graves’ treatment-related liver transplant was 2009; nine years ago.”

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Matching Expectations and Guidelines to Treatment-Worthy Thyroid Cancers
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