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AACE Patient Safety - Editorials

Propylthiouracil (PTU) Hepatotoxicity and Graves` Disease Therapy


Scott A. Rivkees, M.D.
Yale Pediatric Thyroid Center
Yale University School of Medicine
New Haven, CT


Donald R. Mattison MD, CAPT,
Obstetric and Pediatric Pharmacology Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health
Bethesda MD

David S. Cooper, M.D.
Division of Endocrinology and Metabolism
The Johns Hopkins University School of Medicine
Baltimore MD


Address Correspondence:
Scott A. Rivkees, M.D.
Yale Pediatric Thyroid Center
Yale University School of Medicine
464 Congress Ave; Room 237
New Haven CT 06520
Phone:203-737-5975; fax 203-737-5972
scott.rivkees@yale.edu


As recently reported1, 2, a significant problem related to the use of propylthiouracil (PTU) in children has come to light, as PTU use for the treatment of pediatric Graves` disease is associated with an unacceptable risk of liver failure. Although the recommendations of the New England Journal of Medicine letter published April 9th were from two individuals1, The Endocrine Society alerted their members on April 14th about the hepatotoxicity risk in children and recommend that PTU stop being used in the pediatric population3. On April 15th, The Lawson Wilkins Pediatric Endocrine Society sent their members a "blast" email, alerting their members about the New England Journal of Medicine letter. The "PTU problem", though, is not pediatric specific, as there has been a smoldering stream of adults treated with PTU who have experienced liver failure and death.
The PTU problem came to attention at a recent Eunice Kennedy Shriver National Institutes of Child Health (NICHD)-sponsored workshop on October 28, 20084. Based on epidemiology and adverse event data presented, it was estimated that the risk of PTU-related liver failure leading to liver transplantation or death was about 1 in 2,000 treated children2, 4. Ten-fold more children were estimated to sustain reversible liver damage2, 4. Based on more recently data of PTU-related adverse events that have come to light after over the past month, the risk of PTU-related acute liver injury may be even greater than previous estimates and may be 1 in 1,000 or higher.
Although the focus of the NICHD workshop was on pediatric hepatotoxicity!!!!, it was clear at that time that the PTU-problem is not pediatric-specific. On April 19, 2009, in Washington D.C., a workshop was sponsored by the American Thyroid Association (ATA) and the Food and Drug Administration (FDA) was thus held to examine PTU hepatoxicity in adults5. Based on presented data, it was estimated that the risk of PTU-related liver injury is between 0.1 to 1%5, 6, and the incidence of acute liver failure may be about 1 in 10,000 treated adults, although this estimate is not precise7.
In the published medical literature, there are at least 32 reports of severe PTU-related liver failure in adults and 10 in children2, 4!!!!. Data from the United Network of Organ Sharing (UNOS) reveals 16 liver transplants in adults and 7 in children over the past 17 years due to PTU-induced liver failure2, 4, 8FDA Adverse Event Reporting System (AERS) databases contain reports of severe liver injury in 22 adults over the past 20 years, 9 of whom died and 5 received liver transplants5. Over a comparable period, 12 pediatric patients sustained severe liver injury resulting in 3 deaths and 6 liver transplants5. The average dose of PTU associated with liver failure was close to 300 mg per day in both children and adults. Liver failure occurred 6 to 450 days after treatment onset5.
Liver failure related to PTU use is idiosyncratic4, 5. There are no pretreatment biomarkers that can be used to assess hepatotoxicity risk4, 5. Of major concern, monitoring of liver function (bilirubin and alkaline phosphatase) and assessment of transaminase levels (ALT/AST) will not identify individuals who will develop PTU-induced liver failure, as liver failure can be sudden, unpredictable and rapidly progressive4, 5.
It is estimated that about 60,000 adults and 4,000 children develop new onset Graves` disease each year4, 5. In 2008, 340,000 individuals were prescribed methimazole and 101,000 individuals were prescribed PTU5. Over the past several years, there has been a reduction in the prescribing of PTU in favor of increased MMI use4, 5. However, a significant number of individuals are taking still taking PTU.
Whereas there is little evidence of MMI-related hepatotoxicity in children, MMI can be toxic to the liver in adults9. MMI-related liver failure has been reported in the medical literature, and there are 5 reports of liver injury in adults in the FDA AERS5. MMI hepatotoxicity in adults is associated with the use of very high doses, older age, and the presence of preexisting liver disease9. Whereas there have been 1 to 3 liver transplants per year in PTU treated individuals in the United States for the past 17 years, we are unaware of reports of MMI-related liver transplants over the same period4.
The use of MMI in the treatment of Graves` disease has several advantages over PTU10 !!!. MMI is more efficacious than PTU in controlling the hyperthyroid state11, compliance with once a day MMI is better than with PTU prescribed three times a day12, and PTU is more toxic than MMI4, 5. PTU use is also associated with a higher rate of antineutrophilic cytoplasmic antibody (ANCA) positivity and the risk of ANCA-mediated vasculitis than MMI13, 14. As such, there is no reason to use PTU as a first line drug in the treatment of Graves` disease.
Because there is no good plan for managing the risk of hepatotoxicity with PTU, PTU use should be restricted to circumstances when neither surgery, nor radioactive iodine are treatment options in a patient who has developed a toxic reaction to MMI and antithyroid drug therapy is needed2. In this situation, patients should be informed of the risk of liver failure. If patients taking PTU develop tiredness, nausea, anorexia, pharyngitis, or feel ill, the medication should be immediately discontinued and a white blood cell count, bilirubin, alkaline phosphatase, and ALT/AST obtained.
Whereas MMI is recommended as first line antithyroid drug therapy for nearly all individuals10, 15. PTU remains the drug of choice during pregnancy in the United States16-18. MMI use during early pregnancy, has been associated with scalp defects (aplasia cutis) and choanal atresia in offspring17-20. The incidence of skin defects is estimated to be about 1 in 4000 to 10,000 pregnancies, and it has been suggested that this level is not above background21. The relative risk of choanal atresia in pregnant women taking MMI, was found to about 17-fold greater than the general population, but the birth defects were attributed to maternal hyperthyroidism, not MMI20. In another study of effects of maternal hyperthyroidism and MMI on congenital malformations, hyperthyroidism itself was associated with a risk of malformations (6%); MMI was not associated with congenital defects2.
In addition to considering potential adverse effects of MMI on the fetus during embryogenesis, one needs to consider reports of maternal and fetal liver failure and death during pregnancy associated with PTU use23. We are also aware of two reports of serious maternal liver injury due to PTU during pregnancy, and two reports of liver injury in fetuses whose mothers took PTU, in FDA AERS data5. Liver injury in an infant born to a mother taking PTU during pregnancy has been reported, as well24.
At present we do not have clear data to assess the risk of liver injury and liver failure in women taking either MMI or PTU during pregnancy, or to the fetus. Epidemiologic studies are needed to assess the relative risks of fetal birth defects associated with MMI vs. liver failure risks to the mother and fetus with prenatal PTU use. Until such studies are completed, we are left to choose between a drug that may be associated with a small risk of birth defects in infants and a small, but real, risk of liver injury in expectant mothers.
As suggested, the risk of antithyroid drug use during pregnancy can be reduced by limiting PTU use to the first trimester and then changing to MMI! Antithyroid drugs can also be stopped in about 30% of women in the third trimester, as well16-18.
Considering this issue, and the risks involved for women with active thyrotoxicosis during pregnancy, it is important that that definitive treatment with radioactive iodine or surgery be considered for women with Graves` disease who desire to become pregnant. Eliminating the need for antithyroid drugs during gestation eliminates the risk of drugs associated with a potential birth defects or liver injury in the mother. We can also reduce the much more common risks to the fetus of birth defects (6%)22 and growth retardation (>20%) associated with active hyperthyroidism in pregnancy.
Graves` disease is a serious medical condition that warrants treatment at all ages10, 15, and all treatments have potential risks26. Looking back over the sixty years since PTU was introduced for the treatment of Graves` disease, it is clear that PTU is associated with a concerning risk of serious or fatal liver injury. The "PTU problem" affects both children AND adults. Thus, in adults PTU use should be avoided, and used with caution when prescribed. Because the risk of PTU appears to be substantially greater in children than adults, PTU should not be used in children, except in exceptional circumstances.

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Prof. Dr. Balázs Csaba
2014-12-18 12:15:09