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
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 defects22.
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 MMI16-18. 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 pregnancy25.
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.
Acknowledgement: Please note that 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 or other organizations.


  1. Rivkees SA, Mattison DR. Ending propylthiouracil-induced liver failure in children. N Engl J Med 2009;360(15):1574-5.
  2. Rivkees SA, Mattison DR. Propylthiouracil (PTU)-induced Liver Failure and Recommendations for the Discontinuation of PTU Use in Children. International Journal of Pediatric Endocrinology 2009. http://www.hindawi.com/GetArticle.aspx?doi=10.1155/2009/132041.
  3. The Endocrine Society Statement on the New England Journal of Medicine Letter to the Editor on PTU Use In Children. April 14, 2009. http://www.endo-society.org/advocacy/legislative/SocietyStatementontheNEJMLettetotheEditoronPTUUseInChildren.cfm
  4. Conference Proceeding: Hepatic Toxicity Following Treatment for Pediatric Graves’ Disease Meeting: October 28, 2008. Eunice Kennedy Shriver National Institute of Child Health and Human Development. http://bpca.nichd.nih.gov/outreach/index.cfm.
  5. Propylthiouracyl (PTU)-Related Liver Toxicity; Public Workshop. April 18, 2009, Washington, D.C. http://www.fda.gov/CDER/meeting/ptu_toxicity.htm
  6. Kim HJ, Kim BH, Han YS, et al. The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study. Am J Gastroenterol 2001;96(1):165-9.
  7. Cooper DS, Rivkees SA. Putting Propylthiouracil in Perspective. Journal of Clinical Endocrinology & Metabolism 2009;(in press).
  8. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10(8):1018-23.
  9. Woeber KA. Methimazole-induced hepatotoxicity. Endocr Pract 2002;8(3):222-4.
  10. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352(9):905-17.
  11. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007;92(6):2157-62.
  12. Nicholas WC, Fischer RG, Stevenson RA, Bass JD. Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J 1995;88(9):973-6.
  13. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, Zoric S, Bukilica M. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res Ther 2005;7(5):R1072-81.
  14. Huang CN, Hsu TC, Chou HH, Tsay GJ. Prevalence of perinuclear antineutrophil cytoplasmic antibody in patients with Graves’ disease treated with propylthiouracil or methimazole in Taiwan. J Formos Med Assoc 2004;103(4):274-9.
  15. Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006;19(9):1095-111.
  16. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92(8 Suppl):S1-47.
  17. Chan GW, Mandel SJ. Therapy insight: management of Graves’ disease during pregnancy. Nat Clin Pract Endocrinol Metab 2007;3(6):470-8.
  18. Chattaway JM, Klepser TB. Propylthiouracil versus methimazole in treatment of Graves’ disease during pregnancy. Ann Pharmacother 2007;41(6):1018-22.
  19. Bachrach LK, Burrow GN. Aplasia cutis congenita and methimazole. Can Med Assoc J 1984;130(10):1264.
  20. Barbero P, Valdez R, Rodriguez H, et al. Choanal atresia associated with maternal hyperthyroidism treated with methimazole: a case-control study. Am J Med Genet A 2008;146A(18):2390-5.
  21. Van Dijke CP, Heydendael RJ, De Kleine MJ. Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 1987;106(1):60-1.
  22. Momotani N, Ito K, Hamada N, Ban Y, Nishikawa Y, Mimura T. Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol (Oxf) 1984;20(6):695-700.
  23. Morris CV, Goldstein RM, Cofer JB, Solomon H, Klintmalm GB. An unusual presentation of fulminant hepatic failure secondary to propylthiouracil therapy. Clin Transpl 1989:311.
  24. Hayashida CY, Duarte AJ, Sato AE, Yamashiro-Kanashiro EH. Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil. J Endocrinol Invest 1990;13(11):937-41.
  25. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al. Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin Endocrinol (Oxf) 2001;54(3):365-70.
  26. Rivkees SA. Graves’ disease therapy in children: truth and inevitable consequences. J Pediatr Endocrinol Metab 2007;20(9):953-5.
MRR – Texas
March 31, 2009 – 16:29

Several interesting points came to mind when I reviewed the NICE-SUGAR study; the degree of severe hypoglycemia, the degree of cardiovascular mortality, the conventional group’s blood glucose levels are significantly lower than the vast majority of other outcome studies, and the number of severe septic patients in the intensive control branch of the study. According to the 2008 sepsis guidelines, the glycemic control target level for the septic patient is already in question and perhaps sepsis should be an exclusion criteria?

I was tasked with the development and oversight of a Tight Glycemic Control Program pilot study from May 2006 through April 2008 for a South Texas community hospital/level 2 trauma center. This included a 14 bed CCU, 12 bed M/S ICU and 12 bed trauma ICU as well as 4 M/S wards. Clinical inertia was our most difficult element to overcome and for the most part this was never accomplished. Clinical inertia was not only evident on physician’s part, but also administration, nursing, nutritional services, pharmacy, and the patients themselves. Accountability to noncompliance to protocols was lacking as well. The philosophy that inpatient glycemic control was not necessarily treating diabetes, yet acute hyperglycemia was never fully accepted. When results like ACCORD, ADVANCE, and VADT were released, I would usually take the phone off the hook and leave the hospital because those wbeepdo not support inpatient glycemic control would come out en mass wishing to compare apples to oranges. That is not necessarily the case with NICE-SUGAR. In our Trauma ICU, where support was highest, for the entire year of 2007, we had only 7% BG > 200mg/dL, less than 2% hypoglycemia under 50 mg/dL, and nearly 75% BG between 80 – 150 mg/dL.

Overall, I applaud the NICE-SUGAR research team for a job very well done and thank them for their contribution to this ongoing discussion. I do support further research to differentiate specific glycemic control target ranges for specific diagnosis, but I too fear this could cause a pendulum swing in the opposite direction resulting in less facilities participating in inpatient glycemic control resulting in less data for differentiation.

March 26, 2009 – 15:25
Subject: NICE -SUGAR

I think that the central goal of the ADA/AACE impatient glucose targets is safe with the protocols .
Hospitals should have protocols in place for using insulin to treat and prevent hyperglycemia.
Subcutaneous insulin may be used for both purposes in most noncritically ill patients, whereas intravenous infusion of
insulin is preferred in critically ill patients.
Be careful with this trial [NICE -SUGAR] to overcome clinical inertia.

Dr. Orlin Sergev – Charleston, SC
March 16, 2009 – 16:28

Dear Dr Hellman:
I enjoyed all the editorials on patients’ safety that you have recently published. I think that they raise questions which we as physicians are not always open about. Safety itself is frequently a topic that we love to discuss but it’s never our fault. In this connection, the article about overconfidence and medical errors is timely – especially, at this time of expected health care changes. Briefly, I do not think we as physicians are different from any other specialists in different areas. Lack of adequate knowledge in a special area is always a good reason to be noisy and seemingly overconfident. Most of us agree that the more you know the more you realize how much more you do not know. Overconfident behavior in front of outsiders seem to be the cover of ignorance. I think we have to improve medical education in order to make medical decisions safer. Just remember the pilot of the plane that landed in Hudson river – quiet professional on top of his performance. We in medical profession must lead in patients’ safety. In order to do that we have to lead the health care reform. We have to regain our authority, responsibility and accountability. (accountability without authority and responsibility is meaningless – see Dr Hellman’s article on Medicare). We have to lead the health education of the society – most of the tragic mistakes in life happen from ignorance. First and foremost, of course, we have to maintain the superiority in medical knowledge. We must improve the quality of medical education. Instead of multiple choice questions we have to put back in place the stern professor wbeepmade clinical judgements based on knowledge, experience, and gut feeling and set up a good personal example for the next generation of physicians. Pilot “Sully” did not read the manual and the guidelines how to handle the critical situation – all his life before, however, prepared him for the right on the spot decision. Decisions based on profound knowledge and experience are the safest! Let’s start the health care reform with ourselves.
Do not stop learning and teaching your team about sound and safe medical practices. When we have achieved that, we can confidently go out and regain our authority over various bureaucracies (government agencies-Medicare, insurances, medical malpractice law, etc).

james t poulos – west lafayette in
March 03, 2009 – 15:09

There was an article in acta scandinavia in january that showed very little hypoglycemia when intensive therapy is done right! I came across the article on medlinx in mid January, but it was actually published in October 2008. authors: Kaukonen KM et al in acta anaethesiol scandinavia and titled severe hypoglycemia in intensive insulin therapy.

Reply to james t poulos
Dr Hellman
March 04, 2009 – 16:12
Subject: Further thoughts related to the NICE-SUGAR study

Dear Dr. Poulos,

Thank you for calling attention to the study by Kaukonen KM et al. Your excellent point adds to the discussion generated by the NICE-SUGAR study. Their preliminary data analysis showed that error by provider was the most common cause of hypoglycemia. Their data implied, as I stated in my recent editorial, that improving the training and performance of those managing the insulin infusions greatly decreases the threat of hypoglycemia.

In this study by Kaukonen, done at the Helsinki University Central Hospital in Helsinki, Finland, the authors evaluated the incidence of hypoglycemia in all patients treated in two intensive care units between February 2005 and June 2006. They showed that severe hypoglycemia during intensive insulin therapy was rare in clinical practice. Analyzing data for 1124 patients and 61,203 glucose measurements, they found 36 measurements of severe (≤ 2.2mmol/L) hypoglycemia in 25 patients, with an incidence of 0.06% of severe hypoglycemia.

They commented that the frequency of blood glucose monitoring correlated inversely with the frequency and magnitude of severe hypoglycemia. In surgical patients, it is of note that five of the six instances of hypoglycemia occurred when a nurse failed to comply with the protocol.

The Helsinki group’s observations are entirely in keeping with the preliminary data from the NICE-SUGAR study and make a good deal of common sense. When the rate of decrease of glucose is rapid, for example greater than 1mg/dl/minute, simple arithmetic can tell us when the next glucose determination needs to occur to be able to safely avoid severe hypoglycemia. But if the frequency of checking of glycemic levels is arbitrary, and set too low, then hypoglycemia is to be expected much more often. The Kaukonen group avoided this by making sure the blood glucose sampling was relatively frequent.

In our clinical practice setting as well, the principles of safe handling of insulin infusions have been:

1.frequent monitoring, always at least hourly in ICU settings, more often when dealing with lower glycemic levels;
2.intensive training of nurses to make them expert in understanding how best to use algorithms;
3.specific points at which prolonged hyperglycemia or hypoglycemia necessitates immediate consultation with the responsible physician;
4.review of data to indicate variations in performance and appropriate correction and retraining when appropriate.

We too have extensive experience over many years with the safe use of insulin infusions in inpatient settings with relatively rare severe hypoglycemic episodes and little morbidity.

The NICE-SUGAR study should provide important information. We should not get too far ahead of their forthcoming data, but there is already abundant data, such as the important study from Helsinki, which show us that with a safer system of care, more ambitious glycemic control is both achievable and safe.

Kaukonen KM et al. Severe hypoglycemia during intensive insulin therapy, Acta Anaesthesiol Scand. 2009 Jan;53(1):61-65. Epub 2008 Oct 20.