The aim of this study was to determine the optimal management of patients with propylthiouracil (PTU) hepatotoxicity. A MEDLINE search for English language cases of PTU hepatotoxicity between 1966 and April 1996 was performed, and additional cases were cross-referenced. Twenty-seven cases were selected based on the availability of information on patient management after the onset of hepatotoxicity. Eighty-five percent of the selected cases met this criterion. A detailed summary of the management of two cases of PTU hepatotoxicity at our institutions is also provided. Although most patients recovered once PTU was stopped, seven patients died. Patients with PTU hepatotoxicity who survived were more likely to have received 131I during the course of their illness than those who died (P < 0.03, by Fisher's exact test). In our two patients, hyperbilirubinemia was linearly associated with progressively decreasing T4 levels (r = 0.91; P < 0.001) despite the presence of clinical thyrotoxicosis in one of the patients. These findings demonstrate the need for appropriate clinical evaluation and treatment of thyroid disease during the course of hepatotoxicity. Additionally, we report the first pediatric patient with PTU hepatotoxicity to undergo liver transplantation. The emerging role of liver transplantation in these patients is discussed.

Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned?

Objective: To evaluate the incidence, severity, and course of propylthiouracil-induced hepatic injury in patients with hyperthyroidism. Design: Cohort study. Setting: Outpatient clinic of a univers...

Hepatic Injury during Propylthiouracil Therapy in Patients with Hyperthyroidism: A Cohort Study

The diagnosis of Graves' disease in pregnancy can be complex because of normal gravid physiologic changes in thyroid hormone metabolism. Mothers with active Graves' disease should be treated with antithyroid drugs, which impact both maternal and fetal thyroid function. Optimally, the lowest possible dose should be used to maintain maternal free thyroxine levels at or just above the upper limit of the normal nonpregnant reference range. Fetal thyroid function depends on the balance between the transplacental passage of thyroid-stimulating maternal antibodies and thyroid-inhibiting antithyroid drugs. Elevated levels of serum maternal anti-TSH-receptor antibodies early in the third trimester are a risk factor for fetal hyperthyroidism and should prompt evaluation of the fetal thyroid by ultrasound, even in women with previously ablated Graves' disease. Maternal antithyroid medication can be modulated to treat fetal hyperthyroidism. Serum TSH and either total or free thyroxine levels should be measured in fetal cord blood at delivery in women with active Graves' disease, and those with a history of (131)I-mediated thyroid ablation or thyroidectomy who have anti-TSH-receptor antibodies. Neonatal thyrotoxicosis can occur in the first few days of life after clearance of maternal antithyroid drug, and can last for several months, until maternal antibodies are also cleared.

Therapy insight: management of Graves' disease during pregnancy.

Introduction: Propylthiouracil (PTU) has been used for the treatment of hyperthyroidism since the 1940s, but over the years reports of significant hepatotoxicity have come forth, particularly in children. This led to a black box warning being issued by the US FDA in 2009, followed by a similar warning by the European Medicines Agency and the United Kingdom Medicines and Healthcare Regulatory Agency later that year.Areas covered: This article provides a concise review of the data on hepatotoxicity associated with the currently available antithyroid drugs: PTU, methimazole (MMI) and carbimazole. The differences in mechanism are examined in detail, as well as clinical presentation, management and monitoring. Use in special populations and trends in use of antithyroid medication are also discussed.Expert opinion: PTU is known to cause severe hepatic failure, particularly in children. Its use in children should be avoided. In adults, it is beneficial to use in the first trimester of pregnancy and thyroid storm...

/pdf/propylthiouracil-and-methimazole-and-carbimazole-related-2fvn6c8c8w.pdf

Propylthiouracil, and methimazole, and carbimazole-related hepatotoxicity

Background: Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs). Methods: In an integrated health care delivery system, we examined the prevalence of thyrotoxicosis and gestational ATD use (propylthiouracil [PTU] or methimazole [MMI]) in women with delivered pregnancies from 1996 to 2010. Birth outcomes were compared among all infants and those born to mothers with diagnosed thyrotoxicosis or ATD therapy during gestation, with examination of ATD-associated hepatotoxicity and congenital malformations in the latter subgroups. Results: Among 453,586 mother–infant pairs (maternal age 29.7±6.0 years, 57.1% nonwhite), 3.77 per 1000 women had diagnosed thyrotoxicosis and 1.29 per 1000 had gestational ATD exposure (86.5% PTU, 5.1% MMI, 8.4% both). Maternal PTU-associated hepatotoxicity occurred with a frequency of 1.80 per 1000 pregnancies. Infants of mothers with diagnosed thyro...

/pdf/gestational-thyrotoxicosis-antithyroid-drug-use-and-neonatal-4nps0wy29u.pdf

Gestational thyrotoxicosis, antithyroid drug use and neonatal outcomes within an integrated healthcare delivery system.

A female newborn whose mother was taking propylthiouracil (PTU) for Graves' disease, presented with transient thyrotoxicosis (serum triiodothyronine 1,710 ng/dl) and signs of acute hepatic injury. Jaundice and choluria were evident on her fourth day of life. Serum total bilirubin reached 14 mg/dl, with a direct fraction of 11 mg/dl. Serum alanine aminotransferase and aspartate aminotransferase showed moderate elevations (110 IU/l and 61.5 IU/l, respectively), as well as the alkaline phosphatase which increased to about twice the upper limit of normal. When incubated with PTU, the patient's cultured peripheral lymphocytes underwent transformation to more than twice the values found in 2 controls, with a stimulation index (SI) of 3.19, compared to SI of 1.45 and 1.15 for the controls, suggesting a hypersensitivity mechanism involved in the hepatic injury. Although about 20 cases of PTU induced hepatic damage were reported in the medical literature, this is, as far as we know, the first description of neonatal liver injury probably caused by placental transfer of this drug.

Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil

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Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil