propylthiouracil and Liver-Failure

To bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982-2008) for acute liver failure in PTU-treated hyperthyroid patients, and propose recommendations for the clinical use of PTU. Thirteen files of PTU-related severe liver adverse effects were analyzed for the pediatric population, seventeen for nonpregnant adults and two for pregnant women.. The recent findings showed that the daily PTU dose administered was high in the children, with a mean of 300 mg/day for an average 10-year-old individual. With regard to treatment duration, PTU administration lasted for at least 4 months in 75% of pediatric cases. Similarly, in a majority of adult cases (64%), PTU-induced liver injury occurred after a relatively long treatment period (4 months to >1 year).. PTU should not be used in children, in whom methimazole (MMI) represents the logical alternative. In adults, PTU should be restricted to those rare patients with Graves' disease for whom no better alternative can be offered and in patients with thyroid storm. For the special circumstance of pregnancy, PTU is the preferred choice during early gestation; switching back to MMI during later gestational stages remains a matter of clinical judgment. It is unknown whether liver function tests monitoring is worthwhile to prevent life-threatening, PTU-related hepatotoxicity.

Topics: Adult; Age Factors; Antithyroid Agents; Child; Drug Administration Schedule; Female; Graves Disease; Humans; Hyperthyroidism; Liver Failure; Male; Methimazole; Patient Selection; Pregnancy; Pregnancy Complications; Propylthiouracil; United States; United States Food and Drug Administration

Propylthiouracil (PTU), methimazole (MMI) and carbimazole are indicated for the treatment of hyperthyroidism in adult and pediatric patients. The aim of this review is to present all the relevant information regarding the use of antithyroid drugs (ATD) in pediatric thyrotoxic cases, the pediatric toxicology of ATD and the warning which has recently been issued for PTU by the FDA.. Epidemiology, diagnosis and treatment of pediatric thyrotoxicosis are all presented in this article. The authors also extensively discuss the details regarding the pharmacology, bioactivation, biodisposition, bioavailability and pharmacokinetic properties of the two main ATD (MMI and PTU).. The FDA recently reported that use of PTU is associated with a higher risk for clinically serious or fatal liver injury compared to MMI in both adult and pediatric patients. They also found that congenital malformations were reported approximately three times more often with prenatal exposure to MMI compared with PTU and especially with the use of MMI during the first trimester of pregnancy. The authors believe that PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of MMI, and there are no other treatment options available. That being said, PTU may be the treatment of choice during, and just before, the first trimester of pregnancy.

Topics: Agranulocytosis; Animals; Antithyroid Agents; Carbimazole; Child; Child, Preschool; Evidence-Based Medicine; Female; Graves Disease; Humans; Hyperthyroidism; Liver Failure; Methimazole; Pregnancy; Propylthiouracil; Randomized Controlled Trials as Topic; Thyrotoxicosis; Vasculitis

Hyperthyroidism is a common endocrine disorder affecting 2% of females and 0.5% of males worldwide and antithyroid drugs constitute the first line of treatment in the majority of cases. These agents may cause severe adverse effects and among them liver failure, although rare, is a potential lethal one. This case illustrates the sudden and abrupt deterioration of hepatic function due to antithyroid drug administration. This case along with a concise literature review is presented aiming to increase the awareness of endocrinologists of possible fatal complications from the everyday use of common agents such as antithyroid drugs.

Topics: Adult; Antithyroid Agents; Female; Humans; Hyperthyroidism; Liver Failure; Methimazole; Propylthiouracil; Thyroidectomy

Topics: Adult; Antithyroid Agents; Female; Humans; Hyperthyroidism; Liver Failure; Pregnancy; Pregnancy Complications; Propylthiouracil

Topics: Antithyroid Agents; Delayed Graft Function; Fatal Outcome; Female; Graft Rejection; Hepatorenal Syndrome; Humans; Hyperthyroidism; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Male; Middle Aged; Propylthiouracil; Renal Insufficiency; Tissue Donors; Treatment Outcome; Young Adult

A 19-year-old female diagnosed with Graves' disease had treatment initiated with propylthiouracil (PTU). Pretreatment complete blood count and liver-associated enzymes (LAEs) were normal, but no further LAEs were obtained, reflecting U.S. guidelines written in 1995. Three months later, she presented with nausea, vomiting, abdominal pain, and jaundice. LAEs were markedly elevated with: total bilirubin, 6.5 mg/dl; aspartate aminotransferase (AST), 1747 IU/L; and alanine aminotransferase (ALT) 1589 UL/L. After 6 days at an outside hospital, she was transferred to our tertiary care center in acute liver failure with coagulopathy and stage II encephalopathy. Liver transplant evaluation was promptly initiated and she was listed as status 1. PTU was the only medication she had taken; and all serologic, autoimmune, and metabolic studies were negative. She demonstrated rapid clinical deterioration, and on hospital day 7 she underwent orthotopic liver transplant but succumbed to tonsillar herniation immediately after surgery. Pathology from her explanted liver revealed marked necrosis and collapse, consistent with her acute liver failure. PTU-associated hepatotoxicity and myelotoxicity have been well-recognized serious adverse effects for more than 50 years. However, as deaths related to hepatic injury from PTU are rare, American Thyroid Association guidelines do not call for routine monitoring of LAEs, although monitoring of white blood cell count levels is advised. Given the wide spectrum of PTU-related liver injury, ranging from asymptomatic elevations in ALT to fatal acute liver failure, we urge consideration of an LAE monitoring program to prevent irreversible liver damage and call for a reappraisal of monitoring guidelines in the United States.

Topics: Antithyroid Agents; Diagnosis, Differential; Fatal Outcome; Female; Follow-Up Studies; Humans; Hyperthyroidism; Liver Failure; Liver Function Tests; Propylthiouracil; Young Adult

Topics: Antithyroid Agents; Child; Drug Utilization; Graves Disease; Humans; Liver Failure; Propylthiouracil; United States; United States Food and Drug Administration

Topics: Adult; Antithyroid Agents; Female; Graves Disease; Humans; Liver Failure; Methimazole; Pregnancy; Propylthiouracil; Societies, Medical; United States; United States Food and Drug Administration

This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.

Topics: Antithyroid Agents; Cadaver; Child; Female; Graves Disease; Hepatitis, Autoimmune; Humans; Length of Stay; Liver Failure; Liver Transplantation; Propylthiouracil; Treatment Outcome

Propylthiouracyl (PTU)-related liver toxicity is likely to occur in about 1% of treated patients. In case of acute or subacute hepatitis, liver failure may occur in about one third. We report two further cases of PTU-induced subacute hepatitis, in whom the delay between occurrence of liver damage after the initiation of treatment, the underestimation of its severity and the delayed withdrawal of the drug were all likely responsible for liver failure. The high incidence of liver toxicity related to PTU, its potential severity and delayed occurrence after initiation of treatment are in favor of monthly alanine aminotransferase monitoring, at least during the first six months of therapy.

Topics: Adult; Alanine Transaminase; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Liver Failure; Propylthiouracil

Topics: Adult; Antithyroid Agents; Female; Humans; Liver Failure; Propylthiouracil; Thyrotoxicosis