propylthiouracil and Necrosis

Two cases of propylthiouracil-associated acute hepatitis, one case of fatal methimazole-associated hepatocellular necrosis and one case of propylthiouracil-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism.

Topics: Adult; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Lupus Erythematosus, Systemic; Methimazole; Necrosis; Propylthiouracil

Topics: Acetaminophen; Acetylcysteine; Animals; Cell Membrane; Chemical and Drug Induced Liver Injury; Cimetidine; Cysteamine; Glucuronates; Glutathione; Humans; Inactivation, Metabolic; Lipid Peroxides; Liver; Methionine; Necrosis; Propylthiouracil

Topics: Desoxycorticosterone; Dogs; Epinephrine; Heart Diseases; Hyperthyroidism; Hypokalemia; Isoproterenol; Myocardial Infarction; Necrosis; Norepinephrine; Potassium Deficiency; Propylthiouracil; Rats; Research; Thyroidectomy; Toxicology

Topics: Adrenal Cortex Hormones; Antithyroid Agents; Diagnosis, Differential; Disease Progression; Female; Humans; Immunosuppressive Agents; Middle Aged; Necrosis; Predictive Value of Tests; Propylthiouracil; Skin; Time Factors; Treatment Outcome; Vasculitis; Wound Healing

Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic myopathy. We herein report an unusual case of thyrotoxic myopathy presenting as unilateral drop foot. Histopathological examinations of the left tibialis anterior muscle showed marked variation in the fiber size, mild inflammatory cell infiltration, and necrotic and regenerated muscle fibers with predominantly type 1 fiber atrophy. Medical treatment with propylthiouracil resulted in complete improvement of the left drop foot. This case expands the phenotype of thyrotoxicosis and suggests that thyrotoxicosis be considered as a possible cause of unilateral drop foot.

Topics: Adolescent; Antithyroid Agents; Biopsy; Female; Gait Disorders, Neurologic; Humans; Magnetic Resonance Imaging; Muscle, Skeletal; Muscular Diseases; Necrosis; Paralysis; Propylthiouracil; Thyrotoxicosis

A 43-year-old Chinese female had been diagnosed with hyperthyroidism 15 years ago. She was recently administered 150 mg/day propylthiouracil (PTU). After 3 weeks of PTU administration, she developed necrotizing stomatitis and osteonecrosis, most likely due to secondary effects from the PTU treatment. Her neutrophil count was reduced below normal to 0.24×10(9)/L but normalized after withdrawal of PTU therapy. About 1 month after onset, the patient came to our hospital and began to receive intravenous treatments of metronidazole and amoxicillin. Following review of her medical history and a series of clinical and laboratory examinations, the patient was diagnosed with secondary necrotizing gingivostomatitis and osteonecrosis possibly associated with PTU-induced agranulocytosis. One-year after treatment, the patient's oral manifestations remained unchanged. This case demonstrates the need for dental practitioners to more closely monitor oral symptoms in patients with hyperthyroidism treated with antithyroid drugs.

Topics: Adult; Antithyroid Agents; Biopsy; Combined Modality Therapy; Female; Gingivitis; Humans; Hyperthyroidism; Necrosis; Osteonecrosis; Propylthiouracil; Radiography, Panoramic; Stomatitis

Propylthiouracil (PTU), a thyonamide class drug commonly used to treat hyperthyroidism has been reported to cause adverse reactions in 3% to 12% of patients. The side effects have been described more frequently as mild, but ocasionally severe fatal reactions may occur. We report the case of a fourteen years old patient in use of PTU for the last three years who presented with fever, hemorrhagic blisters, necrotic ulcers, and that developed purpuric lesions and nodules in lower extremities. Laboratory and histopathologic findings were compatible with skin leukocytoclastic vasculitis, a pattern found in hypersensitivity reaction vasculitis. Suspension of PTU and introduction of prednisone, induced complete remission of symptoms and healing of the skin lesions. The importance of this study is to call attention to the occurrence of serious cutaneous manifestation with a mortality rate that might reach 10%, associated with a systemic drug frequently used in internal medicine. Early diagnosis and withdrawal of the suspected medication is mandatory. Administration of corticosteroids and/or immunosuppressives agents must be considered.

Topics: Adolescent; Antithyroid Agents; Humans; Male; Necrosis; Prednisone; Propranolol; Propylthiouracil; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Female; Follow-Up Studies; Glomerulonephritis; Humans; Hyperthyroidism; Necrosis; Plasmapheresis; Propylthiouracil; Radiography, Thoracic; Time Factors; Treatment Outcome; Vasculitis

The effect of hyper or hypoactive thyroid on the renal toxicity of arsenic trioxide has been studied in rats. It was observed that pre-treatment of rats with thyroxine stimulates arsenic excretion in urine. The anti-thyroid drug n-propylthiouracil (PTU), inhibits the accumulation of arsenic in renal tissue. Both treatments affect the renal pathology. Histopathological lesions are less severe in PTU and arsenic-treated rats in comparison to thyroxine and arsenic-treated rats. Ultrastructural studies support light microscopical observations. An adaptive response was noticed against arsenic in PTU pre-treated rats. We attribute this response to decreased glutathione-S-transferase (GSH) activity and increased GSH synthesis in the kidney. A relationship between thyroidal activity and arsenic toxicity is suggested by present observations.

Topics: Animals; Antithyroid Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Creatinine; Glomerulonephritis; Glutathione; Glutathione Transferase; Hyperthyroidism; Hypothyroidism; Kidney; Male; Necrosis; Oxides; Propylthiouracil; Rats; Rats, Wistar; Thyroxine; Triiodothyronine

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bax protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bax protein expression.

Topics: Annexin A5; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Cell Line; Cell Membrane; Cell Survival; Cells, Cultured; Cycloheximide; HeLa Cells; Humans; Iodide Peroxidase; Kinetics; Necrosis; Oxidative Stress; Phosphatidylserines; Potassium Iodide; Propylthiouracil; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Thyroid Gland; Tumor Cells, Cultured; Tumor Suppressor Protein p53

A teenage girl with crescentic glomerulonephritis had antineutrophil cytoplasmic antibody (ANCA) detected after she had received propylthiouracil (PTU) for hyperthyroidism without cutaneous vasculitis. ANCA was detected on admission; renal biopsy showed crescentic glomerulonephritis with focal necrotizing glomerulonephritis but no immune deposits. Administration of steroid and decreasing the dose of PTU produced a good clinical response and the ANCA disappeared. It was concluded that ANCA is closely related to the pathogenesis of crescentic glomerulonephritis and that treatment with PTU appeared to induce ANCA.

Topics: Adolescent; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Humans; Hyperthyroidism; Necrosis; Propylthiouracil

Methimazole, an anti-thyroid drug, was recently found to be useful in the treatment of systemic lupus erythematosus and other autoimmune diseases. Moreover, decreased thyroid hormone production is associated with a variety of immunological manifestations, such as reduced activation of CD4+ cells, increased CD8+ cell activity and reduced soluble IL-2 receptors. In the present study we examined the effects of methimazole and propylthiouracil on a rat model of experimental colitis.. Colitis was induced by intracolonic administration of 30 mg trinitrobenzene sulphonic acid (TNB). Two weeks prior to induction of colitis, rats were treated by either methimaziole (0.04%) or propylthiouracil (0.01%) in drinking water after a week of free access to water. Rats were sacrificed 48 h or 7 days after induction of colitis. The colon was isolated, rinsed with ice-cold water and weighed. Damage was assessed both macroscopically and microscopically and myeloperoxidase (MPO) activity determined.. All treated rats were hypothyroid as manifested by a significant elevation of thyroid stimulating hormone (TSH), by comparison with the control groups (mean -1.82 +/- 0.40 versus 0.11 +/- 0.02 mmol/L, respectively). The inflammatory response elicited by TNB resulted in severe mucosal damage 48 h after damage induction, which persisted for 7 days. Pre-treatment with either methimazole 0.04% or propylthiouracil 0.01% significantly decreased mucosal damage macroscopically (lesion area, lesion score and segmental weight) microscopically and also significantly decreased MPO level at both time points (P < 0.01).. Methimazole and propylthiouracil significantly reduce mucosal damage and colonic weight in a rat model of colitis. The mode by which they do so remains to be studied.

Topics: Animals; Antithyroid Agents; Colitis, Ulcerative; Intestinal Mucosa; Male; Methimazole; Necrosis; Peroxidase; Propylthiouracil; Rats; Rats, Inbred Strains; Trinitrobenzenesulfonic Acid

Drug induced hepatitis is a rare complication of thiourea antithyroid drugs. In some patients, the hepatotoxicity may be severe and lead to submassive hepatic necrosis (SHN). Submassive hepatic necrosis is a potentially fatal complication which is usually recognized on the liver biopsy and histological examination or autopsy. In the case presented here, SHN was identified on Tc-99m SC liver images. Sharply defined intrahepatic photopenic abnormalities without significant colloid shift were noted. SPECT images were most remarkable and exhibited extensive liver necrosis. Resolution of hepatic abnormalities correlated with clinical and biochemical resolution of SHN. In patients with propylthiouracil hepatotoxicity, serial liver SPECT images with Tc-99m SC appear helpful for the diagnosis and follow up of SHN and, in an appropriate clinical context, may obviate the need for liver biopsy.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Graves Disease; Humans; Liver; Necrosis; Propylthiouracil; Technetium Tc 99m Sulfur Colloid; Tomography, Emission-Computed, Single-Photon

We present a fatal case of acute submassive hepatic necrosis occurring in a 42-yr-old black woman treated for hyperthyroidism with propylthiouracil for 1 yr. Alcohol and drug abuse were ruled out and all serological tests for hepatitis A and B, cytomegalovirus, and Epstein-Barr virus infection were negative. At autopsy the liver was shrunken and presented a yellow granular appearance. Microscopy disclosed submassive necrosis with bile stasis and severe chronic inflammation, as well as mild bile duct proliferation. Although non-A, non-B hepatitis cannot be ruled out (there was no transfusion of blood or its products), this is considered to be the third fatal case and ninth instance of propylthiouracil-induced hepatic necrosis.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Liver; Necrosis; Propylthiouracil

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Glutathione; Hypothyroidism; Liver; Male; Necrosis; Propylthiouracil; Rats; Thyroid Gland; Thyroidectomy

Topics: Amino Acids; Ammonia; Animals; Caseins; Dietary Proteins; Hypoxia; Liver; Liver Diseases; Male; Necrosis; Oxygen Consumption; Propylthiouracil; Rats; Time Factors; Urea

Rats given a single intragastric dose of carbon tetrachloride (CCl4), 0.25, 0.50, or 1.0 ml per kg) showed a dose-dependent increase in SGOT, serum ornithine carbamyltransferase, and liver necrosis (graded histologically as 0 to 4+) 24 hr after the treatment. Daily intubation with propylthiouracil (PTU) for 10 days in doses of 5 to 50 mg per kg significantly reduced the elevation of SGOT activity, completely suppressed the serum ornithine carbamyltransferase changes, and reduced the degree of necrosis found 24 hr after the intragastric administration of CCl4. Similar protection was found when CCl4 was given intraperitoneally. When PTU was given in liguid diets for 6 days, protection against CCl4 was increased. PTU did not affect the absorption or covalent binding of 14CCl4 to lipids or proteins. Also, control and PTU-treated rats did not differ with respect to glucose-6-phosphatase activity and conjugated diene production after CCl4. Thus, it has been observed that PTU affords partial protection against some end-stage consequences of CCl4 liver injury such as cell necrosis and release of intracellular enzymes. However, PTU afforded no protection against early chemical effects such as covalent binding of CCl4 carbon, lipid peroxidation, or loss of glucose-6-phosphatase. Therefore, it is concluded that the mechanism of the PTU effect comes into play after the initial effects of CCl4 are exerted and in some unknown manner modulates the expression of these early effects.

Topics: Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Glucose-6-Phosphatase; Liver; Male; Necrosis; Ornithine Carbamoyltransferase; Premedication; Propylthiouracil; Protein Binding; Rats

Fulminant hepatic failure developed in a 24-year-old black woman who had been treated with propylthiouracil and propranolol for hyperthyroidism. Clinical and biochemical recovery followed discontinuation of drug therapy. Liver biopsy disclosed submassive hepatic necrosis. During the acute phase of the disease, lymphocyte transformation studies revealed sensitization of the patient's lymphocytes to propylthiouracil but not to propranolol. Sensitization remained demonstrable 2 months after cessation of the former drug. Lymphocytes obtained from a hyperthyroid patient treated with propylthiouracil without complications failed to show evidence of sensitization. These observations indicate that submassive hepatic necrosis may result from treatment with propylthiouracil and are consistent with the notion that sensitization mechanisms may be responsible for the hepatic injury induced by this drug.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Liver; Lymphocyte Activation; Lymphocytes; Necrosis; Propylthiouracil

We have previously reported that a hypermetabolic state, resembling that produced by thryoid hormones, exists in the livers of animals treated chronically with ethanol. We propose that this alteration produces a relative hypoxia in the centrilobular zone of the liver which, if severe enough, leads to cellular death and to the production of hepatitis. Rats consuming ethanol for 30 days, given with a nutritionally adequate diet, and exposed to reduced oxygen tensions for only 6 hr, developed histological and biochemical evidence of hepatocellular necrosis and inflammatory lesions confined to the centrilobular zone. The severity was proportional to the degree of hypoxia. Pair-fed (nonalcohol) controls showed no such lesions. Treatment of the animals with propylthiouracil for 3-10 days abolished the hypermetabolic state of the liver in ethanol-consuming animals, and drastically reduced the histological and biochemical effects of hypoxia in them. These findings may have implications for pathogenesis and treatment of alcoholic hepatitis in man.

Topics: Animals; Chemical and Drug Induced Liver Injury; Ethanol; Hypoxia; Liver; Male; Necrosis; Oxygen Consumption; Propylthiouracil; Rats

Topics: Animals; Bile Acids and Salts; Cholesterol; Diet, Atherogenic; Dietary Fats; Dihydrotachysterol; Fludrocortisone; Heart Diseases; Myocardial Infarction; Necrosis; Nephrocalcinosis; Phosphates; Propylthiouracil; Rats; Stress, Physiological; Thrombosis

Topics: Adrenal Glands; Animals; Edema; Hemorrhage; Hyperemia; Necrosis; Propylthiouracil; Rats; Thyroxine

Topics: Angina Pectoris; Aspartate Aminotransferases; Heart; Isocarboxazid; Isoproterenol; L-Lactate Dehydrogenase; Lactates; Models, Theoretical; Monoamine Oxidase Inhibitors; Myocardial Infarction; Necrosis; Papillary Muscles; Propylthiouracil; Rats; Research; Thiouracil; Toxicology