methimazole and Chemical-and-Drug-Induced-Liver-Injury

Rash and cholestatic liver injury caused by methimazole (MMI) in patients with Turner syndrome (TS) and Graves's disease (GD) are rarely reported, and there is a paucity of reports on the management of this condition. It is not clear whether propylthiouracil (PTU) can be used as a safe alternative in this case.. A 37-year-old woman was admitted to our hospital with rash, severe pruritus and a change in urine colour after 2 months of GD treatment with MMI. Physical examination showed rash scattered over the limbs and torso, mild jaundice of the sclera and skin, short stature, facial moles, immature external genitals and diffuse thyroid gland enlargement. Liver function tests indicated an increase in total bilirubin, direct bilirubin, total bile acid, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase and alkaline phosphatase. The level of sex hormones suggested female hypergonadotropic hypogonadism. The karyotype of peripheral blood was 46, X, i(X)(q10)/45, X. After excluding biliary obstruction and other common causes of liver injury, combined with rash and abnormal liver function following oral administration of MMI, the patient was diagnosed as having TS with GD and rash and cholestatic liver injury caused by MMI. MMI was immediately discontinued, and eleven days after treatment with antihistamine and hepatoprotective agents was initiated, the rash subsided, and liver function returned to nearly normal. Because the patient did not consent to administration of. While patients with TS and GD are undergoing treatment with MMI, their clinical manifestations, liver functions, and other routine blood test results should be closely monitored. When patients with TS and GD manifest adverse reactions to MMI such as rash and cholestatic liver injury, it is necessary to discontinue MMI and treat with antihistamine and hepatoprotective agents. After the rash subsides and liver function returns to nearly normal, PTU can effectively control hyperthyroidism without adverse drug reactions.

Topics: Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Cholestasis; Exanthema; Female; Graves Disease; Humans; Methimazole; Prognosis; Turner Syndrome

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

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.. 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.. 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. In the rest of the adult population, it should be used with caution. Carbimazole and MMI are associated with less severe hepatic injury and should be preferred when choosing thionamides as a treatment option.

Topics: Adult; Antithyroid Agents; Carbimazole; Chemical and Drug Induced Liver Injury; Child; Drug Labeling; Female; Humans; Hyperthyroidism; Methimazole; Pregnancy; Propylthiouracil; Severity of Illness Index

Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration "black box alert." We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety.. We conducted a systematic search of PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google. Both English and non-English publications were included. We excluded studies using anti-thyroid therapies other than PTU and MMI, studies not allowing interpretation of results, and abstracts of meetings.. Overall, insufficient statistical power precluded determination of accurate rates of either MMI teratogenicity or PTU hepatotoxicity in cohort studies. However, a case-control study helped identify the relative risk of MMI-induced choanal atresia. A second case-control study failed to show that aplasia cutis congenita is associated with MMI. PTU has been associated with a rare but serious form of hepatic failure.. MMI causes a specific pattern of rare teratogenic effects after first trimester exposure, while PTU therapy may be followed by rare but severe hepatotoxic sequelae. It is therefore appropriate to use PTU to treat maternal hyperthyroidism during the first trimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.

Topics: Abnormalities, Drug-Induced; Antithyroid Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Gestational Age; Humans; Hyperthyroidism; Methimazole; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Propylthiouracil

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

Drug-induced autoimmune diseases have two immunological peculiarities. Firstly, some autoantibodies are present, which are virtually never seen in spontaneous human diseases and may be regarded as specific. This applies to antimitochondria antibody type 3 (anti M3) in the lupus-like syndrome caused by Venocuran, to antimitochondria antibody type 6 (anti M6) in iproniazide-induced hepatitis, to anti-insulin antibody found after treatment with methimazole, and to anti liver/kidney microsome antibody type 2 (anti LKM2) associated with hepatitis induced by tielinic acid. Secondly, a search for other autoantibodies shows that the immune disorder is much more limited than in spontaneous autoimmune diseases. Thus, contrary to myasthenia and idiopathic autoimmune haemolytic anaemia, we never found autoantibodies specifically directed against the thyroid, the stomach or the adrenal gland during treatment with D-penicillamine and alpha-methyldopa. Only some hypotheses may account for these peculiarities. Cross-reaction between drug and autoantigen may occur, but the fact that the antigen-antibody reaction is not inhibited by the drug or its metabolites does not support this explanation. Much more attractive is the "T-cell bypass" theory, according to which autoreacting suppressor T-cells are circumvented by helper T-cells stimulated by the drug-modified autoantigen. In this case, the autoimmune reaction would indicate to which body substance the drug is bound, thus making it immunostimulant, and not a structural similarity between the drug and the autoantigen.

Topics: Animals; Autoimmune Diseases; Cardiac Glycosides; Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Iproniazid; Lymphocytes; Methimazole; Methyldopa; Penicillamine; Plant Extracts; Pyrazoles; T-Lymphocytes; Ticrynafen

Over the past four decades, a great deal has been learned about the pharmacology and mechanisms of action of antithyroid drugs. Their ability to inhibit hormone biosynthesis involves complex interactions with thyroid peroxidase and thyroglobulin, many of which are still poorly understood. Their spectrum of activity is much wider than previously thought, and a number of clinically important extrathyroidal actions have been identified. Despite a greater appreciation for the intricacies of antithyroid-drug pharmacology, controversies still surround the use of these agents in the treatment of thyrotoxicosis. These controversies are apt to continue until the pathophysiology of Graves' disease is fully elucidated.

Topics: Adult; Agranulocytosis; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Child; Female; Fetus; Graves Disease; Humans; Hyperthyroidism; Immunity; Immunoglobulins; Infant, Newborn; Insulin Antibodies; Leukopenia; Lupus Vulgaris; Methimazole; Milk, Human; Pregnancy; Pregnancy Complications; Propylthiouracil; Vascular Diseases

Topics: Alkaline Phosphatase; Aspirin; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Halothane; Humans; Hyperbilirubinemia; Jaundice; Liver; Liver Diseases; Male; Methimazole; Paraquat; Transaminases

Methimazole (MMI), the first-line anti-thyroid agent used in clinical practice is known to induce hepatotoxicity in patients with Grave's disease (GD), although its exact mechanism remains largely unclear. This cohort study aimed to examine the mechanism of MMI-induced hepatotoxicity using metabolomic approach. A total of 40 GD patients with MMI-induced hepatotoxicity (responders) and 80 GD patients without MMI-induced hepatotoxicity (non-responders) were included in this study and their plasma metabolomics was profiled with targeted gas chromatography-tandem mass spectrometry (GC-MS/MS). The plasma levels of 42 metabolites, including glucuronic acid, some amino acids, fatty acids, ethanolamine and octopamine were found to be significantly different between responders and non-responders. In agreement with our previous genotyping data, the genetic polymorphism of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*6, which affects the glucuronidation activity and circulating glucuronic acid level was identified as one of the determinants of MMI-induced hepatotoxicity. Plasma level of ethanolamine has a significant correlation with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The pathway analyses further revealed that monoamine oxidase (MAO) inhibition, reactive oxygen species (ROS) production, mitochondria dysfunction, and DNA disruption might contribute to MMI-induced hepatotoxicity. Interestingly, the metabolomic data further suggested the responders had a higher risk of developing osteoporosis and fatty liver disease in comparison to the non-responders. This mechanistic study sheds light on the pathogenesis of MMI-induced hepatotoxicity and prompts personalized prescription of MMI based on UGT1A1*6 genotype in the management of GD.

Topics: Adult; Alanine Transaminase; Antithyroid Agents; Aspartate Aminotransferases; Blood; Chemical and Drug Induced Liver Injury; Female; Gas Chromatography-Mass Spectrometry; Glucuronosyltransferase; Graves Disease; Humans; Male; Metabolomics; Methimazole; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antithyroid Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Child; Female; Graves Disease; Humans; Japan; Male; Methimazole; Middle Aged; Prevalence; Propylthiouracil; Retrospective Studies; Severity of Illness Index; Young Adult

Drug-induced liver injury is a major concern in clinical studies as well as in post-marketing surveillance. Previous evidence suggested that drug exposure during periods of inflammation could increase an individual's susceptibility to drug hepatoxicity. The antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU) can cause adverse reactions in patients, with liver as a usual target. We tested the hypothesis that MMI and PTU could be rendered hepatotoxic in animals undergoing a modest inflammation. Mice were treated with a nonhepatotoxic dose of LPS (100 µg/kg, i.p) or its vehicle. Nonhepatotoxic doses of MMI (10, 25 and 50 mg/kg, oral) and PTU (10, 25 and 50 mg/kg, oral) were administered two hours after LPS treatment. It was found that liver injury was evident only in animals received both drug and LPS, as estimated by increases in serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and TNF-α. An increase in liver myeloperoxidase (MPO) enzyme activity and tissue lipid peroxidation (LPO) in addition of liver glutathione (GSH) depletion were also detected in LPS and antithyroid drugs cotreated animals. Furthermore, histopathological changes including, endotheliitis, fatty changes, severe inflammatory cells infiltration (hepatitis) and sinusoidal congestion were detected in liver tissue. Methyl palmitate (2 g/kg, i.v, 44 hours before LPS), as a macrophage suppressor, significantly alleviated antithyroids hepatotoxicity in LPS-treated animals. The results indicate a synergistic liver injury from antithyroid drugs and bacterial lipopolysaccharide coexposure.

Topics: Animals; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Inflammation; Lipopolysaccharides; Male; Methimazole; Mice; Mice, Inbred BALB C; Propylthiouracil

Methimazole (MMI) has been used for the treatment of Graves' Disease (GD) for more than half a century. The MMI treatment has been reported to be associated with hepatotoxicity. Previous studies have demonstrated that human leukocyte antigen (HLA) genetic polymorphisms were associated with many drugs-induced liver injuries. To investigate HLA genetic susceptibility to MMI-induced liver injury (MMI-DILI), we characterized both HLA class I and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-DILI cases and 118 MMI-tolerant controls. Among the 40 MMI-DILI cases, 57.5% were women and 50% were cholestatic liver damage with occurring time from days to months after MMI dosing. The frequency of HLA-C*03:02 was 6.7% (5/75) in the MMI-DILI case patients and 6.4% (4/62) in MMI-induced cholestatic/mixed liver damage, which were significantly different from the percentage of 0.4% (1/231) in the MMI-tolerant patients (odds ratio (OR) = 15.4, 95% confidence interval (CI) = 1.77-133.9, adjusted P = 0.0292; OR=14.9, 95% CI=2.38-182.9, adjusted P = 0.0323; respectively). HLA-A*02:01 was also found to be associated with MMI-induced cholestatic/mixed liver injury (OR = 3.13, 95%CI=1.45-6.91, adjusted P = 0.0464). The present study demonstrated that individuals carrying HLA-C*03:02 allele are at increased risk of developing MMI-induced DILI. These results may assist doctors to prevent the occurrence of hepatotoxicity in GD patients receiving MMI.

Topics: Adult; Alleles; Chemical and Drug Induced Liver Injury; Female; Genetic Predisposition to Disease; Graves Disease; HLA-C Antigens; Humans; Liver; Male; Methimazole; Polymorphism, Genetic; Retrospective Studies

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug-induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug-metabolizing enzymes and drug transporters have been associated with drug-induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug-metabolizing enzymes and drug transporters to the MMI-DILI. A total of 44 GD patients with MMI-DILI and 118 GD patients without MMI-DILI development were included in the study. Thirty-three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI-DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI-DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11-4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29-0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI-DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI-induced hepatotoxicity.

Topics: Adult; Aged; Aged, 80 and over; Alleles; ATP Binding Cassette Transporter, Subfamily B; Chemical and Drug Induced Liver Injury; Female; Genetic Predisposition to Disease; Genotype; Glucuronosyltransferase; Graves Disease; Haplotypes; Humans; Liver-Specific Organic Anion Transporter 1; Male; Methimazole; Middle Aged; Multidrug Resistance-Associated Proteins; Oxygenases; Polymorphism, Genetic

Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors.. We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls].. For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis.. Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.

Topics: Adolescent; Adult; Aged; Antibodies; Antithyroid Agents; Carbimazole; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Eruptions; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Graves Disease; Humans; Male; Methimazole; Middle Aged; Receptors, Thyrotropin; Young Adult

Methimazole (MMI) is a widely used drug for hyperthyroidism. However, its clinical use is associated with hepatotoxicity. Though the precise mechanism of hepatic damage is still far from clear, role of metabolic activation and reactive metabolites have been implicated. The present study was designed to investigate the role of enzyme induction in bioactivation based hepatotoxicity of methimazole in mice. Thirty male mice were randomly divided into five groups. Hepatotoxicity was induced by single intraperitoneal injection of methimazole (1000mg/kg). Pretreatment with rifampicin which is a potent enzyme inducer was carried out for 6 days prior to administration of methimazole. The extent of hepatic damage was determined by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) along with histopathological grading of liver samples. The elevated levels of biochemical markers by methimazole were potentiated by pretreatment with rifampicin. This potentiation of hepatic injury was also observed in liver histopathological examination. These findings suggest induction of microsomal enzymes as a potentiating factor of methimazole induced hepatotoxicity.

Topics: Alanine Transaminase; Animals; Antibiotics, Antitubercular; Antithyroid Agents; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Drug Synergism; Liver; Male; Methimazole; Mice, Inbred BALB C; Rifampin

Treatment choices are limited, when deciding how to manage thyrotoxicosis and moderate to severe Graves ophthalmopathy (GO) with suspected optic nerve damage in patients with elevated liver transaminase levels. The situation become even more complicated, if methimazole induced hepatotoxicity is suspected and intravenous methylprednisolone is co-administrated.. A 74-year-old woman presented with spontaneous retro-bulbar pain, eyelid swelling and inconstant diplopia.. Thyrotoxicosis and severe GO with suspected optic nerve damage and drug induced liver injury (DILI).. Intravenous methylprednisolone pulse therapy was administered to treat GO and methimazole was continued for thyrotoxicosis. Dose of methimazole was reduced after exclusion of concurrent infection and active liver disease.. The GO symptoms (eyelid swelling, sight loss, proptosis, retro-bulbar pain, diplopia) markedly decreased after the treatment course. Liver transaminases spontaneously returned to normal ranges and remained normal during the next 12 months until the Graves' disease until the treatment was completed.. 1. The interaction of methimazole and methylprednisolone may result in DILI. 2. In a patient without concomitant liver diseases MP can be continued if the methimazole dose is reduced if no other treatment options are available.

Topics: Administration, Intravenous; Aged; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Female; Glucocorticoids; Graves Ophthalmopathy; Humans; Liver Function Tests; Medication Therapy Management; Methimazole; Methylprednisolone; Optic Nerve Diseases; Pulse Therapy, Drug; Symptom Assessment; Thyrotoxicosis; Treatment Outcome

Methimazole is an antithyroid drug that is widely used for the treatment of hyperthyroidism. As an inhibitor of the enzyme thyroperoxidase, methimazole is generally well-tolerated. However, there have been increasing reports of methimazole-induced liver damage, although this effect of methimazole has been limited by the absence of objective diagnosis of the liver condition or the inappropriate use of the Naranjo scale. We present the case of an elderly man with hyperthyroidism, gastritis, and epilepsy who developed liver damage after administration of multiple drugs.. Considering the low sensitivity of the Naranjo scale in detecting rare reactions associated with liver damage, we used the Roussel-Uclaf Causality Assessment Method scale, with a finding of cholestatic jaundice hepatitis induced by methimazole. The patient's liver enzyme levels improved after discontinuation of methimazole.. Our case underlines the possible hepatoxicity associated with the use of methimazole. A review of the literature confirmed a selective hepatoxicity risk in individuals of Asian ethnicity, which has not been identified in Caucasian or Black populations. Physicians should be aware of the risk of hepatoxicity when prescribing oral methimazole to patients of Asian ethnicity.

Topics: Aged; Antithyroid Agents; Asian People; Chemical and Drug Induced Liver Injury; Humans; Hyperthyroidism; Jaundice, Obstructive; Liver Function Tests; Male; Methimazole

The objective of this work is to report our experience with (131)I therapy without recent antithyroid drug (ATD) pretreatment for refractory severe hyperthyroidism complicated by hyperbilirubinemia due to hepatic dysfunction.. Five patients with refractory severe hyperthyroidism were treated with (131)I at 90 to 120 μCi/g-thyroid (total activity, 6.2 to 10.1 mCi). The patients previously had received ATD treatment from 2 months to 12 years and discontinued ATDs from 2 months to 4 years before (131)I treatment due to treatment failure or severe jaundice. Prior to (131)I therapy, the patients were asked to take a low-iodine diet and were treated with bisoprolol fumarate, digoxin, furosemide, S-adenosylmethionine, polyene phosphatidylcholine, and plasma exchange as supportive treatment for related clinical conditions. Four of the patients also received lithium carbonate in conjunction with their (131)I treatment. The patients were followed for 4 to 9 years after (131)I therapy.. After (131)I treatment, jaundice disappeared completely within 3 to 4 months in all patients, and liver function tests returned to normal. Concurrent atrial fibrillation and heart failure, leukopenia and thrombocytopenia, or thrombocytopenia and left cardiac enlargement improved remarkably in 3 patients during the follow-up period. Three to 45 months after (131)I treatment, hypothyroidism was noted in the patients and they were treated with L-thyroxine replacement therapy.. (131)I therapy without recent ATD pretreatment for refractory severe hyperthyroidism complicated by serious jaundice appears to be safe and effective, with good long-term results. It may be the preferred therapy for such patients and should be used as early as possible.

Topics: Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; China; Female; Humans; Hyperbilirubinemia; Hyperthyroidism; Iodine Radioisotopes; Jaundice; Liver Diseases; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies; Severity of Illness Index

MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury.

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Female; Glutathione; Liver; Lymphoid Enhancer-Binding Factor 1; Methimazole; Mice, Inbred BALB C; MicroRNAs; SOXC Transcription Factors; Th2 Cells

Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed. In the in vitro experiments, intact isolated liver mitochondria were incubated with increasing methimazole concentrations (10μM-100mM). It was found that methimazole decreased liver mitochondrial ATP and glutathione, increased mitochondrial swelling, lipid peroxidation and reactive oxygen species (ROS), and collapsed mitochondrial membrane potential when administered to mice. Paradoxically, methimazole not only caused no significant injury toward isolated liver mitochondria in vitro but improved mitochondrial function and protected this organelle. The differences between two investigated models in the current study might be associated with drug bioactivation and reactive metabolites formation. These findings suggest mitochondrial dysfunction as a mechanism for methimazole-induced liver injury. Moreover, methimazole seems to be a novel mitochondrial protecting agent in vitro.

Topics: Animals; Antithyroid Agents; Biomarkers; Chemical and Drug Induced Liver Injury; Male; Membrane Potential, Mitochondrial; Methimazole; Mice; Mice, Inbred BALB C; Mitochondria, Liver; Molecular Structure; Random Allocation

Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients.. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated.. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31).. Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

Topics: Adult; Aged; Antithyroid Agents; Chemical and Drug Induced Liver Injury; China; Female; Graves Disease; Humans; Hyperthyroidism; Liver; Male; Methimazole; Middle Aged; Propylthiouracil; Retrospective Studies; Thyroxine; Treatment Outcome; Triiodothyronine; Young Adult

Topics: Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Graves Disease; Hepatitis, Autoimmune; Humans; Methimazole

Liver injury is a deleterious adverse effect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive intermediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)-depleted mice and the role of glyoxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate aminotransferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole-treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was observed in liver histopathology. Methimazole-induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necrosis of the liver. Glyoxal trapping agents effectively diminished methimazole-induced liver injury both in intact and/or GSH-depleted animals.

Topics: Acetylcysteine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carnosine; Chemical and Drug Induced Liver Injury; Male; Metformin; Methimazole; Mice; Necrosis; Oxidative Stress; Protective Agents

Increasing attention has focused on the prevalence and outcomes of hyperthyroidism in pregnancy, given concerns for hepatotoxicity and embryopathy associated with antithyroid drugs (ATDs).. 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.. 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 thyrotoxicosis (odds ratio [OR] 1.28, 95% confidence interval [CI 1.05-1.55]) or gestational ATD use (OR 1.31 [1.00-1.72]) had an increased risk of preterm birth compared to those born to mothers without thyrotoxicosis or ATD. The risk of neonatal intensive care unit (NICU) admission was also higher with maternal thyrotoxicosis (OR 1.30 [1.07-1.59]) and ATD exposure (OR 1.64 [CI 1.26-2.13]), adjusting for prematurity. Congenital malformation rates were low and similar among infants born to mothers with thyrotoxicosis or ATD exposure (30-44 per 1000 infants).. Gestational ATD exposure occurred in 1.29 per 1000 mother-infant pairs while a much larger number had maternal diagnosed thyrotoxicosis but no drug exposure during pregnancy. Infants of mothers with gestational ATD use or diagnosed thyrotoxicosis were more likely to be preterm and admitted to the NICU. The rates of congenital malformation were low for mothers diagnosed with thyrotoxicosis and did not differ by ATD use. Among women with gestational PTU therapy, the frequency of PTU-associated hepatotoxicity was 1.8 per 1000 delivered pregnancies. These findings from a large, population-based cohort provide generalizable estimates of maternal and infant risks associated with maternal thyrotoxicosis and related pharmacotherapy.

Topics: Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Congenital Abnormalities; Delivery of Health Care, Integrated; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Methimazole; Pregnancy; Pregnancy Complications; Premature Birth; Prevalence; Propylthiouracil; Thyrotoxicosis; Young Adult

The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner.. We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively.. The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22).. MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis.

Topics: Adolescent; Adult; Aged; Antithyroid Agents; Carbimazole; Chemical and Drug Induced Liver Injury; Cohort Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperthyroidism; Incidence; Male; Methimazole; Middle Aged; Proportional Hazards Models; Propylthiouracil; Retrospective Studies; Taiwan; Young Adult

This study aimed to investigate the protective effect of selenium (Se) on methimazole (MMI; an antithyroid drug)-induced hepatotoxicity in adult rats and their progeny. Female Wistar rats were randomly divided into four groups of six rats in each group: group I served as controls that received standard diet; group II received MMI in drinking water as 250 mg L(-1) and standard diet; group III received both MMI (250 mg L(-1), orally) and Se (0.5 mg kg(-1) of diet); group IV received Se (0.5 mg kg(-1) of diet) as sodium selenite. Treatments were started from the 14th day of pregnancy until day 14 after delivery. Exposure of rats to MMI promoted oxidative stress with an increase in liver malondialdehyde levels, advanced oxidation protein products and protein carbonyl contents and a decrease in the levels of glutathione, nonprotein thiols and vitamin C. A decrease in the activities of liver glutathione peroxidase, superoxide dismutase, catalase and lactate dehydrogenase and in the levels of plasma total protein and albumin was also observed. Plasma transaminase activities and total, direct and indirect bilirubin levels increased. Coadministration of Se through diet improved all biochemical parameters. The histopathological changes confirmed the biochemical results. Therefore, our investigation revealed that Se, a trace element with antioxidant properties, was effective in preventing MMI-induced liver damage.

Topics: Animals; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Female; Lipid Peroxidation; Liver; Malondialdehyde; Methimazole; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Selenite

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Population-based estimates of the prevalence of thyrotoxicosis (TTX), the frequency of antithyroid drug (ATD) use, and risk of adverse events in pregnant women and their infants are lacking. Therefore, our objective was to obtain epidemiologic estimates of these parameters within a large population-based sample of pregnant women with TTX.. A retrospective claims analysis was performed from the MarketScan Commercial Claims and Encounters health insurance database for the period 2005-2009. Women aged 15-44 years, enrolled for at least 2 years, and who had a pregnancy during the study period were included. Diagnosis of TTX was based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes using narrow (TTX-1=ICD 242.0) and broad (TTX-2=ICD 242.0 or 242.9) definitions. ATD use was based on prescriptions filled for propylthiouracil (PTU) or methimazole (MMI). Adverse events in mothers and infants were determined from the ICD-9-CM diagnosis codes recorded on submitted claims.. The database contained 904,497 eligible women. The average yearly prevalence per 1000 pregnant women was 2.46 for TTX-1 and 5.88 for TTX-2. Thirty-nine percent used ATD at any time during the study period. Compared to women without a TTX diagnosis, there was more than a twofold increase for liver disease among women with TTX (odds ratio [OR]=2.08, p<0.001) and a 13% increased risk for congenital anomalies (OR=1.13, p=0.014), but no association was observed with ATD use. The rates of congenital defects (per 1000 infants) associated with ATD use were 55.6 for MMI, 72.1 for PTU, and 65.8 for untreated women with TTX, compared to 58.8 among women without TTX.. There was some indication of an elevated risk of liver disease and congenital anomalies in women with TTX, but the risk did not appear to be related to the ATD use. There seems to be a higher pregnancy termination rate for women with TTX on MMI, which likely reflects elective pregnancy terminations.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Congenital Abnormalities; Drug Prescriptions; Female; Hepatic Insufficiency; Humans; Infant; Infant, Newborn; Insurance, Health; International Classification of Diseases; Methimazole; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Prevalence; Propylthiouracil; Retrospective Studies; Thyrotoxicosis; United States; Young Adult

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical practice. The pathogenesis of DILI usually involves the participation of the parent drug or metabolites that either affect cellular function or elicit an immune response. However, the mechanisms leading to DILI are unknown in most cases. Methimazole (MTZ) is used as an antithyroid drug and is well known to have induced liver injuries such as cholestatic hepatitis in a small number of human cases. Immune-mediated reactions were also suggested to play a role in MTZ-induced acute liver injury, but the mechanism underlying this process has not been elucidated. To address this issue, we measured plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic glutathione levels, hepatic expression of CD4⁺ Th cell-related transcriptional factors, cytokines and chemokines, plasma interleukin (IL)-4 levels and histopathological changes in the liver following MTZ (450 mg kg⁻¹ , p.o.) administration in mice. The hepatic expression of mRNA for Th2 cell-related factors, such as GATA-binding protein, macrophage inflammatory protein-2 (MIP-2) and plasma IL-4 levels, as well as plasma AST and ALT levels, was significantly increased in mice treated with MTZ. These changes were markedly enhanced by pre-treatment with L-buthionine sulfoximine (3 mmol kg⁻¹, i.p.) and MTZ (15 mg kg⁻¹, p.o.). Neutralization of IL-4 using a monoclonal anti-mouse IL-4 antibody (100 µg/mouse, single i.p.) suppressed the hepatotoxic effect of MTZ. In conclusion, this report is the first to demonstrate that Th2 cytokine-mediated immune responses are involved in MTZ-induced acute liver injury in mice.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antimetabolites; Antithyroid Agents; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Cytokines; Dose-Response Relationship, Drug; Female; GATA3 Transcription Factor; Gene Expression Regulation; Glutathione; Interleukin-4; Liver; Methimazole; Mice; Mice, Inbred BALB C; RNA, Messenger; Th2 Cells

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

The antithyroid drugs propylthiouracil and methimazole were introduced for clinical use about 60 yr ago and are estimated to be used in more than 6000 children and adolescents per year in the United States. Over the years that these medications have been used, reports of adverse events involving hepatotoxicity have appeared. To date, there has not been a systematic and comparative evaluation of the adverse events associated with antithyroid drug use.. Our objective was to assess safety and hepatotoxicity profiles of propylthiouracil and methimazole by age in the U.S. Food and Drug Administration's Adverse Event Reporting System (AERS).. We used the multi-item gamma-Poisson shrinker (MGPS) data mining algorithm to analyze more than 40 yr of safety data in AERS. MGPS uses a Bayesian model to calculate adjusted observed to expected ratios [empiric Bayes geometric mean (EBGM) values] for every drug-adverse event combination in AERS, focusing on hepatotoxicity events.. MGPS identified higher-than-expected reporting of severe liver injury in pediatric patients treated with propylthiouracil but not with methimazole. Propylthiouracil had a high adjusted reporting ratio for severe liver injury (EBGM 17; 90% confidence interval = 11.5-24.1) in the group less than 17 yr old. The highest EBGM values for methimazole were with mild liver injury in the group 61 yr and older [EBGM 4.8 (3.3-6.8)], which consisted of cholestasis. Vasculitis was also observed for propylthiouracil in children and adolescents, reaching higher EBGM values than hepatotoxicity signals.. MGPS detects higher-than-expected reporting of severe hepatotoxicity and vasculitis in children and adolescents with propylthiouracil but not with methimazole.

Topics: Adolescent; Adverse Drug Reaction Reporting Systems; Age Factors; Algorithms; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Child; Data Mining; Databases, Factual; Female; Humans; Male; Methimazole; Propylthiouracil; Severity of Illness Index; United States; United States Food and Drug Administration

Topics: Antithyroid Agents; Chemical and Drug Induced Liver Injury; Child; Humans; Methimazole; Propylthiouracil

Topics: Acute Disease; Aged; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Methimazole; Middle Aged

Glutathione (GSH) levels are modulated in human liver slices to evaluate if drug induced liver injury is enhanced by a poor liver GSH status. Liver slice GSH levels were decreased by: 1) BSO (L-buthionine-S-sulfoximine) to inhibit GSH synthesis, and by 2) APAP (acetaminophen) which consumes GSH via conjugation to a metabolite. In this study, methimazole (MMI) liver injury was evaluated in the presence of a poor GSH status. MMI was selected because its structural thione moiety is linked with hepatotoxicity and during metabolism GSH is co-oxidized. MMI (500-1000 µM) affected oxidative stress pathways and mitochondrial function, resulting in lower liver slice GSH and ATP levels. Co-incubation of MMI with BSO or APAP led to further decreases of GSH and ATP levels in some human livers, at time points and concentrations not detected with MMI alone. Variation in human response was evident and demonstrated that some subjects with a poor liver GSH status could be further compromised with high MMI concentrations. MMI induced an up-regulation of gene expression linked with the GSH pathway, mitochondrial GSH and inflammation. Co-treatment of MMI with BSO induced a mixed response of oxidative stress related genes and an up-regulation of heat shock genes. The combination of MMI with APAP increased the expression of genes involved with oxidative stress and anti-oxidant defense, likely to protect the cells from mitochondrial injury. In summary, MMI induces oxidative stress at high concentrations, which can be augmented when liver GSH levels are decreased by the co-administration of some drugs or health status.

Topics: Acetaminophen; Adenosine Triphosphate; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Gene Expression; Glutathione; Humans; In Vitro Techniques; Liver; Methimazole; Mitochondria; Oxidation-Reduction; Oxidative Stress

Topics: Adult; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Incidence; Liver Diseases; Liver Transplantation; Male; Methimazole; Pregnancy; Pregnancy Complications; Propylthiouracil; United States

We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

Topics: Abdominal Pain; Antithyroid Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Humans; Hyperthyroidism; Male; Methimazole; Middle Aged; Scleral Diseases

Topics: Adrenergic beta-Antagonists; Adult; Anesthesia, Intravenous; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Dexamethasone; Drug Therapy, Combination; Female; Graves Disease; Humans; Hypertension; Iopanoic Acid; Kidney Diseases; Methimazole; Preoperative Care; Propranolol; Tachycardia; Thyroidectomy

Hyperthyroidism is one of the most common endocrinology disorders. Treatment can be either pharmacological, surgical or using radioactive iodine. In Europe methimazole is the antithyroid drug of choice because it can be administered in a single daily dose and has a lower risk of adverse reactions. Around 5% of patients taking thionamides can present any of their side effects, which are usually mild. Liver toxicity due to thionamides is very rare, and severe due to propylthiouracil. We present a clinical case of a cholestatic jaundice and acute toxic hepatitis due to methimazole and a cross-reaction with propylthiouracil. Based on this case a review is presented.

Topics: Aged; Antithyroid Agents; Case Management; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Female; Graves Disease; Humans; Methimazole; Thyroidectomy

Drug-induced liver injury might be responsible for 1 of 600 to 3500 of all hospital admissions. About 2-3% of all drug adverse effects may be connected with the liver. There could be pure injury of heaptic cells or impairment of hepatocellular bile secretion. In our case there was cholestatic liver injury after the use of thiamazole with the complete regression after the discontinuation of the drug. For two years' the patient was treated with methyltiouracyl without any side effects. After 19 years, because of thyreotoxicosis, the methimazole was used. The acute cholestatic liver injury with the high serum bilirubin level (41.4 mg/dl) was observed. Despite the discontinuation of the drug the patient was deceased.. There are possible cross reactions among imidazolines in patients who are predispose to develop drug-induced liver failure. The doctors should pay much more attention to possible drug side effects.

Topics: Aged; Bilirubin; Chemical and Drug Induced Liver Injury; Cholestasis, Intrahepatic; Female; Humans; Hyperthyroidism; Liver Failure, Acute; Liver Function Tests; Methimazole; Treatment Outcome

Topics: Antithyroid Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Liver Function Tests; Methimazole; Middle Aged; Treatment Outcome

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), methimazole (2-mercapto-1-methylimidazole, MMI) causes liver injury characterized by centrilobular necrosis of hepatocytes and an increase in serum alanine transaminase (SALT) activity. MMI requires metabolic activation by both P450 monooxygenase and flavin-containing monooxygenase (FMO) before it produces the hepatotoxicity. MMI and its analogues were examined for the ability to increase SALT activity in GSH-depleted mice. Saturation of the C-4,5 double bond in MMI resulted in a complete loss of hepatotoxicity. Similarly, ring fusion of a benzene nucleus to the C-4,5 double bond, forming 2-mercapto-1-methylbenzimidazole, abolished the toxic potency. As for MMI, 2-mercapto-1,4,5-trimethylimidazole, and 2-mercapto-1-methyl-4, 5-di-n-propylimidazole, the toxic potency decreased with the increasing bulk of the 4- and 5-alkyl substituents. Furthermore, methylation of the thiol group of MMI totally reduced its toxicity. These structural requirements and the known toxicity of thiono-sulfur compounds led us to the hypothesis that MMI would undergo epoxidation of the C-4,5 double bond by P450 enzymes and, after being hydrolyzed, the resulting epoxide would be then decomposed to form N-methylthiourea, a proximate toxicant. Before N-methylthiourea would produce toxicity, it would be further biotransformed to its S-oxidized metabolites mainly by FMO. Evidence for this hypothesis was provided by the facts that N-methylthiourea and glyoxal as the accompanying fragment were identified as urinary metabolites in mice treated with MMI and that N-methylthiourea caused a marked increase in SALT activity when administered to mice in combination with BSO.

Topics: Animals; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Glutathione; Liver; Male; Methimazole; Mice; Mice, Inbred ICR; Necrosis; Structure-Activity Relationship; Thiourea

We present a case of 52 years old woman with cutaneous lupus erythematosus and methimazole induced bone marrow aplasia with agranulocytosis and liver damage.

Topics: Anemia, Aplastic; Antithyroid Agents; Bone Marrow; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Leukocytosis; Lupus Erythematosus, Cutaneous; Methimazole; Middle Aged

Cholestatic jaundice caused by imidazole derivates is a rare complication of antithyroid therapy. Only 20 such cases have been reported in the literature since the introduction of methimazole in 1949 and of carbimazole in 1953. We present a further case of methimazole-induced cholestatic liver injury, mimicking sclerosing cholangitis, where the etiology has been proven by a clear chronological relationship and the lack of other causative factors.

Topics: Adenoma; Aged; Antithyroid Agents; Bile Ducts, Intrahepatic; Chemical and Drug Induced Liver Injury; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Cholestasis, Intrahepatic; Diagnosis, Differential; Humans; Hyperthyroidism; Liver Function Tests; Male; Methimazole; Thyroid Neoplasms

A very rare case of granulomatous hepatitis in a 56-year old woman with hyperthyroidism, under long-term treatment with methimazole, is reported. Liver biopsy showed multiple non caseous granulomas in the portal triads, consisted of epithelioid and multinucleated cells, lymphocytes and isolated eosinophils. The presence of eosinophils in granulomas, could indicate an iatrogenic aethiology.

Topics: Chemical and Drug Induced Liver Injury; Female; Granuloma; Humans; Hyperthyroidism; Methimazole; Middle Aged

We report a case of methimazole-induced acute hepatic failure, which occurred 17 weeks after initiation of the drug in a 43-year-old man with hyperthyroidism and hepatitis B surface antigenemia. Postmortem needle autopsy of the liver revealed an established micronodular cirrhosis secondary to hepatitis B with moderate septal/portal inflammation, marked cholestasis and scattered acidophilic bodies. The serum hepatitis B surface antigen (HBsAg) was positive, but reactivation of hepatitis B was unlikely in view of the absence of a serum hepatitis B e antigen (HBeAg) and hepatitis B virus deoxyribonucleic acid (HBV-DNA) and negative stain for HBsAg and hepatitis B core antigen (HBcAg) in the liver tissue.

Topics: Acute Disease; Adult; Carrier State; Chemical and Drug Induced Liver Injury; Hepatitis B; Humans; Male; Methimazole

The authors studied 389 Graves' hyperthyroid patients receiving either high propylthiouracil (PTU) or methimazole (MMI) daily doses or low doses to evaluate whether adverse effects were related to the thionamide drugs or its daily dose regimen. Group 1 patients (n = 286) received high PTU (728 +/- 216 mg/day, n = 92) or MMI (60 +/- 19 mg/day, n = 94) doses, and group 2 patients (n = 103) were treated with low PTU (255 +/- 85 mg/day, n = 39) or MMI (23 +/- 10 mg/day, n = 64) doses. Major adverse effects were observed in 11 (2.8%) patients. Of these, four (1.0%) had agranulocytosis, two (0.5%) were granulocytopenic and five (1.3%) had hepatotoxicity. Agranulocytosis occurred in two patients from each group, 0.7% and 1.9%, respectively from group 1 and group 2. There was no significant difference between the groups or the types of thionamide. There also was no correlation with the patients' age. All of the patients were hyperthyroid, and its onset occurred in the first to third month of treatment. Full recovery was achieved in all cases after drug withdrawal. Four of 5 patients with hepatotoxicity were treated with high PTU doses, and one patient received low MMI doses (p less than .05). All patients were euthyroid. Arthralgias, skin rash and gastric intolerance, the minor adverse effects of thionamides studied, were observed in 52 (13.4%) of the patients. Although no significant differences were found, most of the patients experiencing side effects were from group 1 an received MMI therapy. These adverse effects did not demand drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Agranulocytosis; Chemical and Drug Induced Liver Injury; Child; Dose-Response Relationship, Drug; Drug Eruptions; Graves Disease; Humans; Hyperthyroidism; Joints; Methimazole; Middle Aged; Pain; Propylthiouracil; Stomach Diseases

Three cases with drug-induced liver diseases (hepatitis caused by hydralasine, steatosis caused by methimazole, choletasis caused by birth control pill) were investigated with respect to their drug metabolising ability. Clinical diagnoses were based on the exclusion of other pathogenetic factors, on histological findings of liver biopsy specimens and on the clinical chemical tests. Investigation of biotransforming ability was carried out using test materials (menthol loading, antipyrine, sulfadimidine, caffeine, indocyanine green kinetics) and measurement of D-glucaric acid excretion. In all cases the results show a defective capacity in some respect of drug metabolism. Possible pathogenetic role of reactive metabolites is discussed in the pathomechanism of genesis of drug-induced liver diseases.

Topics: Adult; Aged; Biotransformation; Chemical and Drug Induced Liver Injury; Contraceptives, Oral, Combined; Female; Humans; Hydralazine; Liver Diseases; Methimazole; Middle Aged; Pharmaceutical Preparations

Topics: Chemical and Drug Induced Liver Injury; Female; Humans; Methimazole; Middle Aged; Thyrotoxicosis

We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Carbimazole; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Male; Methimazole; Middle Aged; Propylthiouracil

In order to investigate the incidence of side effects of antithyroid drugs and to study if there were any factors related to the onset of the side effects, clinical and laboratory findings were examined in 71 untreated Graves' patients. The overall incidence was 28.2% among 71 cases who were initially administered methimazole or propylthiouracil. The incidences were 23.2% (13 of 56 cases) for methimazole and 46.7% (7 of 15 cases) for propylthiouracil, respectively, which were significantly higher than those previously reported. Seventeen of 20 cases with side effects under the drug of first choice were administered the another antithyroid drug. Four of 17 (23.5%) cases successively had side effects. The side effects were observed within 1.5 months of administration of less than 150 tablets in total in most of the cases. The serum concentration of Ig-E and peripheral eosinophils(/mm3) at the onset of the side effects were significantly higher than those before treatment. These results suggest that allergic mechanism rather than accumulating may concern the onset of side effects. Since in cases without the side effects the peripheral eosinophils at 3 to 4 weeks after administration were significantly higher than those before treatment and 19 of 51 (38.0%) cases without side effects had a high concentration of Ig-E of more than 500 u/ml, it is suggested that allergic mechanism may be triggered in most of Graves' patients who were administered methimazole or propylthiouracil. Thus, immunological disturbances in Graves' disease seems to be the cause of the side effects of antithyroid drugs, although there was no correlation between antithyroid autoantibodies and development of the side effects.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Eosinophils; Female; Graves Disease; Humans; Immunoglobulin E; Leukocyte Count; Male; Methimazole; Middle Aged; Propylthiouracil

Topics: Adult; Carbimazole; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Male; Methimazole; Middle Aged

Topics: Aged; Autoimmune Diseases; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Insulin Antibodies; Methimazole; Propylthiouracil

The results of medical and surgical therapy were determined in 107 hyperthyroid children. After surgery, 85% of patients were rendered free of hyperthyroidism; however, 62% became hypothyroid. After medical treatment, 30% of patients were euthyroid and 2% became hypothyroid. The relapse rate, however, was higher after medical (22%) than after surgical (9%) therapy. Serious drug-related complications (arthritis-, hepatitis-, and collagen disease-like syndromes) occurred in 14% of patients. Complications occurred in 9% of surgically treated patients, but recurrent laryngeal nerve injury or permanent hypoparathyroidism did not occur. In medically treated patients, both a goiter size less than three times normal prior to treatment and a reduction in goiter size to less than two times normal at the completion of therapy correlated with a successful outcome.

Topics: Adolescent; Arthritis; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Collagen Diseases; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Methimazole; Postoperative Complications; Propylthiouracil; Thyroidectomy

Topics: Adult; Agranulocytosis; Chemical and Drug Induced Liver Injury; Female; Humans; Methimazole; Middle Aged

Topics: Aerosols; Animals; Chemical and Drug Induced Liver Injury; Dichloroethylenes; Hydrocarbons, Chlorinated; Liver; Male; Methimazole; Oxygen Consumption; Propylthiouracil; Rats; Thyroid Function Tests; Thyroid Gland; Thyroidectomy; Thyroxine

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Graves Disease; Humans; Liver; Methimazole

Marked, and in some cases long-lasting, taste disturbances occurred in three patients on thiamazole. In addition, all three had a rise in serum transaminases and alkaline phosphatase levels, due to associated liver parenchymal damage. Cause of these changes was the high thiamazole dosage (160 and 120 mg/d). Reduction in dosage restored normal taste sense in all three, but in two the drug had to be discontinued because of persisting high transaminase levels.

Topics: Adult; Chemical and Drug Induced Liver Injury; Female; Humans; Hyperthyroidism; Methimazole; Middle Aged; Taste Disorders; Time Factors

Topics: Adenoma; Aged; Chemical and Drug Induced Liver Injury; Cholangiography; Drug Hypersensitivity; Female; Humans; Hyperthyroidism; Liver; Liver Function Tests; Methimazole; Thyroid Neoplasms

Topics: Agranulocytosis; Chemical and Drug Induced Liver Injury; Cholestasis; Humans; Hyperthyroidism; Liver; Male; Methimazole; Middle Aged

Topics: Antithyroid Agents; Chemical and Drug Induced Liver Injury; Hepatitis; Hepatitis A; Humans; Methimazole; Physiological Phenomena

Topics: Agranulocytosis; Antithyroid Agents; Chemical and Drug Induced Liver Injury; Hepatitis; Humans; Methimazole