Showing papers on "Propylthiouracil published in 2012"
TL;DR: A systematic review of available treatment interventions for hyperthyroidism and hypothyroidism found that methimazole and PTU are effective in preventing pregnancy complications and evidence is insufficient to recommend treatment with levothyroxine.
Abstract: Thyroid disorders are associated with pregnancy complications. Universal screening is currently not recommended because of a lack of evidence on the effectiveness of treatment. Women with hyperthyroidism and hypothyroidism evidently require treatment but this is less clear for women with subclinical hypothyroidism and thyroid autoimmunity. Therefore, we conducted a systematic review to provide a comprehensive overview on the available treatment interventions. Relevant studies were identified by searching Medline, EMBASE and Cochrane Controlled Trials Register, published until December 2011. From a total of 7334 primary selected titles, 22 articles were included for the systematic review and 11 were appropriate for meta-analyses. Eight studies reported on hyperthyroidism. Propylthiouracil (PTU) and methimazole reduce the risk for preterm delivery [risk ratio (RR): 0.23, confidence interval (CI): 0.1-0.52], pre-eclampsia (RR: 0.23, CI: 0.06-0.89) and low birthweight (RR: 0.38, CI: 0.22-0.66). The nine studies that reported on clinical hypothyroidism showed that levothyroxine is effective in reducing the risk for miscarriage (RR: 0.19, CI: 0.08-0.39) and preterm delivery (RR: 0.41, CI: 0.24-0.68). For treatment of subclinical hypothyroidism, current evidence is insufficient. The five studies available on thyroid autoimmunity showed a not significant reduction in miscarriage (RR: 0.58, CI: 0.32-1.06), but significant reduction in preterm birth by treatment with levothyoxine (RR: 0.31, CI: 0.11-0.90). For hyperthyroidism, methimazole and PTU are effective in preventing pregnancy complications. For clinical hypothyroidism, treatment with levothyroxine is recommended. For subclinical hypothyroidism and thyroid autoimmunity, evidence is insufficient to recommend treatment with levothyroxine. The overall lack of evidence precludes a recommendation for universal screening and is only justified in a research setting
119 citations
TL;DR: This study showed that ATD cause hematopoietic changes, which are occasionally severe and potentially fatal, and the pathogenesis of agranulocytosis and pancytopenia might overlap.
Abstract: Context: Although antithyroid drug (ATD)-induced hematopoietic damage is a significant concern, it has not been comprehensively investigated. Objective: Our objective was to describe the clinical features of ATD-induced hematopoietic damage. Design and Setting: This was a retrospective cohort study in Tokyo, Japan. Patients: Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diagnosed with Graves' disease. We retrospectively reviewed their medical, pathological, and laboratory records between January 1983 and December 2010. Main Outcome: Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia were evaluated. Results: Of 55 patients with documented hematopoietic damage, 50 had agranulocytosis and 5 had pancytopenia. All of them received ATD, either methimazole (n = 51) or propylthiouracil (n = 4). Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancytopenia were 69 d (range, 11–233 d) and 41 d (range, 32–97 d), respec...
116 citations
TL;DR: Doses can be reduced in third trimester due to the immune-suppressant effects of pregnancy, and early and effective treatment of thyroid disorder ensures a safe pregnancy with minimal maternal and neonatal complications.
Abstract: Thyroid disorders are common in pregnancy and the most common disorder is subclinical hypothyroidism. Due to the complex hormonal changes during pregnancy, it is important to remember that thyroxine requirements are higher in pregnancy. According to recent American Thyroid Association (ATA) guidelines, the recommended reference ranges for TSH are 0.1 to 2.5 mIU/L in the first trimester, 0.2 to 3.0 mIU/L in the second trimester, and 0.3 to 3.0 mIU/L in the third trimester. Maternal hypothyroidism is an easily treatable condition that has been associated with increased risk of low birth weight, fetal distress, and impaired neuropsychological development. Hyperthyroidism in pregnancy is less common as conception is a problem. Majority of them are due to Graves' disease, though gestational hyperthyroidism is to be excluded. Preferred drug is propylthiouracil (PTU) with the target to maintain free T4 in upper normal range. Doses can be reduced in third trimester due to the immune-suppressant effects of pregnancy. Early and effective treatment of thyroid disorder ensures a safe pregnancy with minimal maternal and neonatal complications.
101 citations
TL;DR: An historical account of the levamisole/cocaine story as it first surfaced in 2008 is provided, and it is proposed that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levam isole be categorized as a new structural alert, which is to be avoided in drug design.
Abstract: The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U.S. market in 2000 because of the frequent occurrence of agranulocytosis. The detection of autoantibodies such as antithrombin (lupus anticoagulant) and an increased risk of agranulocytosis in patients carrying the human leukocyte antigen B27 genotype suggest that toxicity is immune-mediated. In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.
58 citations
TL;DR: PTU should not be used in children, in whom methimazole (MMI) represents the logical alternative, and in adults, PTU should be restricted to those rare patients with Graves’ disease for whom no better alternative can be offered and in patients with thyroid storm.
Abstract: Purpose of review: To bring to the attention of healthcare professionals the additional information on propylthiouracil (PTU)-related hepatotoxicity, based on a reanalysis of medical files reported to the Food and Drug Administration (1982-2008) for acute liver failure in PTU-treated hyperthyroid patients, and propose recommendations for the clinical use of PTU. Thirteen files of PTU-related severe liver adverse effects were analyzed for the pediatric population, seventeen for nonpregnant adults and two for pregnant women. Recent findings: The recent findings showed that the daily PTU dose administered was high in the children, with a mean of 300mg/day for an average 10-year-old individual. With regard to treatment duration, PTU administration lasted for at least 4 months in 75% of pediatric cases. Similarly, in a majority of adult cases (64%), PTU-induced liver injury occurred after a relatively long treatment period (4 months to >1 year). Summary: PTU should not be used in children, in whom methimazole (MMI) represents the logical alternative. In adults, PTU should be restricted to those rare patients with Graves' disease for whom no better alternative can be offered and in patients with thyroid storm. For the special circumstance of pregnancy, PTU is the preferred choice during early gestation; switching back to MMI during later gestational stages remains a matter of clinical judgment. It is unknown whether liver function tests monitoring is worthwhile to prevent life-threatening, PTU-related hepatotoxicity. © 2012 Wolters Kluwer Health
52 citations
TL;DR: The hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy is supported.
Abstract: Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.
50 citations
TL;DR: The BR extract normalized LT4-induced liver oxidative stresses, and also reduced liver and epididymal fat pad changes, indicating their potential in the regulation of hyperthyroidism.
Abstract: Bupleuri Radix (BR), the dried roots of Bupleurum falcatum L., has been used in folk medicine as an antiinflammatory and antioxidative agent. The aqueous extract of BR was evaluated for its possible ameliorative effect in the regulation of hyperthyroidism in l-thyroxine- (LT4-) induced rat model. After oral administration of 300, 150, and 75 mg/kg of BR extracts, once a day for 15 days from 12th LT4 treatments, changes on the body, thyroid gland, liver, and epididymal fat pad weights, serum triiodothyronine, thyroxine, thyroid-stimulating hormone, asparte aminotransferase and alanine aminotransferase concentrations, hepatic lipid peroxidation, glutathione contents, superoxide dismutase, and catalase activities were investigated with thyroid gland, liver, and epididymal fat histopathological changes. The effects of BR extracts were compared with that of propylthiouracil, a standard antithyroid drug 10 mg/kg (intraperitoneally). In this experiment, BR extracts dose dependently reversed LT4-induced hyperthyroidisms, and these effects indicating their potential in the regulation of hyperthyroidism. Further, the BR extract normalized LT4-induced liver oxidative stresses, and also reduced liver and epididymal fat pad changes. BR extracts 150 mg/kg showed comparable effects on the LT4-induced rat hyperthyroidism as compared with PTU 10 mg/kg. These effects of BR may help the improvement of hyperthyroidisms and accompanied various organ damages.
41 citations
TL;DR: Another case with multiple congenital anomalies following in utero exposure to carbimazole is reported and the literature is reviewed to consider the risks and benefits of available pharmacological treatments for thyrotoxicosis in pregnancy.
Abstract: Maternal thyrotoxicosis, predominantly secondary to Graves' disease, affects 0.2% of all pregnancies. The Endocrine Society guidelines recommend the use of propylthiouracil as a first-line drug for thyrotoxicosis in pregnancy because of associations between carbimazole or methimazole and congenital anomalies. However, recent studies have highlighted the risk of severe liver injury with propylthiouracil. Here, we report another case with multiple congenital anomalies following in utero exposure to carbimazole and review the literature to consider the risks and benefits of available pharmacological treatments for thyrotoxicosis in pregnancy.
39 citations
TL;DR: 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, and it is appropriate to use PTU to treat maternal hyperthyroidism during the firsttrimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.
Abstract: Background 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. Methods We conducted a systematic search of PubMed, EMBASE,TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google.Both English and non-English publications were included. Weexcluded studies using anti-thyroid therapies other than PTU andMMI, studies not allowing interpretation of results, and abstracts ofmeetings. Results 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. Conclusion 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.
37 citations
TL;DR: Results suggest that some of the brain defects associated with Fe deficiency may be mediated through altered thyroidal status and the concomitant alterations in TH-responsive gene transcription.
Abstract: Copper (Cu), iron (Fe), and thyroid hormone (TH) deficiencies produce similar defects in late brain development including hypomyelination of axons and impaired synapse formation and function, suggesting that these micronutrient deficiencies share a common mechanism contributing to these derangements. We previously demonstrated that fetal/neonatal Cu and Fe deficiencies lower circulating TH concentrations in neonatal rats. Fe deficiency also reduces whole-brain T3 content, suggesting impaired TH action in the developing Fe-deficient brain. We hypothesized that fetal/neonatal Cu and Fe deficiencies will produce mild or moderate TH deficiencies and will impair TH-responsive gene expression in the neonatal cerebral cortex and hippocampus. To test this hypothesis, we rendered pregnant Sprague Dawley rats Cu-, Fe-, or TH-deficient from early gestation through postnatal d 10 (P10). Mild and moderate TH deficiencies were induced by 1 and 3 ppm propylthiouracil treatment, respectively. Cu deficiency did not significantly alter serum or tissue TH concentrations or TH-responsive brain mRNA expression. Fe deficiency significantly lowered P10 serum total T3 (45%), serum total T4 (52%), whole brain T3 (14%), and hippocampal T3 (18%) concentrations, producing a mild TH deficiency similar to 1 ppm propylthiouracil treatment. Fe deficiency lowered Pvalb, Enpp6, and Mbp mRNA levels in the P10 hippocampus. Fe deficiency also altered Hairless, Dbm, and Dio2 mRNA levels in the P10 cerebral cortex. These results suggest that some of the brain defects associated with Fe deficiency may be mediated through altered thyroidal status and the concomitant alterations in TH-responsive gene transcription.
36 citations
TL;DR: It is found that PTU exposure during embryogenesis is associated with fetal loss and teratogenic potential, and formal studies of ATD teratogenesis effects have not been performed, suggesting thatPTU has teratrogenic potential.
Abstract: Background
Hyperthyroidism during pregnancy is treated with the antithyroid drugs (ATD) propylthiouracil (PTU) and methimazole (MMI). PTU currently is recommended as the drug of choice during early pregnancy. Yet, despite widespread ATD use in pregnancy, formal studies of ATD teratogenic effects have not been performed.
Methods
We examined the teratogenic effects of PTU and MMI during embryogenesis in mice. To span different periods of embryogenesis, dams were treated with compounds or vehicle daily from embryonic day (E) 7.5 to 9.5 or from E3.5 to E7.5. Embryos were examined for gross malformations at E10.5 or E18.5 followed by histological and micro-CT analysis. Influences of PTU on gene expression levels were examined by RNA microarray analysis.
Results
When dams were treated from E7.5 to E9.5 with PTU, neural tube and cardiac abnormalities were observed at E10.5. Cranial neural tube defects were significantly more common among the PTU-exposed embryos than those exposed to MMI or vehicle. Blood in the pericardial sac, which is a feature indicative of abnormal cardiac function and/or abnormal vasculature, was observed more frequently in PTU-treated than MMI-treated or vehicle-treated embryos. Following PTU treatment, a total of 134 differentially expressed genes were identified. Disrupted genetic pathways were those associated with cytoskeleton remodeling and keratin filaments. At E 18.5, no gross malformations were evident in either ATD group, but the number of viable PTU embryos per dam at E18.5 was significantly lower from those at E10.5, indicating loss of malformed embryos. These data show that PTU exposure during embryogenesis is associated with delayed neural tube closure and cardiac abnormalities. In contrast, we did not observe structural or cardiac defects associated with MMI exposure except at the higher dose. We find that PTU exposure during embryogenesis is associated with fetal loss. These observations suggest that PTU has teratogenic potential.
TL;DR: The results indicate that hypothyroidism adversely affects spermatogenesis, suggesting that thyroid hormone might play an important role not only in controllingnormal testicular development but also in maintaining normal testicular function and sperMatogenesis.
Abstract: Hypothyroidism is an underactive thyroid gland that cannot make enough thyroid hormone to keep the body running normally. Here we studied the histopathological, immunohistochemical, and ultrastructural changes in the hypothyroid rat testes at the postpubertal stage, in addition to the ameliorating role of folic acid in enhancing spermatogenesis, boosting sperm concentration and building up the antioxidant status against the oxidants. A total of 50 male albino rats were equally divided into 5 groups; the first and second groups comprised the control and folic acid groups, respectively; while the third group comprised the hypothyroid group in which rats received 6-n-propyl-2-thiouracil in drinking water for 6 weeks to induce hypothyroidism. The fourth and fifth groups comprised hypothyroid rats treated with folic acid for 4 weeks and dissected after 6 and 10 weeks, respectively. Testes in the hypothyroid rats showed marked morphological and histological changes in the seminiferous tubules with a reduction in sperm count. Our results indicate that hypothyroidism adversely affects spermatogenesis, suggesting that thyroid hormone might play an important role not only in controlling normal testicular development but also in maintaining normal testicular function and spermatogenesis. Further, we suggested an ameliorating role of folic acid in the relief of testicular tissue from changes due to hypothyroidism. However, we found that the best results were found in cases where folic acid was used as an adjuvant therapy for returning to the euthyroid state.
TL;DR: Until now, there has been no evidence that children prenatally exposed to methimazole/carbimazoles or propylthiouracil have an increased risk of neurodevelopmental delay.
Abstract: Clinical hyperthyroidism has been associated with an increased risk of maternal, fetal, and neonatal complications. The available antithyroid drugs are methimazole/carbimazole and propylthiouracil. Several case reports and some epidemiologic studies suggest that methimazole/carbimazole exposure during the first trimester of pregnancy is associated with an increased risk of congenital malformations, including ectodermal anomalies, choanal atresia, esophageal atresia, and omphalocele. However, the absolute risk appears to be very small, and it remains unclear whether the association is driven by the maternal disease, the medication, or the combination of both factors. Propylthiouracil exposure has not been associated with an increased risk of congenital malformations and is the recommended drug during the first trimester of pregnancy. Since propylthiouracil-induced hepatotoxicity has been reported in approximately 0.1% of exposed adults and the number of case-reports of severe liver injury is increasing, treatment with low dose methimazole during the second and third trimesters should be considered. Until now, there has been no evidence that children prenatally exposed to methimazole/carbimazole or propylthiouracil have an increased risk of neurodevelopmental delay.
TL;DR: Folic acid had ameliorative effect against cardiac damage induced by 6-n-propyl-2-thiouracil and the best results were found in case of using the folic acid as an adjuvant therapy after returning to the euthyroid state.
Abstract: Thyroid hormones have marked effects on the growth, development, and metabolic function of virtually all organs and tissues. Thyroid status is an important determinant of cardiovascular function. The present work studied the histopathological and ultrastructural changes in the hypothyroid rat left ventricle at post-pubertal stage, in addition to the ameliorating role of folic acid. A total of 50 male albino rats were randomly divided into 5 groups (group I, control; group II, folic acid; group III, propylthiouracil-induced hypothyroid rats; group IV, co-treatment with folic acid; group V, post-treatment). In order to ensure the hypothyroid state, the level of serum triiodothyronine (T(3)) and thyroid stimulating hormone (TSH) through the dose period was regularly determined. The TSH levels were significantly higher while T(3) levels were significantly lower in hypothyroid rats when compared to control group. The high-performance liquid chromatography analysis showed an increase in homocysteine (Hcy) in the hypothyroid rats group when compared to the control group. The histopathological studies of the ventricle in hypothyroid rats revealed hydrophobic changes in myofibrillar structure with striations, myocardial atrophy, nuclear pyknosis, cytoplasmic vacuoles, and cytoplasmic eosinophilia. Transmission electron micrographs in the myocardium of hypothyroid rats revealed a marked reduction in muscle fibre mass, a marked degeneration of muscle fibres, swollen mitochondria, dilated sarcoplasmic reticulum and more prominent perinuclear oedema observed in the cardiac myocytes. In co-treated hypothyroid rats with folic acid, a regular arrangement of muscle fibres, mild swelling of myofibrillar structure with striations and no continuity with adjacent myofibrils were observed while the post-treated hypothyroid rat with folic acid showed normal architecture of myofibrillar structure with striations and continuity with adjacent myofibrils. In conclusion, our results indicated that folic acid had ameliorative effect against cardiac damage induced by 6-n-propyl-2-thiouracil and the best results were found in case of using the folic acid as an adjuvant therapy after returning to the euthyroid state.
TL;DR: PTU induces NIS expression and iodide uptake in rat thyroid FRTL-5 cells in the absence of TSH, and shares similar antithyroid activity with MMI, but their effects on other thyroid functions appear to be quite different, which could affect their therapeutic effectiveness.
Abstract: Background: Propylthiouracil (PTU) and methimazole (MMI) are drugs that are widely used to treat Graves' disease. Although both exert an antithyroid effect primarily by blocking thyroid peroxidase ...
TL;DR: It is highlighted that good outcomes can be achieved in PTU-induced hepatitis in pregnancy and patients on PTU should be warned of the potential risk of hepatic failure and advised to seek medical advice immediately if they develop jaundice.
Abstract: A 32-year-old with no pre-existing liver disease was diagnosed with Graves' disease at week 4 of pregnancy Thyroid-stimulating hormone was undetectable with elevated free thyroxine levels and positive thyroid receptor antibodies She was started on a reducing regime of propylthiouracil (PTU) At week 20 in pregnancy, she became jaundiced Initial bloods revealed: bilirubin 91 μmol/l, alanine aminotransferase 1,796 IU/l, alkaline phosphatase 200 IU/l, international normalized ratio 12, and albumin 33 g/l A presumptive diagnosis of PTU-induced hepatitis was made PTU was immediately discontinued and best supportive care instigated Serum markers for autoimmune and viral hepatitis were negative, abdomen ultrasound, ferritin and caeruloplasmin were normal Although her alanine aminotransferase began to fall, her bilirubin continued to rise, peaking at 378 Two weeks after PTU cessation she became thyrotoxic and was started on a reducing regime of carbimazole Her thyroid function stabilized and liver function tests continued to improve with carbimazole stopped at week 32 Growth scans remained normal with delivery of a healthy baby at 38 weeks This report highlights that good outcomes can be achieved in PTU-induced hepatitis in pregnancy Patients on PTU should be warned of the potential risk of hepatic failure and advised to seek medical advice immediately if they develop jaundice
TL;DR: In hypothyroid chickens, the rise in respiratory rate induced by heat exposure was greatly inhibited by α-lipoic acid administration at 1 h, but this effect had disappeared at 4h, and a similar inhibitory effect on the concentrations of plasma nonesterified fatty acids was subsequently observed at 4′h.
Abstract: 1. The present study was conducted to examine the effects of α-lipoic acid on hypothyroidism-induced negative growth performance and whether α-lipoic acid alleviates acute heat stress in relation to hypothyroid status. 2. Female broiler chickens (14 d-old) were fed diets supplemented with α-lipoic acid (100 mg/kg) and an antithyroid substance, propylthiouracil (200 mg/kg), for 20 d under thermoneutral conditions (25°C). At 42 d of age, chickens were exposed to a high ambient temperature (36°C, 60% RH) for 4 h. 3. Under the thermoneutral condition, propylthiouracil administration decreased feed efficiency and concomitantly increased adipose tissue and thyroid gland weights. Plasma nonesterified fatty acids and triacylglycerol were also increased by propylthiouracil administration. However, α-lipoic acid supplementation did not affect the hypothyroidism-induced effects. 4. In hypothyroid chickens, the rise in respiratory rate induced by heat exposure was greatly inhibited by α-lipoic acid administration at ...
TL;DR: Pre-conception counselling should include discussion as to the optimum treatment of Graves’ hyperthyroidism in women wishing to become pregnant, with emphasis on the very low risk of liver disease with propylthiouracil treatment and embryopathy with methimazoles or carbimazole therapy.
Abstract: Risks to mother, fetus and neonate from untreated Graves' hyperthyroidism during gestation are compelling reasons for recommending pre-conception counselling. Pre-conception counselling should include discussion as to the optimum treatment of Graves' hyperthyroidism in women wishing to become pregnant. Thyrotropin receptor antibodies remain elevated following radioiodine therapy, so medical or surgical treatment may be preferred to avoid fetal or neonatal hyperthyroidism. A TSH level <2.5 mIU/l must be achieved in women receiving LT4 before conception. The patient should be reassured that both she and the fetus can be maintained in a euthyroid state and that neonatal hyperthyroidism can be readily managed with a good outcome. The risks of antithyroid drug therapy during gestation should be fully discussed with emphasis on the very low risk (although real) of liver disease with propylthiouracil treatment and embryopathy with methimazole or carbimazole therapy. While propylthiouracil is the preferred drug for the first trimester, if it is not available other thionamides may be given. Breast-feeding while on antithyroid drugs is not contraindicated provided the dose of drug is low. The patient should also be advised of the importance of thyroid monitoring in the post-partum period.
TL;DR: Reference data from a computerized database of thyroid function tests taken in community pediatric clinics should replace current normal values based on a large sample of children.
Abstract: Background: Current pediatric normal values for thyroid function tests are based on data from relatively few patients.
Objective: To develop new normal pediatric values based on a large sample of children.
Patients and methods: Data were collected from a computerized database in Jerusalem, Israel, of thyroid function tests taken in community pediatric clinics. Samples from patients with antithyroid peroxidase antibodies and/or antithyroglobulin antibodies and from those treated with levothyroxine, methimazole, propylthiouracil, thyrotropin, lithium, phenobarbital, or glucocorticoids were excluded. The analysis included over 11,000 samples tested for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) with the ADVIA Centaur system.
Results: The upper normal limit (UNL) for TSH increased by about 1 mIU/L and the lower normal limit (LNL) for FT3 increased by 0.5-2 pmol/L in different age groups. There was no significant change in FT4 values.
Conclusions: These reference data should replace current normal values.
TL;DR: In the month of Ramadan, patients with thyroid diseases, most of the time, do not need treatment adjustments and can fast safely without any health hazards and can avoid fast for few days after a consultation with their religious scholar.
Abstract: In the month of Ramadan, patients with thyroid diseases, most of the time, do not need treatment adjustments and can fast safely without any health hazards. Patients with hypothyroidism taking thyroxine can take their tablets on an empty stomach at bedtime instead of half an hour before Sehr. Patients with hyperthyroidism, on methimazole/carbimazole can continue their dose in once or twice daily regimes, while those on propylthiouracil need to be switched. Hyperthyroid patients with severe symptoms should start treatment immediately and can avoid fast for few days after a consultation with their religious scholar.
TL;DR: A 12-year-old female neutered ragdoll crossbred cat was presented for investigation of generalised weakness and regurgitation and an acetylcholine receptor antibody titre was consistent with acquired myasthenia gravis.
Abstract: A 12-year-old female neutered ragdoll crossbred cat was presented for investigation of generalised weakness and regurgitation. The cat was being treated with transdermal methimazole for hyper-thyroidism, which had been diagnosed 10 weeks previously. An acetylcholine receptor antibody titre was consistent with acquired myasthenia gravis. Withdrawal of methimazole and treatment with pyridostigmine was followed by resolution of clinical signs and reduction of the acetylcholine -receptor antibody titre. Medical control of hyperthyroidism was subsequently achieved with carbimazole, administered in conjunction with pyridostigmine, and no recurrence of clinical signs was observed. Myasthenia gravis is an uncommon but clinically significant adverse effect of methimazole therapy in cats, and may be caused by immunomodulatory properties of this drug. An adverse drug reaction should be considered in cats receiving methimazole that develop myasthenia gravis, and potentially also other immune-mediated disorders.
TL;DR: The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.
Abstract: Mutations of the thyroid hormone receptor-β gene (THRB) cause resistance to thyroid hormone (RTH). A mouse model of RTH harboring a homozygous thyroid hormone receptor (TR)-β mutation known as PV (Thrb(PV/PV) mouse) spontaneously develops follicular thyroid cancer (FTC). Similar to RTH patients with mutations of two alleles of the THRB gene, the Thrb(PV/PV) mouse exhibits elevated thyroid hormones accompanied by highly nonsuppressible TSH. However, the heterozygous Thrb(PV/+) mouse with mildly elevated TSH (~2-fold) does not develop FTC. The present study examined whether the mutation of a single allele of the Thrb gene is sufficient to induce FTC in Thrb(PV/+) mice under stimulation by high TSH. Thrb(PV/+) mice and wild-type siblings were treated with propylthiouracil (PTU) to elevate serum TSH. Thrb(PV/+)mice treated with PTU (Thrb(PV/+)-PTU) spontaneously developed FTC similar to human thyroid cancer, but wild-type siblings treated with PTU did not. Interestingly, approximately 33% of Thrb(PV/+)-PTU mice developed asymmetrical thyroid tumors, as is frequently observed in human thyroid cancer. Molecular analyses showed activation of the cyclin 1-cyclin-dependent kinase-4-transcription factor E2F1 pathway to increase thyroid tumor cell proliferation of Thrb(PV/+)-PTU mice. Moreover, via extranuclear signaling, the PV also activated the integrin-Src-focal adhesion kinase-AKT-metalloproteinase pathway to increase migration and invasion of tumor cells. Therefore, mutation of a single allele of the Thrb gene is sufficient to drive the TSH-simulated hyperplastic thyroid follicular cells to undergo carcinogenesis. The present study suggests that the Thrb(PV/+)-PTU mouse model potentially could be used to gain insights into the molecular basis underlying the association between thyroid cancer and RTH seen in some affected patients.
TL;DR: After recent recommendations from American Thyroid Association (ATA) and European Thyroid association (ETA), PTU should be administered only in the first trimester of pregnancy and in cases of drug allergy to methimazole.
Abstract: Antithyroid drugs (ATDs) have been widely and effectively used for the treatment of pediatric and adult thyrotoxicosis for more than a half century. Since the very beginning of ATD use, reports of hepatic dysfunction related to propylthiouracil (PTU) therapy have been published. We describe a case of a 12-year-old girl, who, after 4 weeks of therapy for Graves disease (GD) with PTU (300 mg/day at 100 mg given three times a day), developed fatigue, fever, diarrhea, nausea, and vomiting. The initial diagnosis was "viral gastrointestinal infection". Few days after the initiation of her symptoms, the patient developed jaundice, hepatic tenderness, and dark urine. She was admitted to the hospital where, after an extensive investigation, it was found that serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) were elevated (2312 and 1435 IU/L, respectively), alkaline phosphatase (ALP) was 171 IU/L and total bilirubin was 12.7 mg/dL, whereas direct bilirubin was 7.6 mg/dL and prothrombin time was 23.2 s (normal ratio, < 14.5 s). Serology for hepatitis A and B was negative. The diagnosis of PTU-induced hepatitis was established. PTU was discontinued, and a treatment with prednisone (50 mg/day) and vitamin K was initiated. Four weeks after admission, her hepatic tests returned to normal. We searched the English literature and we present details of all cases with PTU-related hepatic toxicity in children and adolescents published so far. Also, we provide information regarding the mechanisms and treatment of this appalling clinical entity. Finally, after recent recommendations from American Thyroid Association (ATA) and European Thyroid Association (ETA), PTU should be administered only in the first trimester of pregnancy and in cases of drug allergy to methimazole.
Journal Article•
TL;DR: For both subclinical hypothyroidism and thyroid auto-immunity, treatment with levothyroxine has not yet been proven to be effective in preventing complications during pregnancy and treatment with propylthiouracil or thiamazole is recommended.
Abstract: Hypothyroidism and hyperthyroidism are associated with maternal and neonatal pregnancy complications. Hypothyroidism should be treated with levothyroxine. Hyperthyroidism requires treatment with propylthiouracil or thiamazole. Subclinical hypothyroidism and thyroid auto-immunity are also associated with maternal and neonatal pregnancy complications. For both subclinical hypothyroidism and thyroid auto-immunity, treatment with levothyroxine has not yet been proven to be effective in preventing complications during pregnancy. For the Dutch population the following reference values for TSH levels during pregnancy may be used: 0.01-4.00 mU/l in the first and second trimesters. Reference values for the third trimester have not reported for this population, but are probably comparable with those of the second trimester.
TL;DR: In this paper, the authors conducted a systematic review to provide a comprehensive overview on the available treatment interventions for women with hypothyroidism and thyroid auto-immunity and concluded that evidence is insufficient to recommend universal screening and is only justified in a research setting.
Abstract: Thyroid disorders are associated with pregnancy complications. Universal screening is currently not recommended because of a lack of evidence on the effectiveness of treatment. Women with hyperthyroidism and hypothyroidism evidently require treatment but this is less clear for women with subclinical hypothyroidism and thyroid autoimmunity. Therefore, we conducted a systematic review to provide a comprehensive overview on the available treatment interventions. Relevant studies were identified by searching Medline, EMBASE and Cochrane Controlled Trials Register, published until December 2011. From a total of 7334 primary selected titles, 22 articles were included for the systematic review and 11 were appropriate for meta-analyses. Eight studies reported on hyperthyroidism. Propylthiouracil (PTU) and methimazole reduce the risk for preterm delivery [risk ratio (RR): 0.23, confidence interval (CI): 0.1-0.52], pre-eclampsia (RR: 0.23, CI: 0.06-0.89) and low birthweight (RR: 0.38, CI: 0.22-0.66). The nine studies that reported on clinical hypothyroidism showed that levothyroxine is effective in reducing the risk for miscarriage (RR: 0.19, CI: 0.08-0.39) and preterm delivery (RR: 0.41, CI: 0.24-0.68). For treatment of subclinical hypothyroidism, current evidence is insufficient. The five studies available on thyroid autoimmunity showed a not significant reduction in miscarriage (RR: 0.58, CI: 0.32-1.06), but significant reduction in preterm birth by treatment with levothyoxine (RR: 0.31, CI: 0.11-0.90). For hyperthyroidism, methimazole and PTU are effective in preventing pregnancy complications. For clinical hypothyroidism, treatment with levothyroxine is recommended. For subclinical hypothyroidism and thyroid autoimmunity, evidence is insufficient to recommend treatment with levothyroxine. The overall lack of evidence precludes a recommendation for universal screening and is only justified in a research setting
TL;DR: A rare case of acute liver failure after methimazole intake in a 60-year-old man who underwent liver transplantation is described and spontaneous recovery is expected even if it does occur.
Abstract: Antithyroid drugs inhibit the synthesis and excretion of thyroid hormone from the thyroid gland. Propylthiouracil (PTU) and methimazole are well known as antithyroid drugs. In 2011, the American Thyroid Association and American Association of Clinical Endocrinologists published management guidelines for hyperthyroidism and other causes of thyrotoxicosis, and recommended methimazole as the first-choice antithyroid drug for the treatment of hyperthyroidism. Lower hepatotoxicity is an advantage of methimazole. Fulminant hepatitis rarely occurs in methimazole users, and spontaneous recovery is expected even if it does occur. We describe a rare case of acute liver failure after methimazole intake in a 60-year-old man who underwent liver transplantation. (Korean J Med 2012;83:363-368)
TL;DR: In conclusion, although serum levels of thyroid hormones were affected by dietary treatments, manipulation of thyroid status could not improve growth performance.
Abstract: In order to investigate the effects of transient hypo- and hyperthyroidism on growth performance, organ weights and serum thyroid hormones of broilers, 120 one-day-old broiler chicks were randomly divided into four dietary treatments for six weeks. The dietary treatments included: 1) control, 2) hypothyroid (hypo; propylthiouracil (PTU)-treated), 3) hyperthyroid (HYPER; thyroxine (T 4 )-treated) and 4) hypo-hyper ((PTU-T 4 )-treated) groups. PTU and T 4 were administered between the ages of 14 to 28 days. Furthermore, a group of PTU treated birds were restored by administering T 4 between 28 and 35 days of age to form the hypo-hyper group. In the whole experiment, body weight gain and feed intake were significantly (P < 0.01) decreased by dietary inclusion of PTU and T 4 when compared with control birds. Induction of hyperthyroidism significantly impaired feed conversion ratio when compared with other groups (P < 0.01). The relative weight of liver was significantly greater for hypo and hyper when compared with control and hypo-hyper groups (P < 0.01). Induction of hyperthyroidism resulted in decreased abdominal fat when compared with other treatments (P < 0.01). Serum levels of T 3 and T 4 were significantly influenced by hypo- and hyper-thyroidism in 28, 35 and 42 days of age (P < 0.01). In conclusion, although serum levels of thyroid hormones were affected by dietary treatments, manipulation of thyroid status could not improve growth performance. Key words: Hypothyroidism, hyperthyroidism, performance, organ weight, thyroid hormones.
TL;DR: Investigation of alternative pathway activity in male Wistar rats after altering their thyroid hormone levels by treatment with triiodothyronine, propylthiouracil or thyroidectomy concludes that alterations in thyroid hormone Levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factors B in antibody production.
Abstract: Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32%) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.
10 Aug 2012
TL;DR: Folic acid as a treatment was better if it is administered as an adjuvant after returning to the euthyroid state, and the results revealed that the hippocampus of hypothyroid rats showed marked histopathological changes as moderate inflammation, oedema, diffuse vacuolar degeneration and distortion in the pyramidal cells.