Histopathological changes of parotid and larynx in hypothyroid rats: experimental study.

OBJECTIVES: In this study, we aimed to investigate the laryngeal and parotid histopathological alterations in rats with experimentally induced postnatal hypothyroidism. MATERIALS AND METHODS: 200-300 g weighed Wistar albino rats were included in this study. The rats were randomly divided into four groups: group 1 is control and the other groups are experimental groups. Food and water were supplied ad libitum in group 1, no medication was administered. Propylthiouracil (PTU) was administered intraperitoneally for 15 days in group 2; for 30 days in group 3, for 45 days in group 4. The larynx and parotid glands of the rats were removed and intracardiac blood samples were collected for thyroid-stimulating hormone (TSH) analysis under anesthesia (ketamine hydrochloride, 100 mg/kg) 24 h after the last PTU injection. The same procedures were done for the control group at day 46. Histopathological evaluation was done for all the specimens. RESULTS: While submucosal vascular dilatation was significantly higher in the experiment groups (p < 0.05), there was not a significant difference in lamina propria edema, inflammation, goblet cell loss, cilia loss between the groups in larynx specimens. In parotid gland specimens, serous asinus atrophy, stromal connective tissue increase were significantly higher in experiment groups (p < 0.05). In addition, there was a significant difference in nuclear morphology between control and experimental groups (p < 0.05). CONCLUSION: The results of the study showed that hypothyroidism may have effect on inflammatory procedure by causing vascular dilation in larynx and serous asinus atrophy nucleus changes, connective tissue increase in stroma in parotid gland.

SIDE EFFECTS OF PTU AND MMI IN THE TREATMENT OF HYPERTHYROIDISM: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Objective: The present study aimed to investigate the adverse effects of the antithyroid drugs propylthiouracil (PTU) and methimazole (MMI)/carbimazole (CMZ) in treating hyperthyroidism. Methods: Qualitative analysis was performed for studies identified in a literature search up to April 20, 2019, and 30 studies were selected for meta-analysis. The study designs included case-control, randomized controlled, and retrospective cohort. Patients were in four age groups: childhood, gestating mothers, older adults, and other ages, and all were receiving PTU or MMI/CMZ. Adverse reactions to MMI/CMZ and PTU were evaluated and compared. Results: Odds of liver function injury were higher in the PTU group than in the MMI/CMZ group (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.16 to 4.96; P = .02). Odds of elevated transaminase were much higher in the PTU group than in the MMI/CMZ group (OR, 3.96; 95% CI, 2.49 to 6.28; P<.00001). No significant between-group differences were found in odds of elevated bilirubin, agranulocytosis, rash, or urticaria; incidence of other adverse events; or in children. Odds of birth defects during the first trimester of pregnancy were higher in the MMI/CMZ group than in the PTU group (OR, 1.29; 95% CI, 1.09 to 1.53; P = .003). Conclusion: The impact of PTU on liver injury and transaminase levels is greater than that of MMI/CMZ, but no significant between-group differences are found in the drugs' effects on bilirubin, agranulocytosis and rash, urticaria, or in children. In treating pregnancy-related hyperthyroidism, PTU should be used in the first trimester and MMI reserved for use in late pregnancy. Abbreviations: ALT = alanine aminotransferase; ATD = antithyroid drug; CI = confidence interval; CMZ = carbimazole; GD = Graves disease; MMI = methimazole; MTU = methylthiouracil; NOS = Newcastle-Ottawa Scale; OR = odds ratio; PTU = propylthiouracil; RAI = radioactive iodine.

Case Studies in Thyroid Dysfunction and Pregnancy.

This chapter represents a selection of 8 clinical scenarios that may commonly be encountered. They help summarize some of the literature and teaching points of the previous chapters. They are not meant to represent every possible presentation of thyroid disease, but rather to present common symptoms and findings that may aid a clinician in making a diagnosis or in selecting initial treatment.

Management of thyroid disorders in pregnancy: Recommendations made simple.

This review covers the current American Thyroid Association recommendations on diagnosis and management of thyroid disease during pregnancy and the postpartum period. It lists the recommendations in a reader-friendly way, and facilitates rational therapy of thyroid disorders, in relation to obstetric health, at the primary care level.

Treatment and management of thyroid storm: analysis of the nationwide surveys: The taskforce committee of the Japan Thyroid Association and Japan Endocrine Society for the establishment of diagnostic criteria and nationwide surveys for thyroid storm.

OBJECTIVE: Thyroid storm (TS) is a life-threatening endocrine emergency. This study aimed to achieve a better understanding of the management of TS by analyzing therapeutic modalities and prognoses reported by nationwide surveys performed in Japan. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective analyses were performed on clinical parameters, outcomes, and treatments in 356 TS patients. RESULTS: Patient disease severities assessed via Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores significantly correlated with mortality. Free triiodothyronine (FT3) and the FT3/free thyroxine (FT4) ratio inversely correlated with disease severity. Methimazole (MMI) was used in the majority of patients (78·1%), and there were no significant differences in mortality or disease severity between those treated with MMI and those receiving propylthiouracil (PTU). Patients who received inorganic iodide (KI) demonstrated higher disease severity but no change in mortality compared to those who did not. Patients treated with corticosteroids (CSs) demonstrated significantly higher disease severity and mortality than those who were not. Disease severity in patients treated with intravenous administration of beta-adrenergic antagonists (AAs) was significantly higher than those treated with oral preparations, although no significant difference in mortality was observed between these groups. In addition, mortality was significantly higher in patients treated with non-selective beta-AAs as compared with other types of beta-AAs. CONCLUSION: In Japan, MMI was preferentially used in TS and showed no disadvantages compared to PTU. In severe TS, multimodal treatment, including administration of antithyroid drugs, KI, CSs and selective beta1 -AAs may be preferable to improve outcomes.

A 2013 European survey of clinical practice patterns in the management of Graves' disease.

OBJECTIVE: Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 American survey. DESIGN: Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey. RESULTS: A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the preferred first-line treatment (83·8%). Compared to the previous European survey, Europeans currently more frequently use TRAb measurement and thyroid ultrasound for diagnosis and evaluation, but first-line treatment remains ATDs in a similar percentage of respondents. Current clinical practice patterns differ from those in North America, where isotopic studies are more frequently used, and radioiodine (RAI) still is first-line treatment. When RAI treatment is selected in the presence of mild Graves' orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis is frequently used. The preferred ATD in pregnancy is propylthiouracil in the first trimester and methimazole in the second and third trimesters, similar to North America. CONCLUSIONS: Significant changes in clinical practice patterns in Europe were noted compared to the previous European survey, as well as persisting differences in diagnosis and therapy between Europe and North America.

Sequential Amniotic Fluid Thyroid Hormone Changes Correlate with Goiter Shrinkage following in utero Thyroxine Therapy.

Several isolated reports of fetal goiter treatment have shown limited generalizability of approaches and provide no real guidance for optimal timing, dosages, and treatment strategies. Graves' disease accounts for >60% of these cases. Maternal treatments of hyperthyroidism include antithyroid medications such as methimazole and more commonly propylthiouracil (PTU). Here, our management of a patient with a fetal thyroid goiter from maternal exposure to PTU diagnosed at 23.6 weeks' gestation and the management of other cases allow us propose a general strategy for treatment. Intrauterine therapy with 200 and then 400 µg of levothyroxine (3 weeks apart) showed an 85% reduction in fetal thyroid goiter volume. We collected amniotic fluid samples at the time of treatments and assayed thyroid hormones and associated antibodies which closely reflected the changes in thyroid goiter mass volume. Our observations suggest a weekly or biweekly therapeutic intervention schedule. Utilizing both goiter size as well as a novel approach in using amniotic fluid hormone levels to monitor therapy efficacy might improve the quality of treatments. Only with a standardized approach and collection of amniotic fluid thyroid panels do we have the opportunity to develop the database required to determine the number and timing of treatments needed.

Maternal hyperthyroidism after intrauterine insemination due to hypertrophic action of human chorionic gonadotropin: a case report.

PURPOSE OF INVESTIGATION: To report a rare case of maternal hyperthyroidism after intrauterine insemination due to hypertrophic action of hCG. MATERIALS AND METHODS: A 36-year-old woman after successful intrauterine insemination and triplet pregnancy, developed hyperthyroidism with resistance to medical treatment. RESULTS: All signs of hyperthyroidism resolved and the results of thyroid function tests returned to normal without any medication after embryo meiosis. CONCLUSIONS: De novo maternal hyperthyroidism may develop during pregnancy as a result of pathological stimulation of the thyroid gland from the high levels of hCG hormone that can be seen in multiple pregnancies. The risk of hyperthyroidism is related to the number of fetuses. Reversibility of symptomatology can be seen after fetal reduction of multiple pregnancies.

Importance of low serum DNase I activity and polyspecific anti-neutrophil cytoplasmic antibodies in propylthiouracil-induced lupus-like syndrome.

OBJECTIVE: To study the role of deoxyribonuclease (DNase) I activity and ANCA in propylthiouracil (PTU)-induced lupus-like syndrome (LLS). METHODS: We compared 36 SLE patients with 17 PTU-induced LLS patients diagnosed from 2008 to 2014. We studied ANCA profile (MPO, PR3, lactoferrin, CTG, elastase, bactericidal/permeability-increasing protein), anti-dsDNA, anti-ENA, anti-nucleosome, anti-histone, anti-C1q, anti-aCL, complement components, cryoglobulins and serum DNase I activity. Healthy persons and patients without LLS treated with PTU comprised the control groups. Twelve LLS patients were serologically and clinically followed for 4.1 (S.D. 2.0) years. RESULTS: PTU-induced LLS patients less frequently had arthritis, renal and neurological manifestations, but more frequently had fever, purpura, urticarial-like vasculitis and ulceration (P < 0.01). PTU-induced LLS patients more frequently had polyspecific ANCA (anti-MPO, anti-elastase and anti-PR3 were most commonly detected) (P < 0.01). SLE patients more frequently had anti-dsDNA, anti-ENA, anti-nucleosome, anti-C1q (P < 0.01) and anti-histone antibodies (P < 0.05). PTU-induced LLS patients had lower DNase I activity than SLE patients and controls (P < 0.01). Discontinuation of PTU increased DNase I activity, although it did not reach the levels of controls (P < 0.01). After remission, MPO-ANCA decreased (P < 0.01), but persisted for a long time. CONCLUSION: PTU, as a trigger, and low DNase I activity, as a predisposing factor, may lead to LLS. Polyspecific ANCAs are useful markers for differentiating SLE from PTU-induced LLS. Low DNase I activity might be an important prognostic biomarker for PTU-induced LLS. Monitoring of ANCA and DNase I activity may prevent long-lasting exposure to causal drugs, unnecessary immunosuppressive therapy and severe complications of LLS.

Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy.

PURPOSE: Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy. METHODS: A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU-treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed. RESULTS: The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy". CONCLUSIONS: While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy.

Pancytopenia in the first trimester: An indicator of hidden hyperthyroidism.

Pancytopenia in the first trimester is very rare. A 33-year-old multiparous woman presented with nausea, loss of appetite, and bodyweight loss of 7.4 kg at 9(1/7) weeks of gestation due to hyperemesis gravidarum. Her laboratory data demonstrated pancytopenia involving white blood cell count of 3500/µL, a hemoglobin level of 9.8 g/dL, and a platelet count of 10.5 × 10(4)/µL. An extensive investigation into the causes of the pancytopenia detected true hyperthyroidism: thyroid-stimulating hormone, <0.02 µU/mL; free triiodothyronine, 11.25 pg/mL; free thyroxine, 4.74 ng/dL; and anti-thyroid-stimulating hormone receptor antibodies, 12.2 IU/L. Propylthiouracil was started at a dose of 300 mg/day at 10(5/7) weeks of gestation, which resulted in the normalization of her blood parameters and concomitant improvements in her free triiodothyronine and free thyroxine levels at 12(0/7) weeks of gestation. Pancytopenia in the first trimester might be indicative of hidden hyperthyroidism.

Atypical propylthiouracil-induced ANCA-positive vasculitis: report of a case with unusual clinical and histopathologic findings.

The side effects of propylthiouracil, including cytopenia and vasculitis, are well established.  We present an interesting case in which cytopenia and cutaneous vasculopathy occurred concomitantly in a critically ill patient.  The patient was initially treated for suspected infection until dermatologic and rheumatologic workup revealed ANCA-positivity and vasculopathy on histopathology, most consistent with an atypical presentation of ANCA-positive vasculitis.  Upon initiation of immunosuppressive therapy, the patient's condition rapidly improved emphasizing the importance of early recognition of this condition.

[Management of hypothyroidism and hyperthyroidism]. / Lécba hypotyreózy a hypertyreózy.

Functional thyropathies present significant health risks for patients. Advanced functional thyropathies are always treated while indications for therapy of subclinical thyropathies are individual and often controversial. It is widely agreed that these disorders should be diagnosed and individuals should be followed. The drug of choice in substitution therapy of hypothyroidism is levothyroxine, in the treatment of hyperthyroidism it is methimazole. Administration of propylthiouracil should be limited to the first trimester of pregnancy, because its serious hepatotoxicity has been described. Hyperthyroidism based on thyroid nodules and immunogenic hyperthyroidism not reaching long-term remission, need to be treated radically: by surgery or radioiodine treatment. When radiation protection requirements are met, radioiodine can also be administered on an outpatient basis. Exceptionally, small doses of methimazole can be administered over an extended period of time in individual cases.

[ANALYSIS OF ULTRASONIC, CYTOLOGICAL AND MORPHOLOGIC RESEARCHES RESULTS OF PATIENTS WITH GRAVES' DISEASE (TOXIC GOITER) DEPENDING ON DISEASE DURATION].

The aim of research is to arrange the results of ultrasonic and cytological researches during long-term drug treatment (more than 1 year) of patients with Graves' disease. From 2008 to 2013 the detailed examination of 220 patients was carried out in Kyiv City Centre for Endocrine Surgery which operates on the basis of the 3d Clinical Hospital. There were established three kinds of echographic patterns which pointed out the ultrasonic changes of the thyroid gland tissue, occurred during the drug treatment. Among 63 (28.6%) patients with long-term drug treatment the development of space-occupying lesions, occurred due to long duration of disease with long-term usage of tyreostatics, was recorded. After the surgical treatment the extracted thyroid gland tissue was subjected to histological study. The papillary carcinoma of thyroid gland was verified in 4 (6,3 %) of 63 patients with space-occupying lesions. The ultrasonic research of thyroid gland in combination with aspiration puncture biopsy and cytological research are the highly informative methods of examination of patients with Graves' disease which allow to objectify the organ structural condition while the disease duration.

Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study.

AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

An update on the medical treatment of Graves' hyperthyroidism.

Medical treatment of Graves' hyperthyroidism is based on the use of thionamides; namely, methimazole and propylthiouracil. In the past, methimazole was preferred by European endocrinologists, whereas propylthiouracil was the first choice for the majority of their North American colleagues. However, because of the recent definition of a better side-effect profile, methimazole is nowadays the first choice world while. Although thionamides are quite effective for the short-term control of Graves' hyperthyroidism, a relatively high proportion of patients relapses after thionamide withdrawal. Other possible medical treatments, include iodine and compounds containing iodine, perchlorate, lithium (as an adjuvant in patients undergoing radioiodine therapy), ß-adrenergic antagonists, glucocorticoids, and some new molecules still under investigation. Management of Graves' hyperthyroidism using thionamides as well as the other available medical treatments is here reviewed in detail, with a special mention of situations such as pregnancy and lactation, as well as neonatal and fetal thyrotoxicosis.

Management of hyperthyroidism during pregnancy in Asia.

Maternal hyperthyroidism in pregnancy is associated with adverse impacts on both mother and fetus. Recently, the American Thyroid Association and the Endocrine Society have published guidelines for the management of thyroid diseases in pregnancy. We aimed to disclose the impact of these guidelines in current practices of Asian members of the Asia-Oceania Thyroid Association (AOTA) regarding the management of hyperthyroidism in pregnancy. Completed questionnaire survey, based on clinical case scenarios, was collected from 321 Asian physician members of AOTA from 21 Asian countries in 2013. For a woman with Graves' disease planning pregnancy, 92% of clinicians favored antithyroid treatment, 52% with propylthiouracil (PTU) while 40% preferred methimazole (MMI). For a pregnant woman with newly diagnosed overt hyperthyroidism, nearly all responders initiated PTU treatment. To monitor dosage of antithyroid drugs, approximately 73% of responders used TSH and free T4 (FT4) levels without free T3 (FT3) (53%) or with FT3 (20%). Majority of responders targeted achieving low serum TSH with FT4 (or total T4) in the upper end of the normal range. For management of gestational thyrotoxicosis, 40% chose to follow up and 52% treated patients with PTU. Although timing of TSH receptor antibodies measurement in pregnant hyperthyroid patients was variable, 53% of responders would check it at least once during pregnancy. Nearly 80% of responders do not treat subclinical hyperthyroidism in pregnancy. Therefore, despite wide variations in the management of hyperthyroidism during pregnancy in Asia, majority of Asian physicians practice within the recommendations of major professional societies.

Glucose variability before and after treatment of a patient with Graves' disease complicated by diabetes mellitus: assessment by continuous glucose monitoring.

A 48-year-old woman was diagnosed and treated for Graves' disease (GD) in 1999 but she discontinued treatment at her own discretion. In 2011, she was admitted to a local hospital for management of thyrotoxic crisis. Treatment with propylthiouracil, iodide potassium (KI), and prednisolone (PSL) was started, which resulted in improvement of the general condition. PSL and KI were discontinued before she was transferred to our hospital. At the local hospital, fasting plasma glucose (FPG) was 212 mg/dL and hemoglobin A1c concentration was 11.2%; intensive insulin therapy had been instituted. Upon admission to our hospital, FPG level was 122 mg/dL, but insulin secretion was compromised, suggesting aggravation of thyroid function and deterioration of glycemic control. The FPG level increased to 173 mg/dL; continuous glucose monitoring (CGM) identified dawn phenomenon at approximately 0400 h. Resumption of KI resulted in improvement of FPG and disappearance of the dawn phenomenon, as assessed by CGM. These results indicate that in patients with compromised insulin secretion, hyperthyroidism can induce elevation of not only postprandial blood glucose, but also FPG level due to the dawn phenomenon and that the dawn phenomenon can be alleviated with improvement in thyroid function. To our knowledge, no studies have assessed glucose variability by CGM before and after treatment of Graves' disease. The observations made in this case shed light on the understanding of abnormal glucose metabolism associated with Graves' disease.

Acute onset of a vesiculopustular rash in an ICU patient.

A 63 year-old woman with hyperthyroidism was admitted to the Medical Intensive Care Unit for ARDS following damage to her lungs from propylthiouracil. She was placed on 250 mg SSKI PO TID as an alternative therapy until thyroidectomy could be performed. Four days after admission, she abruptly developed an acneiform rash on her face, shown to be iododerma. The eruption rapidly resolved after discontinuation of the SSKI.