Effects of levothyroxine in subclinical hypothyroidism and heart failure with reduced ejection fraction: An open-label randomized trial.

We report a randomized, multicenter, open-label trial (ClinicalTrials.gov: NCT03096613) to investigate the clinical benefits of levothyroxine (L-T4) administration in subclinical hypothyroidism (SCH) patients with heart failure with reduced ejection fraction (HFrEF). Overall, 117 patients were enrolled and received L-T4 plus standard HFrEF treatment (experimental group, N = 57) or standard HFrEF therapy alone (control group, N = 60). The change of 6-min walk test distance in the experimental group was significantly higher than that in the control group at 24 weeks (70.08 ± 85.76 m vs. 27.73 ± 82.00 m, mean difference [95% confidence interval (CI)] 46.90 [12.90, 80.90], p < 0.001). Improvements in New York Heart Association (NYHA) classification (p = 0.033) and thyroid function were significant. Adverse event incidence was similar between groups (risk ratio [95% CI]: 0.942 1.053 (0.424, 2.616); p = 0.628). L-T4 addition to HFrEF treatment improved activity tolerance, NYHA class, and thyroid function within 6 months, suggesting its potential for combined therapy in HFrEF patients with SCH. Future double-blind, placebo-controlled trials should be performed to confirm these results.

Levothyroxine Treatment Among Pregnant Women and Risk of Seizure in Children: A Population-Based Cohort Study.

INTRODUCTION AND OBJECTIVE: The risk of seizure in offspring following prenatal exposure to levothyroxine is not well investigated. This study aimed to evaluate the association between levothyroxine treatment among pregnant women and the risk of seizure in their offspring. METHODS: This population-based cohort study included all pregnant women who delivered a live birth between January 2001 to January 2018, with a follow-up to December 2020, using data from the Hong Kong Clinical Data Analysis and Reporting System. Propensity score fine-stratification weighted hazard ratios (wHR) with 95% confidence intervals (CIs) were presented to assess the association between maternal levothyroxine use during pregnancy and seizures in children. RESULTS: Among 528,343 included mother-child pairs, 3044 children were prenatally exposed to levothyroxine at any time during the pregnancy period. A significantly increased risk of seizure was observed in children of the prenatally exposed group compared with the prenatally unexposed group (wHR 1.12, 95% CI 1.02-1.22). An increased risk of seizure was observed when comparing the prenatally exposed group with euthyroid mothers who had no history of thyroid-related diagnosis or prescriptions (wHR 1.12, 95% CI 1.02-1.23). However, no significant difference was observed between the prenatally exposed group and those previously exposed to levothyroxine but had stopped during pregnancy (wHR 0.97, 95% CI 0.66-1.44). No significant difference was observed in the sibling-matched analysis either (wHR 1.23, 95% CI 0.76-2.01). CONCLUSION: The observed increased risk of seizure in children born from mothers exposed to levothyroxine during pregnancy might be due to residual confounding by maternal thyroid disease. The findings support the current guidelines on the safe use of levothyroxine treatment during pregnancy.

Mifepristone-Induced Hypothyroidism.

Medications are known to affect the thyroid physiology and are a known cause of hypothyroidism. There is an ever-growing list of medications that affect the thyroid by 1 or more mechanisms. Mifepristone is presently used for the treatment of mild autonomous cortisol secretion (MACS). Hypothyroidism is not a known side effect of this medication. We present a 71-year-old woman with newly diagnosed impaired fasting glucose, dyslipidemia, and osteopenia presenting with a 3-year history of unintentional 15-pound weight gain (despite exercise and a good diet) and increased anxiety. Her physical examination was pertinent for mild lower extremity edema, easy bruising, and skin thinning. Workup revealed adrenocorticotropic hormone (ACTH)-independent MACS from bilateral micronodular hyperplasia of the adrenals. Since she was not a surgical candidate, medical management with mifepristone was chosen. While on mifepristone, she complained of excessive fatigue, a workup done revealed new-onset hypothyroidism. Given her symptoms and bloodwork, she was started on levothyroxine. After stopping mifepristone, she was biochemically and clinically euthyroid and was eventually off levothyroxine. The mechanism by which mifepristone induces hypothyroidism is unknown. Except for a multicenter case series suggesting that mifepristone increases thyroid hormone requirements in patients with central hypothyroidism, to the best of our knowledge, the literature on euthyroid patients developing hypothyroidism secondary to mifepristone is scarce. In conclusion, while the hypothyroidism seems reversible our case highlights the importance of getting baseline thyroid function tests (TFTs) and repeating them while on the medication. Treatment of hypothyroidism is based on symptoms and bloodwork.

Levothyroxine use and longitudinal changes in thigh muscles in at-risk participants for knee osteoarthritis: preliminary analysis from Osteoarthritis Initiative cohort.

BACKGROUND: We examined the association between levothyroxine use and longitudinal MRI biomarkers for thigh muscle mass and composition in at-risk participants for knee osteoarthritis (KOA) and their mediatory role in subsequent KOA incidence. METHODS: Using the Osteoarthritis Initiative (OAI) data, we included the thighs and corresponding knees of participants at risk but without established radiographic KOA (baseline Kellgren-Lawrence grade (KL) < 2). Levothyroxine users were defined as self-reported use at all annual follow-up visits until the 4th year and were matched with levothyroxine non-users for potential confounders (KOA risk factors, comorbidities, and relevant medications covariates) using 1:2/3 propensity score (PS) matching. Using a previously developed and validated deep learning method for thigh segmentation, we assessed the association between levothyroxine use and 4-year longitudinal changes in muscle mass, including cross-sectional area (CSA) and muscle composition biomarkers including intra-MAT (within-muscle fat), contractile percentage (non-fat muscle CSA/total muscle CSA), and specific force (force per CSA). We further assessed whether levothyroxine use is associated with an 8-year risk of standard KOA radiographic (KL ≥ 2) and symptomatic incidence (incidence of radiographic KOA and pain on most of the days in the past 12 months). Finally, using a mediation analysis, we assessed whether the association between levothyroxine use and KOA incidence is mediated via muscle changes. RESULTS: We included 1043 matched thighs/knees (266:777 levothyroxine users:non-users; average ± SD age: 61 ± 9 years, female/male: 4). Levothyroxine use was associated with decreased quadriceps CSAs (mean difference, 95%CI: - 16.06 mm2/year, - 26.70 to - 5.41) but not thigh muscles' composition (e.g., intra-MAT). Levothyroxine use was also associated with an increased 8-year risk of radiographic (hazard ratio (HR), 95%CI: 1.78, 1.15-2.75) and symptomatic KOA incidence (HR, 95%CI: 1.93, 1.19-3.13). Mediation analysis showed that a decrease in quadriceps mass (i.e., CSA) partially mediated the increased risk of KOA incidence associated with levothyroxine use. CONCLUSIONS: Our exploratory analyses suggest that levothyroxine use may be associated with loss of quadriceps muscle mass, which may also partially mediate the increased risk of subsequent KOA incidence. Study interpretation should consider underlying thyroid function as a potential confounder or effect modifier. Therefore, future studies are warranted to investigate the underlying thyroid function biomarkers for longitudinal changes in the thigh muscles.

Effect of a polyherbal formulation on L-thyroxine induced hyperthyroidism in a rat model: In vitro and in vivo analysis and identification of bioactive phytochemicals.

An excess of thyroid hormones in the blood characterizes hyperthyroidism. Long-term use of prescription medications to treat hyperthyroidism has substantial adverse effects and when discontinued, the symptoms frequently recur. Several plant species have been utilized to cure hyperthyroidism. In the present work, we investigated the impact of polyherbal extract (POH) of four medicinal plants to treat hyperthyroidism. Biochemical analysis revealed the presence of a high concentration of phytochemicals in the POHs. The in vitro antioxidant study revealed their antioxidant and free radical scavenging capacity. The gas chromatography coupled mass spectrometry analysis of the POHs showed the presence of 13 bioactive phytochemical compounds. The effect of various concentrations of POHs on L-thyroxine-induced hyperthyroidism in Wistar albino rats was evaluated for 18 days. The TSH, T3 and T4 levels increased significantly and reduced the increase of liver enzymes caused by hyperthyroidism in POH-treated rats. The data showed that POH therapy could restore thyroid function to normal. The injection of POH increased the size comprising vacuolated cells, columnar follicular cells and highly coloured nuclei with increasing POH content and the number of normal thyroid follicles rose. The findings indicate that polyherbal formulations of these medicinal plants include credible antithyroid compounds that may offer a protective and an effective alternative treatment to synthetic thyroid medications.

Association of maternal levothyroxine use during pregnancy with offspring birth and neurodevelopmental outcomes: a population-based cohort study.

BACKGROUND: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring. METHODS: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model. RESULTS: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD. CONCLUSIONS: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy.

Association between levothyroxine replacement therapy and osteoporosis in Riyadh, Saudi Arabia: a matched case-control study.

Hypothyroidism is a common health problem among elder women. However, conflicting results were observed regarding the association between levothyroxine treatment and osteoporosis risk. Therefore, the current study aimed to evaluate the effect of levothyroxine replacement therapy on osteoporosis risk in the Saudi population. This study was a matched case-control study conducted from June to August 2020. Data were extracted from the electronic medical records and included sociodemographic, clinical characteristics, comorbid conditions, levothyroxine replacement therapy dose, duration, concomitant therapy, and bone mineral density. Cases were matched with controls (1:1 basis) by age; the study included 256 cases and 256 controls. In the multivariate conditional logistic regression analysis, thyroxine use was independently associated with an increased likelihood of osteoporosis. Therefore levothyroxine use in elderly females was associated with an increased risk of osteoporosis, and hence, clinicians must be aware of the levothyroxine replacement therapy outcomes in postmenopausal females at risk of osteoporosis.

Thyroid Antibody Titers and Hypothalamic-Pituitary-Thyroid Axis Activity in Levothyroxine-Treated Women With Autoimmune Subclinical Hypothyroidism Receiving Atorvastatin or Metformin.

Both metformin and statins reduce thyroid antibody titers in individuals with Hashimoto thyroiditis. The present study compared the impact of low-grade systemic inflammation and insulin resistance on levothyroxine action in subjects with this disorder. The study included 3 groups of women with autoimmune subclinical hypothyroidism matched for thyroid antibody titers and hormone levels: patients receiving atorvastatin (group A) or metformin (group B) and statin- and metformin-naïve women (group C). Over the entire study period (6 months), all individuals received levothyroxine. Titers of thyroid antibodies, as well as concentrations of thyrotropin, free thyroid hormones, prolactin, lipids, glucose, insulin, high-sensitivity C-reactive protein (hsCRP), and 25-hydroxyvitamin D were assessed at baseline and 6 months later. At baseline, the study groups differed in plasma lipids, insulin sensitivity, and hsCRP. In all groups of patients, levothyroxine decreased thyroid antibody titers, reduced thyrotropin levels and increased free thyroid hormone levels. Treatment-induced changes in antibody titers and free thyroid hormone levels were strongest in group A, while the changes in thyrotropin were most pronounced in group B. The decrease in antibody titers correlated to a greater degree with hsCRP levels than with insulin sensitivity. The obtained results suggest that low-grade systemic inflammation is a more important factor determining the impact of levothyroxine on thyroid autoimmunity and thyroid hormone levels than insulin resistance.

Cardiovascular protective effects of PPARγ agonists in hypothyroid rats: protection against oxidative stress.

Hypothyroidism disturbs redox homeostasis and takes part in cardiovascular system dysfunction. Considering antioxidant and cardio-protective effects of PPAR-γ agonists including pioglitazone (POG) and rosiglitazone (RSG), the present study was aimed to determine the effect of POG or RSG on oxidants and antioxidants indexes in the heart and aorta tissues of Propylthiouracil (PTU)-induced hypothyroid rats. MATERIALS AND METHODS: The animals were divided into six groups: (1) Control; (2) propylthiouracil (PTU), (3) PTU-POG 10, (4) PTU-POG 20, (5) PTU-RSG 2, and (6) PTU-RSG 4. Hypothyroidism was induced in rats by giving 0.05% propylthiouracil (PTU) in drinking water for 42 days. The rats of PTU-POG 10 and PTU-POG 20 groups received 10 and 20 mg/kg POG, respectively, besides PTU, and the rats of PTU-RSG 2 and PTU-RSG 4 groups received 2 and 4 mg/kg RSG, respectively, besides PTU. The animals were sacrificed, and the serum of the rats was collected to measure thyroxine level. The heart and aorta tissues were also removed for the measurement of biochemical oxidative stress markers. RESULTS: Hypothyroidism was induced by PTU administration, which was indicated by lower serum thyroxine levels. Hypothyroidism also was accompanied by a decrease of catalase (CAT), superoxide dismutase (SOD) activities, and thiol concentration in the heart and aorta tissues while increased level of malondialdehyde (MDA). Interestingly, administration of POG or RSG dramatically reduced oxidative damage in the heart and aorta, as reflected by a decrease in MDA and increased activities of SOD, CAT, and thiol content. CONCLUSION: The results of this study showed that administration of POG or RSG decreased oxidative damage in the heart and aorta tissues induced by hypothyroidism in rats.

Efficacy and safety of supraphysiologic doses of levothyroxine for patients with bipolar depression in adults: A systematic review.

BACKGROUND: In bipolar disorder (BD), depression is the most difficult-to-treat dimension and available evidence suggests that add-on supraphysiological doses of levothyroxine may be an effective augmenting agent. AIM: This systematic review has been conducted to evaluate the efficacy and safety of supraphysiologic doses of levothyroxine in bipolar depression in adults. METHODS: After a comprehensive literature search on MEDLINE/PubMed, Scopus, Cochrane databases and International Clinical Trial Registry Platform (ICTRP), reviewers extracted data from eight relevant articles. PRISMA guidelines were followed in the selection, analysis and reporting of findings. Quality assessment was done using the risk of bias assessment and a random effects model was used to estimate effect size. Meta-analysis could not be done due to the lack of randomized, placebo-controlled trials and adequate data. A systematic review was done on eight studies and analysis on the pre-post change in Hamilton depression rating scale score (HDRS) was done for six studies. RESULTS: The random model analysis of pooled effects showed a standardized mean difference of HDRS score by 2.62 (95% CI: 2.21-3.04; p < 0.0001). The responder and remission rates were not significant as reported in one study. Markov chain analysis performed in one study revealed that patients in the levothyroxine group had a significantly greater increase in time in the euthymic state and a decrease in the mixed state. In most of the studies, levothyroxine therapy was well tolerated, with no serious adverse events. CONCLUSION: Add-on supraphysiological dose of levothyroxine has a potential role in attenuating depressive symptoms in bipolar depression, especially in therapy-resistant BD. PROSPERO REGISTRATION NUMBER: CRD42020218456.

Immunotherapy-Associated Hypothyroidism: Comparison of the Pre-Existing With De-Novo Hypothyroidism.

Background: Immunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism. Methods: A retrospective analysis was conducted using patients who received immunotherapy between 2010-2019 within a multicenter hospital system. Participants were separated in three groups-those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated. Results: 822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6-8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009). Conclusion: It is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg.

Hypothyroidism: Diagnosis and Evidence-Based Treatment.

Hypothyroidism affects up to 5% of the global population. Incidence increases with age and is more common in women and individuals with prolonged estrogen exposure when compared with people who have not been exposed to estrogen. Symptoms can develop slowly and often mimic symptoms of other disorders, including menstrual cycle abnormalities. Understanding risk factors and common presenting symptoms is important in providing high-quality primary and reproductive care. Diagnosis relies on simple-to-obtain, fairly inexpensive testing of thyroid-stimulating hormone (TSH) levels and confirmation with levels of thyroxine. Management of hypothyroidism usually involves monotherapy with levothyroxine taken on an empty stomach. There are 2 methods for beginning levothyroxine treatment, and outpatient primary care clinicians can use shared decision-making to determine the best initiation method for each individual. Follow-up involves regular assessment of levels of TSH and symptom relief. Although some patients may need referral for specialist treatment, the majority of individuals with hypothyroidism can be diagnosed and treated by their outpatient primary care providers.

Possible protective role of L-thyroxin on the parotid gland of adult male albino rat in carbimazole induced hypothyroidism: histological, histomorphometry, and ultrastructural study.

BACKGROUND: Thyroid disorders are among the most common metabolic disorders worldwide. Thyroid dysfunction affects salivary glands function, causing hyposalivation. It also provokes physiological and histological changes in parotid, submandibular, and in particular the sublingual gland. THE AIM OF THIS WORK: The aim of this work was to clarify the histological and ultrastructural changes that occur in the parotid gland following carbimazole-induced hypothyroidism in adult male albino rats. The study also aims to investigate the possible protective role of L-thyroxin supplementation on the rat parotid glands after long and short duration of hypothyroidism. MATERIAL AND METHODS: Fifty-five adult male albino rats of Sprague Dawley strain; were divided into four groups and eleven subgroups, five rats each. G І received nothing. G П given normal saline orally daily. G Ш (medical Hypothyroidism, short duration - long duration - recovery group) given Carbimazole orally by gastric tube in a dose of 0.05 mg/kg daily for 3,6 successive weeks for group (a, b) and for 6 successive weeks then were left without any medication for another 3 weeks in recovery group c. G IV-b, c (L-Thyroxine supplemented group, short duration-long duration) given Carbimazole orally daily for 3,6 successive weeks then L-thyroxine was given orally in a dose of (10 µg/100 g/B.W) daily for another 3 successive weeks. Animals were sacrificed 24 hours after the last dose of Carbimazole in G III-a, b and 3 weeks after stoppage the drug in G III-c. Animals were sacrificed 24 hours after the last dose of L- Thyroxine in G IV-b, c. The parotid specimens were processed for histopathological examination by light and electron microscopy. The medically induced Hypothyroidism resulted in significant parotid gland damage which was more obvious with longer duration; as follow: a) most of the acini had irregular outlines and were widely separated with narrow lumen and cytoplasmic vacuoles. b) some acinar cells contained ill defined, irregular, pyknotic or hyperchromatic nuclei. c)Vascular changes: dilated and engorged with blood. d) the interlobular and striated ducts appeared disrupted and dilated. e) extravasated blood with cellular infiltration were seen in the interstitial space. IN CONCLUSION: Thyroid hormones (THs) had a significant effect in protection of parotid gland against damage induced by carbimazole, as it preserved the normal histological architecture of the parotid gland. This beneficial effect of THs was mostly related to its antioxidant properties. The expression of BCL-2 has certain regularity in apoptosis after drug administration. Regulation of glandular atrophy and apoptosis are closely related. The molecular mechanism of the apoptosis of the gland is not clear, and further study is needed in the future.

Spontaneous reporting of adverse drug reactions as an outlet for patient dismay? The case of Levothyrox® change of excipients.

Following minor changes of excipients of Levothyrox®, the French Pharmacovigilance Database was overwhelmed by patients' spontaneous reports of adverse drug reactions associated with the new formula. After noticing that most of these reports differed from those related to other drugs, we aimed to characterize their features and compared them with spontaneous reports associated with other chronic treatments as comparators. We randomly sampled patient reports associated with either Levothyrox® new formula (n = 200) or comparator drugs (n = 200) from March 2017 till March 2018 from the National Pharmacovigilance Database. We evaluated the number of incriminated drugs and adverse drug reactions per report and verified whether they were "expected" or not according to the Summary of Product Characteristics. Levothyrox®-associated reports included, on average, more adverse drug reactions (8 ± 4) than comparators (2 ± 2, P < 0.01) and mentioned mostly one drug (98.5% of reports), whereas comparators mentioned two at least (P < 0.001). The quantitative distribution of adverse drug reactions per report differed quite significantly, appearing almost Gaussian for Levothyrox® whereas Poisson-like for comparators (P < 0.0001). Age did not differ significantly in the two groups (54.2 vs. 49.7, NS), but female predominated in Levothyrox® group (94.5%) as compared with comparators (60.8%, P < 0.001). A mere third of the Levothyrox®-associated adverse drug reactions were deemed "expected," versus two thirds for comparators (P < 0.001). The pattern of spontaneous reports associated with Levothyrox®, whether fueled by media or influenced by social networks, appears atypical, as compared with that of comparators. Such reports, by their abundance, may impair the automatic detection of relevant concomitant signals.

AMIODARONE AND THYROID DYSFUNCTION.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Increased Risk of Type 2 Diabetes in Patients With Thyroid Cancer After Thyroidectomy: A Nationwide Cohort Study.

CONTEXT: Abnormal thyroid function after thyroidectomy and subsequent thyroid-stimulating hormone suppression can have detrimental effects on glucose homeostasis in patients with thyroid cancer. OBJECTIVE: To investigate whether thyroidectomy increases the risk of type 2 diabetes in patients with thyroid cancer and to explore the association between levothyroxine dosage and type 2 diabetes risk. METHODS: A retrospective population-based cohort study using the Korean National Health Insurance database. We included 36 377 thyroid cancer patients without known diabetes who underwent thyroidectomy between 2004 and 2013. Matched subjects with nonthyroid cancer were selected using 1:1 propensity score matching. The main outcome measure was newly developed type 2 diabetes mellitus. RESULTS: Patients with thyroid cancer who underwent thyroidectomy had a higher risk of developing type 2 diabetes mellitus than the matched controls (hazard ratio [HR] 1.43, 95% CI 1.39-1.47). Among patients with thyroid cancer, when the second quartile group (in terms of the mean levothyroxine dosage; 101-127 µg/day) was considered the reference group, the risk of type 2 diabetes mellitus increased in the first quartile (<101 µg/day; HR 1.45, 95% CI 1.36-1.54) and fourth quartile groups (≥150 µg/day; HR 1.37, 95% CI 1.29-1.45); meanwhile, the risk decreased in the third quartile group (128-149 µg/day; HR 0.91, 95% CI 0.85-0.97). CONCLUSION: Patients with thyroid cancer who underwent thyroidectomy were more likely to develop type 2 diabetes mellitus than the matched controls. There was a U-shaped dose-dependent relationship between the levothyroxine dosage and type 2 diabetes mellitus risk.

Oxcarbazepine was associated with risks of newly developed hypothyroxinaemia and impaired central set point of thyroid homeostasis in schizophrenia patients.

AIMS: Hypothyroxinaemia might be easily ignored, because attention is typically paid to individuals with elevated thyroid stimulating hormone (TSH). In this study, we aimed to evaluate the association of oxcarbazepine use as adjuvant for treatment of schizophrenia with hypothyroxinaemia and central set point of thyroid homeostasis. METHODS: This retrospective cohort study was conducted in the Second Affiliated Hospital of Xinxiang Medical University. Inpatients with a diagnosis of schizophrenia admitted between January 2016 and October 2019 with normal thyroid function at admission were included. Oxcarbazepine use was the exposure measure. Newly developed hypothyroxinaemia was the primary outcome measure and parameters of thyroid homeostasis central set point as measured by TSH index and thyroid feedback quantile-based index (TFQI) were the secondary outcome measures. RESULTS: In total, 1207 eligible patients were included. The occurrence of hypothyroxinaemia in patients who received oxcarbazepine was higher (35/107, 32.7%) than in those patients who did not (152/1099, 13.8%), with adjusted relative risk of 2.24 and 95% confidence interval of 1.57 and 3.17. Oxcarbazepine use was associated with greater reduction in TSH index (adjusted ß -0.33 and 95% confidence interval -0.48, -0.19) and TFQI (adjusted ß -0.24 and 95% confidence interval -0.31, -0.16). CONCLUSION: Oxcarbazepine use was independently associated with increased risk of developing hypothyroxinaemia, and greater reduction in TSH index and TFQI, suggesting that impaired central set point of thyroid homeostasis might be involved in the mechanism of oxcarbazepine-induced hypothyroxinaemia.

Non-inferiority of liquid thyroxine in comparison to tablets formulation in the treatment of children with congenital hypothyroidism.

OBJECTIVES: The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH). METHODS: Thirty-nine children with CH, aged 3-12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months. RESULTS: TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets. CONCLUSIONS: Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L-thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH.

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.