bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oral Liquid L-Thyroxine (L-T4) May Be Better Absorbed in Comparison to L-T4 Tablets in Patients With Lactose Intolerance
Authors: Fallahi Poupak , Ferrari Silvia Martina , Elia Giusy , Ragusa Francesca , Paparo Sabrina Rosaria , Ruffilli Ilaria , Patrizio Armando , Antonelli Alessandro 
Published: May 2021

Abstract
In patients with lactose intolerance (LI), L-thyroxine (L-T4) malabsorption is often present, that leads to the necessity to use elevated L-T4 doses in the substitutional treatment of hypothyroidism. After excluding non-compliance, the differential diagnosis should include such disorders as LI, atrophic gastritis, coeliac disease, and others. In case of a diagnosis of LI, a low lactose diet and a lactose-free L-T4 preparation should be administered, to decrease the dose of the L-T4 formulation, and restore euthyroidism. We report the normalisation of circulating thyrotropin (TSH) levels in 8 patients with LI who received L-T4 tablets, after switching to an oral liquid lactose-free formulation. After switching from oral tablets to the liquid L-T4 (at the same dose, 30 minutes before breakfast) TSH was significantly reduced (TSH, evaluated 1-3 months after the switch, decreased: from 7.5±3.1 to 3.2±2.4 μIU/mL, P&lt;0.05). The return back to tablets (at the same dosage, 30 minutes before breakfast) caused thyrotropin levels to worsen again. This result leads us to believe that the absorption of oral liquid formulation of thyroxine is greater in these patients. In conclusion, these data suggest that the L-T4 oral liquid formulation could bypass the issue of malabsorption in patients with lactose intolerance.
Quality of Life in Patients With Hypothyroidism
Authors: Pereira Miguel , Neves Celestino , Neves João Sérgio , Carvalho Davide 
Published: May 2021

Abstract
Introduction: The quality of life (QoL) of thyroid diseases has been less studied than other chronic diseases. There is however evidence suggesting long lasting physical and psychological symptomatology related to thyroid diseases.
Objective: To analyze the QoL in patients with hypothyroidism.
Methods: We evaluated 274 patients with a mean age of 56.2 ± 14.2 years, 89.1 % female and divided them by diagnosis: autoimmune thyroiditis (AIT, n = 145), multinodular goiter (MG, n = 31), total thyroidectomy (TT) for thyroid cancer (n = 46), total thyroidectomy for MG (n = 36), TT for Graves disease (GD, n = 9) and radioactive iodine therapy (RAI) for GD (n = 7), and assessed thyroid function tests, thyroid antibodies, lipid profile, high-sensitivity C-reactive protein, vitamin B12, folic acid and applied the Thyroid Dependent Quality of Life questionnaire (ThyDQoL). Statistical analysis was performed with the One-way ANOVA test and Pearson’s correlation test. P values ≤ 0.05 were considered as statistically significant.
Results: In this sample, the subgroups who reported worse QoL were the TT for thyroid cancer (-2.47 points) followed by the RAI for GD (-2.14 points) and the AIT (-2.11 points), although these differences were not statistically significant. Regarding the internal domains of the ThyDQoL, we found a significant difference between the subgroup TT for thyroid cancer and MG in bodily discomfort (-4.03 ± 3.61 vs -1.47 ± 1.66; p = 0.04) and household tasks (-2.95 ± 2.92 vs -0.90 vs 1.61; p = 0.02). Within the subgroups, we observed significant correlations involving QoL and vitamin B12 in the AIT subgroup (r = 0.16; p = 0.05), between QoL and lipoprotein(a) (r = -0.50; p = 0.03) in the MG subgroup, between QoL and free T3 (r = -0.31; p = 0.03) in the TT for thyroid cancer subgroup and between QoL and free T3 (r = -0.76; p = 0.04) in the RAI for GD subgroup.
Conclusions: In this study we found that patients submitted to TT for thyroid cancer had the worse QoL among patients with hypothyroidism. This may be related to the use of thyroid hormone suppressive therapy. We also observed that certain domains of QoL are more affected by some causes of hypothyroidism. Further studies are needed to analyze more deeply the symptomatology that contributes to worsening of QoL in these patients.
The Application of ThyPRO Questionnaire in Patients With Graves’ Disease Treated With Antithyroid Medications
Authors: Chng Chiaw Ling , Soh Shui Boon , Chiam Priscilla Pei Sze , Fook-Chong Stephanie Man Chung , Tay Wei Lin , Yew Jielin 
Published: May 2021

Abstract
Background: The ThyPRO-39 questionnaire assesses health-related QoL (HRQoL) in patients with benign thyroid disease and has been validated for use in the local setting. The aim of the study is to investigate disease specific health-related quality of life using ThyPRO-39 in patients with newly diagnosed Graves’ disease treated with antithyroid medications over one year. Methods: Patients with newly diagnosed Graves’ disease were recruited in the outpatient setting. The ThyPRO-39 questionnaire was administered at baseline, 6 and 12 months of antithyroid medication treatment. Relevant demographic and clinical information was collected at the three time points of the study. Results of clinical parameters and various ThyPRO scales were compared between baseline, 6 months and 12 months of treatment. Results: There were 32 patients with newly diagnosed Graves’ disease recruited between April 2018 and May 2019. All except 2 patients completed all 3 time points of the study. Two patients missed their 6 months questionnaire. There were 24 females (75%) and 8 males (25%) in the study. Analysis of the clinical parameters showed significant changes in weight from baseline (59.7 + 17.7kg) to 6 months (59.4 + 9.9kg) to 12 months (63.4 + 17.4Kg), all p&lt;0.001, TSH receptor antibody level from baseline (17.3 + 12.9IU/L) to 12 months (7.1 + 10.8IU/L), NR &lt;1.76IU/L, p&lt;0.001, fT4 levels from baseline (49.9 + 18.1pmol/L) to 6 months (14.3 + 6.9pmol/L) and from baseline to 12 months (11.8 + 2.3pmol/L), NR 8.8-14.4pmol/L, all p&lt;0.001 and TSH levels from baseline (0.011 + 0.009mU/L) to 6 months (1.38 + 1.74mU/L, p=0.001) and from baseline to 12 months (1.80 + 1.72mU/L, p&lt;0.001), NR 0.65-3.70mU/L. After 6 months of treatment, 7 out of 13 ThyPRO scales improved and 9 out of 13 ThyPRO scales improved after 12 months of treatment. Large treatment effects were observed on 2 ThyPRO scales (Hyperthyroid symptoms and Anxiety) while moderate effects were seen in 5 ThyPRO scales (Tiredness, Cognitive complaints, Depressivity, Impaired daily Life and overall QoL) from baseline to 6 months. Large treatment effects were observed on 2 ThyPRO scales (Hyperthyroid symptoms and Anxiety) while moderate effects were seen in 5 ThyPRO scales (Tiredness, Depressivity, Emotional susceptibility, Impaired daily Life and overall QoL) from baseline to 12 months. Small treatment effects were observed in 2 ThyPRO scales (Goiter symptoms and Tiredness) from 6 to 12 months. Conclusion: There are significant improvements in many aspects HRQL during the first 6 months of antithyroid drug treatment, with hyperthyroid symptoms and anxiety showing the most improvements throughout the 12 month treatment period. Our results complement clinical monitoring of patients with Graves’ disease and provide realistic outcome measures of disease impact and treatment outcomes from the patient’s perspective.
Amiodarone-Induced Thyrotoxicosis, Risk Factors and Predictors of Outcome: A Retrospective Study
Authors: Khalaili Luai , Aker Amir , Naoum Ibrahim , Kassem Sameer 
Published: May 2021

Abstract
Background Amiodarone induced thyrotoxicosis (AIT) is not uncommon and is often associated with significant morbidity and mortality. Factors that predict poor prognosis in AIT have not yet been sufficiently investigated. Objective: To examine the characteristics and short-term clinical outcomes of patients with AIT (up to six months from diagnosis). We evaluated the relationship between T3 and T4 levels at the time of presentation and complications associated with AIT. Methods: A retrospective epidemiological study on patients admitted to Carmel Medical Center between the years 2004-2018. We reviewed electronic medical records of patients who bear the diagnosis of thyrotoxicosis and consumed amiodarone. Demographic and clinical characteristics of patients that develop AIT were evaluated. We evaluated the association between T3 and T4 levels at the time of presentation a poor prognosis. Three primary outcomes were defined: 1. Mortality. 2. Development of AIT-related complications that required hospitalization. 3. The need for thyroidectomy. Results: 400 patients bear a diagnosis of thyrotoxicosis and consumed amiodarone. However, only 39 patients met the full definition of AIT. The composite outcome of mortality, AIT-related complications and thyroidectomy was achieved in the vast majority of patients (94.8%, 37 out of 39 participants). Three patients (7.6%) died, 35 (89.7%) were hospitalized with AIT-related complications and 8 (20.5%) required thyroidectomy. There was a statistically significant relationship between high T4 levels and the composite of two main endpoints: mortality and the need for thyroidectomy in the first half year of diagnosis (P=0.009). Conclusions: AIT is associated with significant morbidity and mortality. An elevated level of free T4 reflects the severity of AIT. In patients with significantly increased T4 values, an early surgical intervention should be considered.
Hearing Loss and Teprotumumab
Authors: Kossler Andrea , Sears Connie Martin , Dosiou Chrysoula 
Published: May 2021

Abstract
Thyroid eye disease (TED) is an unpredictable autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring. Teprotumumab (IV infusion every 3 weeks x 8 doses) was recently approved as the first and only FDA-approved drug for TED in 2020. Phase 2 and 3 studies showed significant improvement in proptosis, double vision, soft tissue inflammation and quality of life for patients with active moderate to severe TED. Side effects were experienced by 85% of patients on teprotumumab. Hearing loss symptoms were reported in 10% of patients and were reported to be reversible upon stopping the drug. Objective: To explore the incidence of hearing loss symptoms and sensorineural hearing loss in patients treated with teprotumumab. Methods: All patients, followed at one institution, treated with at least 4 infusions of teprotumumab were evaluated. Charts were evaluated for baseline hearing symptoms and hearing symptoms during or after therapy with teprotumumab. Those patients with hearing symptoms were referred for audiogram testing and patulous eustachian tube (PET) testing. Results: Twenty-eight patients were included in this analysis. Thirteen patients (46%) complained of hearing symptoms. The most common symptoms were autophony or an ear plugging sensation and hearing loss or muffled hearing. Hearing symptoms developed after a mean of 3.6 infusions. Of the patients with hearing symptoms, three patients (23%) had sensorineural hearing loss documented on audiogram (n=2) or patulous eustachian tube (n=1) documented on PET testing. To date, the patient with PET has experienced some improvement, but not resolution, of her symptoms. The two patients with documented sensorineural hearing loss have not experienced a significant improvement in hearing, on audiogram, on average 3 months after stopping teprotumumab. Conclusion: Teprotumumab is a promising new therapy for active moderate to severe thyroid eye disease. Providers should consider performing a baseline audiogram with PET testing and performing audiograms with PET testing for patients that develop hearing symptoms during or after therapy. Hearing loss is a concerning adverse event and its mechanism and reversibility should be further studied.
In Vitro Splicing Assay Proves the Pathogenicity of Intronic Variants in MRAP
Authors: Smith Chris , Maharaj Avinaash Vickram , Qamar Younus , Read Jordan , Williams Jack , Chan Li , Marimuthu Vidhya , Metherell Louise 
Published: May 2021

Abstract
Introduction: Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency in a patient who retains normal mineralocorticoid production. FGD causing mutations in the MC2R accessory protein, MRAP, are often splice-site or nonsense mutations resulting in a truncated protein. Many of these mutations occur at the canonical donor splice-site of intron 3, where it has been shown previously that c.106 + 2_3dupTA, for example, results in skipping of the first coding exon with unknown consequences at the protein level. Patients and methods: DNA was isolated from three consanguineous individuals diagnosed with early onset FGD (0 - 13 months) with high ACTH and/or low cortisol levels and underwent whole exome sequencing. The proband in family 1 (P1) presented at 13 months and had a hyperpigmented sibling who died in neonatal period due to adrenal failure. Patient 2 (P2), who also had a family history of adrenal insufficiency, was noted to be hyperpigmented at birth with markedly raised ACTH, patient 3 (P3) was noted to have diffuse hyperpigmentation in the early neonatal period and on formal testing at 16m was found to have low serum cortisol. Variants were confirmed using Sanger sequencing and predicted splice-site mutations were investigated using an in vitro splicing assay. Results: Homozygous mutations in MRAP were identified in all three cases which were heterozygous in their parents. Previously described mutations, c.106 + 1delG (chr21:33671388delG; rs1476574441; CD050155) in P1 and c.106 + 2dupT (Chr21: 33671390_91insT; rs761576317; CI118288) in P2 at the canonical donor splice-site of intron 3, were identified, with the former predicted to destroy the splice site and the latter to weaken it. These mutations in vitro resulted in the complete skipping of exon 3, which contains the translational start site, and presumably result in no protein product. A novel homozygous mutation in intron 4, c.206 + 5G&gt;T; (chr21:33679055G&gt;T rs1064796398) was identified in P3, but was not predicted to alter splicing. In vitro, this mutation negates the canonical donor splice site and creates two different alternative sites, both resulting in frameshifts and predicted early termination of the protein (p.Val44fs*50, p.Pro72fs*90). Conclusion: All mutations reported here are predicted to produce no protein, either because the start site is excluded (for c.106 + 1delG and c.106 + 2dupT) or because the transcripts are likely to undergo nonsense mediated decay (for c.206 + 5G&gt;T), resulting in the early onset FGD seen in the patients. Splice prediction protocols, although effective for variants within 2bp of exon/intron boundaries may not predict the true outcome of a base change whereas the splice assay conclusively revealed the effect of all three variants allowing us to assign pathogenicity to them.
What Are the Common Characteristics of Pediatric Patients With Antibody Negative Primary Hypothyroidism?
Authors: Alradadi Rasha , Eugster Erica A 
Published: May 2021

Abstract
Background: The most common cause of acquired primary hypothyroidism is autoimmune thyroiditis which is typically associated with positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies. However, some children present with primary hypothyroidism and negative antibodies. Whether there are differences between patients with acquired primary hypothyroidism who have positive vs negative anti-thyroid antibodies has not been systematically examined. Aim:To define the characteristics of patients with primary hypothyroidism and negative antibodies. Methods: A retrospective chart review of patients with hypothyroidism seen in the pediatric endocrine clinic at Riley Hospital for Children in Indianapolis, Indiana from August 2016 until December 2019 was performed. Variables examined included age at diagnosis, signs and symptoms at presentation, height, weight, BMI, TSH, FT4, T4, thyroid peroxidase and anti-thyroglobulin antibodies, family history of thyroid disease, physical exam at diagnosis, and associated diseases. Results: Of 173 patients aged 10.6 ± 3.9 years, 128 (74%) had positive antibodies and 44 (26%) had negative antibodies. Of those with positive antibodies, 80 % were female and 20% were male. Of those with negative antibodies, 53% were female and 47% were male. No differences were seen in the incidence of obesity or Down syndrome in patients with positive antibodies compared with those who had negative antibodies. A positive family history of thyroid disease was present in 45% of those with positive antibodies and in 22% of those with negative antibodies, P=0.006 Fifty-eight patients (45%) with positive antibodies reported excessive fatigue and 40 (31%) had a goiter. In contrast, 10 (22.7%) who had negative antibodies reported mild intermittent fatigue, P=0.006 and 7 (15.9 %) had a goiter, P=0.04 The average TSH in the antibody positive group was 129± 230 mcu/ml compared with 48 ± 131 mcu/ml in those with negative antibodies, p=0.04. A trend was also noted for a lower FT4 in those with positive antibodies (0.68±0.37 vs 0.85±0.27, p=0.050) No other differences in baseline characteristics were seen between patients with negative vs positive antibodies. Conclusion: Patients with positive anti-thyroid antibodies had more severe hypothyroidism and were more likely to report extreme fatigue than those with negative antibodies. It is unknown why some children with acquired primary hypothyroidism presumed due to autoimmune thyroid disease have negative antibodies. Long-term follow-up will be needed to determine whether the natural history of thyroid disease in children with primary hypothyroidism is associated with antibody status.
Analysis of Enigma Gene-Signaling Pathways in Thyroid Cancer
Authors: Churdsuwanrak Narudee , Niihara Robert , Rood Kristiana , Yamauchi Celina , Wright Kharl , Adil Md Shafayet , Mirshahidi Saeid , Perez Mia C , Simental Alfred A , Firek Anthony , Khan Salma 
Published: May 2021

Abstract
Fine-needle aspiration (FNA) is one of the most accurate modes of obtaining thyroid nodule biopsies, however, up to 25% of biopsies still yield indeterminate results. There is an increasing number of thyroidectomies due to indeterminate nodules by FNA alone. Therefore, more accurate and time efficient diagnostic approaches for analyzing indeterminate thyroid nodules is required. Recent studies showed that Enigma is associated with different cancer types, including thyroid cancer progression and calcification through its interaction with bone morphogenic protein-1 (BMP-1) and tyrosine kinases linked to mitogen-activated protein kinase (MAPK) signaling pathway. Our published data on Enigma protein analysis with immunohistochemistry showed promising findings to discriminate malignant versus benign nodules. We also showed a thyroid cancer stage-dependent enhancement of Enigma protein expression. In this study, we are investigating Enigma at a gene expression level by quantitative reverse transcription polymerase chain reaction (RT-qPCR), which is more time-efficient, quantitative, and requires less tissue than immunohistochemistry. We extracted mRNA/DNA/proteins from fresh malignant and benign thyroid nodules using a Qiagen AllPrep DNA/RNA/Protein Mini Kit. After verification of the quantity and purity by NanoDrop, isolated mRNA was then run through Enigma-RT-qPCR. MAPK assay was done by western blotting using MAPK-antibody. Our initial results found that Enigma-mRNA expression level was 3-fold higher in malignant compared to benign thyroid tissues. This finding supports our previous protein expression data with a relative quantitative difference in Enigma-mRNA expression level between malignant and benign thyroid nodules. MAPK expression was upregulated in thyroid cancer compared to benign nodules. We conclude that Enigma-RT-qPCR can be used effectively in FNA samples derived from thyroid nodules, which could potentially enhance the diagnostic accuracy of indeterminate nodules and decrease unnecessary thyroidectomies. Furthermore, both Enigma and MAPK were highly expressed in advanced tumor in the same tissues. Future study is needed to establish the functional interaction of Enigma-MAPK activity in thyroid cancer cells.
Association Between Body Mass Index and Aggressive Features of Differentiated Thyroid Cancer
Authors: Almotawa Fahad , Alturki Abdulrahman , AlGhamdi AbdulJabbar , AlEnezi Mohammed , AlJohani Naji , Alhuzaim Omar Nasser 
Published: May 2021

Abstract
Background: Obesity is recognized as a risk factor for several types of cancers, including differentiated thyroid cancer (DTC). However, the association between obesity and aggressiveness of DTC is controversial. The aim of this study was to assess the relationship between body mass index (BMI), aggressive clinicopathological features of DTC and response to therapy in Saudi population. Methods: We evaluated 209 patients retrospectively who underwent total thyroidectomy at a referral center and diagnosed with DTC. Patients were stratified into 2 groups based on their BMI: non-obese (&lt; 30 kg/m2), and obese (≥ 30 kg/m2). Pathological aggressiveness of DTC as well as clinical outcome were evaluated according to the 2015 American Thyroid Association (ATA) guideline. Data were described as mean ± SD and the categorical data as frequency percent. Mann Whitney test measured the difference in medians of all the metric variables and Chi-square test was applied for the categorical data to measure the intergroup difference between obese and non-obese binary dependent variable. All the inferences were carried out at 95% confidence interval in SPSS 25.0 software. Results: One-hundred twenty (57.4%) of our cohort were obese. Obesity was significantly more common in females (61.7%) than males (29.6%); (p=0.002). There were no differences in histopathological features between the non-obese and obese patients, including tumor size (2.3 ± 1.7 cm vs. 2.5 ± 2.1 cm, respectively, P-value = 0.812), extrathyroidal extension (16.9 % vs. 22.4 %, respectively, P-value=0.336), vascular invasions (25 % vs 18.4 %, respectively, P-value= 0.263) and lymph nodes metastasis (N1a 19.3 % vs 11.6 %, N1b 12.0 % vs. 10.7 % respectively, with P-value = 0.289), were shown between the two groups. In addition, no differences were evident in the ATA risk of recurrence (P-value = 0.843), TNM stage (P-value= 0.797), response to therapy (P-value= 0.252) and survival (P-value= 0.389) across the two groups. Conclusion: No association between BMI and DTC aggressiveness were found in our study population of Saudi patients. In addition, no association were demonstrated between BMI and response to therapy in DTC. These findings suggest that BMI may not be an independent risk factor for aggressiveness in DTC and that other traditional clinicopathological factors should be applied for risk assessment.