Thyroid ultrasound (US) is a key examination for the management of thyroid nodules. Thyroid US is easily accessible, noninvasive, and cost-effective, and is a mandatory step in the workup of thyroid nodules. The main disadvantage of the method is that it is operator dependent. Thyroid US assessment of the risk of malignancy is crucial in patients with nodules, in order to select those who should have a fine needle aspiration (FNA) biopsy performed. Due to the pivotal role of thyroid US in the management of patients with nodules, the European Thyroid Association convened a panel of international experts to set up European guidelines on US risk stratification of thyroid nodules. Based on a review of the literature and on the American Association of Clinical Endocrinologists, American Thyroid Association, and Korean guidelines, the panel created the novel European Thyroid Imaging and Reporting Data System, called EU-TIRADS. This comprises a thyroid US lexicon; a standardized report; definitions of benign and low-, intermediate-, and high-risk nodules, with the estimated risks of malignancy in each category; and indications for FNA. Illustrated by numerous US images, the EU-TIRADS aims to serve physicians in their clinical practice, to enhance the interobserver reproducibility of descriptions, and to simplify communication of the results.
Artificial intelligence algorithms could be used to risk-stratify thyroid nodules and may reduce the subjectivity of ultrasonography. One such algorithm is AIBx which has shown good performance. However, external validation is crucial prior to clinical implementation.
Materials and methods
Patients harboring thyroid nodules 1–4 cm in size, undergoing thyroid surgery from 2014 to 2016 in a single institution, were included. A histological diagnosis was obtained in all cases. Medullary thyroid cancer, metastasis from other cancers, thyroid lymphomas, and purely cystic nodules were excluded. Retrospectively, transverse ultrasound images of the nodules were analyzed by AIBx, and the results were compared with histopathology and Thyroid Imaging Reporting and Data System (TIRADS), calculated by experienced physicians.
Out of 329 patients, 257 nodules from 209 individuals met the eligibility criteria. Fifty-one nodules (20%) were malignant. AIBx had a negative predictive value (NPV) of 89.2%. Sensitivity, specificity, and positive predictive values (PPV) were 78.4, 44.2, and 25.8%, respectively. Considering both TIRADS 4 and TIRADS 5 nodules as malignant lesions resulted in an NPV of 93.0%, while PPV and specificity were only 22.4 and 19.4%, respectively. By combining AIBx with TIRADS, no malignant nodules were overlooked.
When applied to ultrasound images obtained in a different setting than used for training, AIBx had comparable NPVs to TIRADS. AIBx performed even better when combined with TIRADS, thus reducing false negative assessments. These data support the concept of AIBx for thyroid nodules, and this tool may help less experienced operators by reducing the subjectivity inherent to thyroid ultrasound interpretation.
Henrik E. PoulsenLaboratory of Clinical Pharmacology Q7642, Rigshospitalet Department of Clinical Pharmacology, Bispebjerg Hospital Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
Background: Little is known about the whole body oxidative stress burden following radioactive iodine (<sup>131</sup>I) therapy of thyroid diseases. Methods: We studied 17 patients with benign nodular goiter treated with <sup>131</sup>I therapy. The targeted thyroid dose was 50 Gy in 11 patients pretreated with 0.1 mg of recombinant human TSH (rhTSH). In 6 patients, the applied thyroid dose was 100 Gy without rhTSH prestimulation. Well-established biomarkers of oxidative stress to RNA (8-oxo-7,8-dihydroguanosine; 8-oxoGuo) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine; 8-oxodG) were measured in freshly voided morning urine (normalized against the creatinine concentration) at baseline, and 7 and 21 days after rhTSH (not followed by <sup>131</sup>I), and 7 and 21 days after <sup>131</sup>I therapy, respectively. Results: The baseline urinary excretions of 8-oxoGuo and 8-oxodG were 2.20 ± 0.84 and 1.63 ± 0.70 nmol/mmol creatinine, respectively. We found no significant changes in the excretion of any of the metabolites, neither after rhTSH stimulation alone nor after <sup>131</sup>I therapy. Also, no significant differences were found between the rhTSH group (low dose, median <sup>131</sup>I: 152 MBq) and the non-rhTSH group (high dose, median <sup>131</sup>I: 419 MBq; 8-oxoGuo: p = 0.66, 8-oxodG: p = 0.71). Conclusion: Systemic oxidative stress, as detected by nucleic acids metabolites in the urine, is not increased after thyroid stimulation with 0.1 mg of rhTSH, or after <sup>131</sup>I therapy. Our method cannot quantify the oxidative stress induced locally in the thyroid gland, but the study supports that <sup>131</sup>I therapy of benign nodular goiter carries no or only a minute risk of developing subsequent malignancies. It remains to be explored whether our findings also apply to hyperthyroid disorders.
Thyroid nodule ultrasound characteristics are used as an indication for fine-needle aspiration cytology, usually as the basis for Thyroid Imaging Reporting and Data System (TIRADS) score calculation. Few studies on interobserver variation are available, all of which are based on analysis of preselected still ultrasound images and often lack surgical confirmation.
After the blinded online evaluation of video recordings of the ultrasound examinations of 47 consecutive malignant and 76 consecutive benign thyroid lesions, 7 experts from 7 thyroid centers answered 17 TIRADS-related questions. Surgical histology was the reference standard. Interobserver variations of each ultrasound characteristic were compared using Gwet’s AC1 inter-rater coefficients; higher values mean better concordance, the maximum being 1.0.
On a scale from 0.0 to 1.0, the Gwet’s AC1 values were 0.34, 0.53, 0.72, and 0.79 for the four most important features in decision-making, i.e. irregular margins, microcalcifications, echogenicity, and extrathyroidal extension, respectively. The concordance in the discrimination between mildly/moderately and very hypoechogenic nodules was 0.17. The smaller the nodule size the better the agreement in echogenicity, and the larger the nodule size the better the agreement on the presence of microcalcifications. Extrathyroidal extension was correctly identified in just 45.8% of the cases.
Examination of video recordings, closely simulating the real-world situation, revealed substantial interobserver variation in the interpretation of each of the four most important ultrasound characteristics. In view of the importance for the management of thyroid nodules, unambiguous and widely accepted definitions of each nodule characteristic are warranted, although it remains to be investigated whether this diminishes observer variation.
Christina EllervikDepartment of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, United States of America Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Data and Data Support, Region Zealand, Sorø, Denmark
Henrik E PoulsenDepartment of Endocrinology, Copenhagen University Hospital, Bispebjerg-Frederiksberg Hospital, Denmark Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark Department of Cardiology, University Hospital Nordsjælland, Hillerød, Denmark
Filip K KnopDepartment of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Steno Diabetes Center Copenhagen, Herlev, Denmark Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
Birte NygaardDepartment of Medicine, Copenhagen University Hospital – Herlev and Gentofte, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders.
In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects.
Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49–1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53–1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14–1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18–1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91–1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88–1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07–1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88–1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03).
In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.