Prevalence and Management of Complications of Percutaneous Ethanol Injection for Cystic Thyroid Nodules: A Systematic Review of Literature and Meta-analysis.

Background: We assessed the prevalence of complications from percutaneous ethanol injection (PEI) for benign and cystic thyroid nodules (CTNs) and their management. Methods: We conducted a systematic review with meta-analysis of data from published observational studies on PEI of CTNs. We also included unpublished retrospectively collected data on complications after PEI from all consecutive patients with cytologically benign CTNs who underwent PEI at the Unit of Endocrinology and Metabolic Diseases, AOU University of Campania Luigi Vanvitelli (Naples, Italy) between June 1, 2021, and March 31, 2024. A random effects meta-analysis was performed on the prevalence rate data. Pooled prevalence data were presented with confidence intervals (CIs). The I2 statistic index was used to quantify the heterogeneity. The details of the complications and the management were qualitatively described. Results: The literature search yielded 1189 studies, of which 48 studies were included in the systematic review and meta-analysis, in addition to our institutional experience (3670 CTNs in total). The overall quality of each included study was judged as fair. The prevalence of "Overall" complications of PEI was 32% ([CI 25-40%], I2 92.7%, 967 of 3195 thyroid nodules [TNs]). The prevalence of "Minor" complications of PEI was 32% ([CI 25-40%], I2 92.7%, 952 of 3195 TNs). The prevalence of "Major" complications of PEI was 2% ([CI 1-2%], I2 0%, 22 of 3670 TNs). Sensitivity analyses did not modify the results. The pooled prevalence rate of local pain was 21% (CI [16-27] I2 90.3). Local pain was typically transient and mild, sometimes moderate, and requiring analgesics for few days. The pooled prevalence rate of dysphonia was 1% (CI [1-2], I2 0). Dysphonia was transient and could last from several hours to 12 months after PEI. Conclusions: Complications of PEI for benign and CTNs are relatively common, but most are minor and usually transient, not requiring treatment. Dysphonia was a major complication, but it was uncommon and transient. PEI for CTNs could be considered a generally safe technique.

Cervicomediastinal Hematoma: Atypical Presentation of a Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare endocrine neoplasm that typically presents with osteopenia/osteoporosis, nephrolithiasis, asthenia, and neuropsychiatric symptoms. We describe the case of a 48-year-old woman, presenting with a large painful hematoma in the cervicomediastinal area. The neck ultrasound (US) demonstrated a solid lesion measuring 40 × 80 × 55 mm, markedly hypoechoic, which extended from the right thyroid lobe to the mediastinum. The blood tests showed elevated serum calcium and parathyroid hormone (PTH) concentrations, consistent with hypercalcemic primary hyperparathyroidism. The patient was rehydrated and treated with furosemide, cholecalciferol, and bisphosphonate, and underwent right lower parathyroidectomy, right hemithyroidectomy, and lymphadenectomy of the right VI cervical level. Histological examination was diagnostic for nonangioinvasive or neuroinvasive PC, and the thyroid lobe was the site of lymphocytic thyroiditis; all removed lymph nodes were benign. The postoperative course was regular. Postoperative neck US showed a hypoechoic left thyroid lobe without evidence of residual neoplasm in the right thyroid bed. Levothyroxine therapy of 50 mcg/day was started because of serum thyrotropin concentrations elevated at 18 mcIU/mL (normal reference range, 0.35-4.0 mIU/mL). Eight years after diagnosis, the patient is in good general condition, with no clinical, biochemical, or imaging evidence of disease persistence/recurrence.

Clinical Outcomes of Thermal Ablation Re-Treatment of Benign Thyroid Nodules: A Multicenter Study from the Italian Minimally Invasive Treatments of the Thyroid Group.

Background: Thermal ablation (TA) is an established therapeutic option alternative to surgery in patients with solid benign thyroid nodules causing local symptoms. However, a variable part of thyroid nodules remain viable after these nonsurgical treatments, and as many as 15% of nodules treated with TA may require a second treatment over time. This study aimed to evaluate the outcomes of TA re-treatment on symptomatic benign thyroid nodules where the volume decreased by <50% after the first procedure ( = technique inefficacy). Methods: We performed a multicenter retrospective cohort study including patients who underwent re-treatment with TA for benign thyroid nodules, whose volume decreased by <50% after initial treatment. The primary aim was to evaluate volume and volume reduction ratio (VRR) over time and compare the 6- and 12-month VRR after first versus second treatment. The secondary aim was to identify protective or risk factors for technique inefficacy, regrowth, and further treatments, expressed as adjusted hazard ratios (HRs) and confidence interval [CI], after adjustment for sex, age, nodule volume, structure and function, nodule regrowth or symptom relapse, technique used and if the same technique was used for the first and second TA and time between them. Results: We included 135 patients. Re-treatment led to VRR of 50% and 52.2% after 6 and 12 months. VRR after re-treatment was greater than after first treatment in small and medium size nodules (<30 mL), while there were no differences for large nodules (>30 mL). After re-treatment technique inefficacy rate was 51.9%, regrowth rate was 12.6%, and further treatment rate was 15.6%. Radiofrequency ablation (RFA) was protective toward technique inefficacy (HR = 0.40 [CI 0.24-0.65]) and need of further treatments (HR = 0.30 [CI 0.12-0.76]). Large nodule volume (>30 mL) was associated with increased risk of re-treatment (HR = 4.52 [CI 1.38-14.82]). Conclusions: This is the first study evaluating the outcomes of re-treatment on symptomatic benign thyroid nodules with a VRR <50% after the initial TA treatment. Best results were seen in small and medium nodules (<30 mL) and after RFA. Prospective confirmatory studies are needed.

Case Report: Papillary thyroid carcinoma in Goltz-Gorlin syndrome.

Goltz-Gorlin syndrome (GGS), also known as focal dermal hypoplasia, is a rare X-linked disorder caused by pathogenic variants in the PORCN gene and characterized by several abnormalities, including skin and limb defects, papillomas in multiple organs, ocular malformations, and mild facial dysmorphism. To date, only approximately 300 cases have been described in the literature. A 16-year-old female patient, born with multiple congenital dysmorphisms consistent with GGS and confirmed by genetic exam, was referred to our outpatient clinic for the workup of a thyroid nodule. A thyroid ultrasound showed a bilateral nodular disease with a 17-mm large hypoechoic nodule in the right lobe. Cytological exam of fine needle aspiration biopsy was suspicious for malignancy. Thus, she underwent total thyroidectomy plus lymphadenectomy of the right central compartment. A histological exam disclosed a papillary thyroid carcinoma (PTC) with lymph node micrometastases. Radioiodine (131-Iodine) therapy was performed. At 3- and 6-month follow-up, the patient did not present either ultrasound or laboratory PTC recurrence. To our knowledge, we report the first case of PTC in a patient with GGS. Since thyroid cancer is rare among children and adolescents, we hypothesize that the PORCN pathogenic variant could be responsible for tumor susceptibility. We also provide an overview of the clinical findings on GGS patients already reported and discuss the possible pathogenetic mechanism that may underlie this rare condition, including the role of PORCN in tumor susceptibility.

Neck Ganglioneuroma Mimicking a Thyroid Nodule in a Four-Year-Old Child: A Case Report and Review of the Literature.

Introduction: Ganglioneuromas are tumors of neurogenic origin usually located in the abdomen, the adrenal glands, and the mediastinum but infrequently found in the neck region. Case Presentation: We describe the case of a four-year-old Albanian girl presenting with an anterior neck mass initially suspected to be a thyroid nodule. From a clinical point of view, there was no evidence of compression on vital cervical structures. Lab tests detected normal serum thyrotropin, calcitonin, and parathormone concentrations. A neck ultrasound showed a huge mass apparently originating from the left thyroid lobe. Cytological examination of fine needle biopsy demonstrated a population of large cells with eosinophilic cytoplasm, regular nuclei, and prominent nucleoli and spindle cells without significant atypia, consistent with a benign lesion of neurogenic origin. Also, the neck MRI displayed a mass with well-defined margins, likely arising from the peripheral nervous system. The patient underwent surgical excision of the mass without complications. The histological exam was diagnostic for ganglioneuroma. Conclusions: We discuss the cytological and histological features peculiar to such a rare neck lesion and review the differential diagnosis.

Plurihormonal (TSH-GH-prolactin Secreting) PIT-1-Positive pituitary Macroadenoma/Pituitary Neuroendocrine Tumor (PitNET) Associated with Graves' Disease: A Case Report.

BACKGROUND: Differential diagnosis of primary and secondary hyperthyroidism can be challenging. Moreover, although extremely rare, the two conditions can coexist. CASE PRESENTATION: A 58-year-old woman presented with symptoms of thyrotoxicosis, gradual changes in face shape, headache and progressive enlargement of hands and feet in the last year. When she was 46 years old, she was diagnosed with Graves' disease, and treated with 4-year methimazole therapy. Since 2016, a progressive increase of free-T4 and free-T3 with normal-TSH and positive TrAb was noticed. RESULTS: At biochemical examination, fT3 was 5.3pg/ml (n. v. 2.5 - 3.9 pg/ml), fT4 was 20.6 pg/ml (n.v 6-12 pg/ml), IGF1 was 698 ng/ml (57 - 240 ng/ml*), GH (basally and after OGTT), and prolactin were significantly increased; while TSH was 1.8 (n.v. 0.35-4.0 mcUI/ml). A pituitary MRI demonstrated a large sellar tumor with suprasellar extension. The patient underwent endoscopic transsphenoidal surgery. Histological examination revealed a plurihormonal (GH-PRLTSH- secreting) PIT-1-positive pituitary adenoma/pituitary neuroendocrine tumor (PitNET). At 3- month follow-up, the pituitary function was normal, and no residual tumor was detected at the MRI. CONCLUSION: We report a rare case of Graves' disease coexisting with a plurihormonal PIT-1-positive pituitary adenoma/PitNET.

Impact of the introduction of minimally invasive treatments of the thyroid (MITT) for benign thyroid nodules in an Italian hospital: a cost-minimization analysis.

BACKGROUND: Prevalence of thyroid nodules is high in the adult population, approaching 60% in women and older people. Most thyroid nodules are benign and asymptomatic. However, a not negligible part of them causes compressive symptoms and/or cosmetic concerns and need to be treated. In the last two decades, minimally-invasive treatments of the thyroid (MITT) have been proposed in routine clinical practice as a reliable cost-effective alternative to surgery in patients with symptomatic benign thyroid nodules (SBTNs). AIM OF THE STUDY: To perform a cost-minimization analysis comparing direct, indirect and intangible costs of radiofrequency (RFA) and laser thermal ablation (LTA) with traditional surgery in patients with SBTNs. METHODS: Data of patients treated by MITT for SBTNs from October 1st 2019 to September 30th 2022 in a single Italian tertiary Center were analyzed. Costs were compared to those of traditional surgery reported in the 2022 Associazione Medici Endocrinologi Guidelines on the Management of SBTNs. RESULTS: In the study lapse, 157 MITT of SBTNs were performed in 148 patients, 114 females and 34 males (mean age: 59 yrs; median age: 57 yrs). Before MITT, the mean thyroid nodule volume was 19 ml; 1 year after MITT, volume reduction rate >50% and symptom relief were achieved in 89% and 93% of patients, respectively. No major complications occurred. Adding up pre-operative, operative and post-operative costs, total direct costs per single procedure are the following: 1361.43 € for LTA when using one optic fiber; 1761.43 € for LTA when using two optic fibers; 1968.53 € for RFA; 3338.39 € for hemithyroidectomy plus isthmectomy; 4034.99 € for total thyroidectomy. Surgery was impactful on direct-i.e., preoperative, operative and postoperative-costs, due to longer operating room occupation time and hospital stay. Overall, a total saving for the Italian National Health Service of 285,377.15 € has been obtained treating the 148 patients by MITT instead of surgery. Likewise, MITT was advantageous also for indirect costs-i.e., those related to "loss of productivity" caused by time off work due to hospital stay and recovery time-, for both the self-employed workers and the Government, the latter saving 53,838.50 € overall. Finally, intangible costs, related to patients' quality of life-e.g., residual surgical scar, stress related to general anesthesia, convalescence, and life-long intake of L-Thyroxine replacement therapy-were all in favor of MITT. CONCLUSIONS: This real-life cost-minimization analysis demonstrates that LTA and RFA are safe and cost-effective procedures for the treatment of SBTNs. In our 3 years experience, adding the savings of 285,377.15 € for direct costs to those of 53.838,50 € for indirect costs, in total 339,215.65 € were saved. The saving concern patients, the National Health System and the Government.

The ancient Greek poet Sappho and the first case report of the fight-or-flight response.

Sappho has always been regarded as one of the greatest lyric poets of ancient Greece. Her famous poem Fragment 31 V., also known as the "Ode to Jealousy", accurately describes the profound emotional reaction triggered by the sight of her beloved. The poet's precise description of each sign and symptom triggered by this arousal makes Sappho 31 V., to the best of our knowledge, the first analytical description of the acute stress response, the so-called "fight-or-flight" response, in human history. Here, Fragment 31 V. is re-read from a medical point of view, correlating the ancient Greek lyric text, the corresponding medical terms, and the underlying catecholamine mechanism of action.

Cushing's Syndrome Effects on the Thyroid.

The most known effects of endogenous Cushing's syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus-pituitary-thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the "central hypothyroidism". These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus-pituitary-thyroid axis activity. During active Cushing's syndrome, the "immunological tolerance" guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing's syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing's syndrome patients, both during the active disease and after its remission.

Cortisol circadian rhythm and jet-lag syndrome: evaluation of salivary cortisol rhythm in a group of eastward travelers.

PURPOSE: The activity of the hypothalamus-pituitary-adrenal axis plays a crucial role as an endogenous stress-reactive system. Lifestyle and work often interfere with the endogenous circadian rhythms and can modify the physiological patterns of stress-hormones secretion, including cortisol. We evaluated the cortisol circadian rhythm in the "jet-lag syndrome" that is the most known condition associated with the desynchronization of the circadian rhythm. METHODS: To assess the modifications of cortisol secretion after a long-haul flight, we compared baseline and post-travel salivary cortisol rhythm in a group of 28 healthy eastward travelers (from the U.S.A. or Canada to Italy). The salivary samples were collected about 1 week before the departure at 11 p.m. on day 0 and at 8 a.m., 12 a.m. (midday) and 11 p.m. on day 1 (R0). The same samples were obtained after the landing, the day they flew back home (R1). RESULTS: Statistical analysis showed a significant difference between R0 and R1 for each sample considered (p < 0.005). In particular, the post-travel salivary cortisol levels detected at 11 p.m. both on day 0 and on day 1, were significantly higher than at baseline. Post-travel morning salivary cortisol levels were lower compared with basal rhythm and increased during the morning, reaching the acrophase at 12 a.m. CONCLUSIONS: In eastward travelers, crossing more than five time zones, the cortisol circadian rhythm after the return to the East "remained behind," being synchronized with the West time. This impaired cortisol secretion can contribute to the pathogenesis of the jet-lag syndrome.

Subclinical hypothyroidism.

Subclinical hypothyroidism (i.e. a condition characterized by serum TSH concentrations above the normal reference range in the presence of normal serum T4 levels) affects 4 to 20% of the population living in iodine-sufficient areas. The present work reviewed the clinical challenges regarding the signs and symptoms possibly related to subclinical hypothyroidism and the most recent guideline recommendations to treatment.

Medical Approaches in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) represents one of the most aggressive endocrine tumors. In spite of a correct therapeutic strategy based on a multidisciplinary approach between endocrinologist, surgeon and oncologist, the prognosis is often poor. Surgery is the mainstay treatment in ACC. Mitotane, a dichloro-diphenyl-trichloro-ethane derivate, represents the main medical treatment of ACC in consideration of its adrenocytolitic activity and it is mainly employed as adjuvant treatment after complete surgical resection and for the treatment of advanced ACC. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. The recurrence of disease is frequent, especially in advanced disease at the diagnosis. Therefore, in these contexts, conventional chemotherapy must be considered in association with mitotane, being the combination etoposide, doxorubicin and cisplatin (EDP) the standard of care in this setting. A more modern therapeutic approach, based on the need of a salvage therapy for advanced ACC that progresses through first-line EDP, is focused on molecular-targeted therapies. However, robust clinical trials are necessary to assess the real efficacy of these treatments.

A novel MEN1 pathogenic variant in an Italian patient with multiple endocrine neoplasia type 1.

The multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the predisposition to developing multiple endocrine and non-endocrine tumors, typically characterized by the association between parathyroid gland hyperplasia or tumors, gastroenteropancreatic tumors and pituitary adenomas. The MEN1 gene is located on the long arm of chromosome 11 (11q13) and it encodes for the protein "menin". We here reported the case of a MEN1-patient, affected by primary hyperparathyroidism, insulinoma, pituitary non-hyperfunctioning adenoma and bilateral adrenal masses, carrying a novel heterozygous pathogenic variant (c.1252_1254delGACinsAT), located in exon 9 of MEN1 gene.

Handwriting characteristics in patients with overt autoimmune hypothyroidism: a prospective case-control study.

PURPOSE: Previous studies have demonstrated handwriting changes in patients with overt hyperthyroidism due to Graves' disease. The aim of the present study was to investigate handwriting features in patients affected by overt autoimmune hypothyroidism. METHODS: Thirty subjects - 24 females and 6 males, mean and median age of 50.15 ± 16.8 years and 52.5 years, respectively - with overt hypothyroidism (OH) related to Hashimoto's thyroiditis (Group 1), and 30 age- and sex-matched euthyroid individuals (Group 2) were recruited to write a "standard text". Group 1 patients repeated the text once the euthyroid state was reached on L-T4 substitution therapy. Group 2 subjects wrote the text again 1 to 4 weeks thereafter. The letters underwent a detailed analysis by a handwriting expert, through inspection, a stereoscopic microscope and a magnifying glass. Furthermore, the time that both Groups took to go through with the text was clocked. RESULTS: None of the handwriting variables differed significantly within each Group and between the two Groups. Hypothyroid patients took significantly more time to go through with the text compared to the time taken once they became euthyroid (3.29 ± 1.66 vs 2.63 ± 1.55 minutes, respectively) and the time taken by the control group (p < 0.01). Of note, three Group 1 patients missed to copy some words or even whole sentences on the paper while they were overtly hypothyroid. CONCLUSIONS: The present study demonstrates that handwriting speed is able to disclose the impact of thyroid hormone deficiency on the central nervous system's functions. In particular, the longer time taken to go through with the text and the sentences missed by some hypothyroid patients, are the counterpart of psychomotor slowdown, impaired attention and memory loss peculiar to OH.

Effect of vitamin D supplementation on TSH levels in euthyroid subjects with autoimmune thyroiditis.

PURPOSE: The impact of vitamin D supplementation on thyroid function is not clear and the relationship between hypovitaminosis D and autoimmune thyroiditis (ATD) incidence and evolution is still a matter of debate. The aim of this study was to retrospectively evaluate the impact of vitamin D supplementation on thyroid function in subjects with and without ATD. METHODS: One hundred and ninety-eight euthyroid subjects, with diagnosis of "hypovitaminosis D" (<30 ng/mL) who had been taking supplementation therapy with cholecalciferol for different time periods, were included. They were divided in two groups according to the previous diagnosis of ATD: "ATD-neg" group including subjects without ATD [n = 103 (52%)]; "ATD-pos" group including subjects with a confirmed diagnosis of ATD [n = 95 (48%)]. For both groups, we considered TSH and 25 hydroxyvitamin D (25OHD) levels before (T0) and after (T1) cholecalciferol supplementation. We also considered the treatment duration and the monthly dose of cholecalciferol expressed as IU/month. RESULTS: In hypovitaminosis D subjects with ATD, TSH levels significantly decreased after therapy with cholecalciferol 100.000 IU/month [mean ± SD, TSH at T0: 2.67 ± 1.21 vs. TSH at T1: 2.28 ± 0.86, p = 0.028]. No significant TSH variation was observed in ATD-neg group, irrespective of treatment dose and duration. As expected, 25OHD levels significantly improved with all monthly doses and especially in the group receiving 100.000 IU/month. CONCLUSIONS: Cholecalciferol supplementation improved thyroid function in euthyroid ATD-pos subjects affected with severe hypovitaminosis D. In particular, a significant reduction in TSH levels was observed in subjects with very low baseline 25OHD levels, after taking high monthly doses of cholecalciferol.

Immunoassay Interference on Thyroid Function Tests During Treatment with Nivolumab.

Background: Immune checkpoint inhibitors (ICIs) are associated with several endocrine side effects. In particular, the use of programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors is related to a higher incidence of thyroid dysfunction. Patient Findings: An 85 years-old patient, diagnosed with a metastatic melanoma treated with nivolumab, presented to our hospital with severe ICI-related thyrotoxicosis. Diagnosis was complicated by a biochemical interference on thyroid hormones assay, probably induced by nivolumab. Summary: Baseline laboratory examination conducted before onset of anticancer therapy showed normal thyroid function test (TFTs). A few days after receiving the second nivolumab administration, the patient developed a severe thyrotoxicosis. According to destructive thyroiditis, in a short period thyrotropin (TSH) levels normalized and rapidly increased, but free thyroxine (fT4) levels were inappropriately elevated and did not decrease as expected. The sample was processed by using a Siemens Centaur® immunoassay. We reanalyzed the same sample at another laboratory and with a different immunoassay method (Roche Elecsys®). The results obtained from this assay confirmed severe hypothyroidism with appropriately low fT4 levels. We suspected a possible nivolumab-associated interference on the fT4 assay. Therefore, we subjected the same sample to a polyethylene glycol (PEG) 6000 precipitation, a simple method for the removal of macromolecules, before assaying for fT4 levels. Evaluation of the post-PEG-precipitation sample (Siemens Centaur immunoassay) revealed appropriately low fT4 levels. The patient was started on levothyroxine (LT4) therapy, with monthly TFT monitoring using the Roche immunoassay. Approximately 9 months after starting nivolumab therapy, the patient was advised treatment cessation. A month later, the TFTs were retested on a Siemens Centaur immunoassay, and appropriate fT4 levels were observed in accordance with normal TSH levels on adequate LT4 replacement therapy. Conclusions: We report a possible novel nivolumab-induced biochemical interference on assays of fT4 levels. The hypothesis of a biochemical drug-induced interference is further supported by the disappearance of the interference after the withdrawal of nivolumab. Further studies are needed to prove the biochemical mechanisms of this interference.

Lenvatinib for thyroid cancer treatment: discovery, pre-clinical development and clinical application.

Introduction: About one third of patients affected with thyroid cancer present with recurrent disease. Unresectability, advanced disease and radioiodine refractoriness are considered poor prognostic factors. Treatment with small molecules inhibiting molecular signaling can be considered for patients with progressive disease, when other therapeutic strategies cannot be applied. Lenvatinib is a tyrosine kinase inhibitor targeting multiple molecular factors involved in angiogenesis and tumor progression. Preclinical studies have demonstrated the utility of lenvatinib as a targeted therapy for different tumors, including both differentiated and anaplastic thyroid cancer.Areas covered: The authors provide an overview of the preclinical development of lenvatinib in the treatment of thyroid cancer and review its clinical application. They also provide their expert opinion on its development.Expert opinion: Preclinical studies have helped in the understanding of the mechanisms of thyroid carcinogenesis and in the development of a targeted therapy. These findings have represented the rationale for the use of lenvatinib in clinical trials, which have confirmed its utility but yet failed to prove a clear benefit in overall survival. The decision to start a systemic treatment with lenvatinib must be personalized for each patient evaluating the risk/benefits ratio. Treatment emergent adverse events must be considered and reasonably managed by a multidisciplinary approach.

Iodothyronine deiodinases and reduced sensitivity to thyroid hormones.

Iodothyronine deiodinases are selenoproteins that regulate thyroid hormone metabolism. Of the three types of deiodinases, type 2 is the major regulator of intracellular triiodothyronine concentration in both the hypothalamus and pituitary, and therefore the major regulator of thyrotropin secretion. A defect in iodothyronine deiodinase activity can lead to a reduced sensitivity to thyroid hormones action and the most recent literature includes these defects in the so-called "syndromes of reduced sensitivity to thyroid hormones". To date, the pathogenic variants of the selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene are the first and only inherited disorder of iodothyronine metabolism described. Moreover, there is a growing interest in understanding the possible role of polymorphisms of DIO1 and DIO2 genes in some pathological conditions and in determining the requirement of levothyroxine replacement and the role of combined levothyroxine-liothyronine therapy in carrying subjects affected by hypothyroidism and who need replacement therapy. Results on this topic are still conflicting and more studies are needed to assess the efficacy of combined levothyroxine-liothyronine replacement therapy in this subset of patients.

Factors Predicting Time to TSH Normalization and Persistence of TSH Suppression After Total Thyroidectomy for Graves' Disease.

Hyperthyroidism related to Graves' disease is associated with a suppression of TSH values which may persist after surgery in spite of a LT4 replacement therapy at non-TSH-suppressing doses. The aim of this retrospective study was to evaluate the time to TSH normalization in a group of patients who underwent total thyroidectomy for Graves' disease receiving a LT4 therapy dose regimen based on a previously published nomogram, and to identify possible correlations between the time to normalization of post-operative TSH values and preoperative clinical and biochemical parameters. 276 patients affected by Graves' disease who underwent surgery between 2010 and 2015, were retrospectively evaluated for clinical and biochemical parameters as well as post-surgical LT4 treatment regimen. Of the 276 subjects, 174 had initiated LT4 dosage corresponding to a previously published nomogram. 59 patients were excluded because their LT4 requirement (in mcg/kg/day) changed and deviated from the nomogram during the follow-up period, 15 patients were excluded because their TSH level was >4 mcU/ml during the first biochemical evaluation and 2 patients were excluded because they had low TSH levels potentially related to central hypothyroidism due to concomitant hypopituitarism. Therefore, 98 patients were included in our statistical analysis. TSH and FT4 were evaluated at the first post-operative assessment and during follow up until the normalization of TSH values was achieved, and then included in the analysis. During the first post-operative evaluation 2 months after surgery, 59/98 patients had TSH values in the normal range (0.4 to 4.0 mcU/ml), while 39/98 patients had a TSH value < 0.4 mcU/mL. The persistence of post-operative TSH levels < 0.4 mcU/ml was significantly correlated (p = 0.022) with longer duration of the disease. The value of anti-TSH receptor autoantibodies (TrAb) at the diagnosis of hyperthyroidism, significantly correlated (p = 0.002) with the time to TSH normalization in the group of patients with TSH < 0.4 mcU/ml at first control. This retrospective analysis confirms that in subjects who have undergone thyroidectomy for Graves' disease, time to normalization of TSH may be prolonged. Hence, the role of TSH as the "gold standard" to assess the appropriate LT4 replacement therapy regimen during the initial months following surgery may need to be reconsidered.