The relationship between thyroid and human-associated microbiota: A systematic review of reviews.

In recent years, a growing number of studies have examined the relationship between thyroid pathophysiology and intestinal microbiota composition. The reciprocal influence between these two entities has been proven so extensive that some authors coined the term "gut-thyroid axis". However, since some papers reported conflicting results, several aspects of this correlation need to be clarified. This systematic review was conceived to achieve more robust information about: 1)the characteristics of gut microbiota composition in patients with the more common morphological, functional and autoimmune disorders of the thyroid; 2)the influence of gut microbial composition on micronutrients that are essential for the maintenance of thyroid homeostasis; 3)the effect of probiotics, prebiotics and synbiotics, some of the most popular over-the-counter products, on thyroid balance; 4)the opportunity to use specific dietary advice. The literature evaluation was made by three authors independently. A five steps strategy was a priori adopted. After duplicates removal, 1106 records were initially found and 38 reviews were finally included in the analysis. The systematic reviews of reviews found that: 1) some significant variations characterize the gut microbiota composition in patients with thyroid disorders. However, geographical clustering of most of the studies prevents drawing definitive conclusions on this topic; 2) the available knowledge about the effect of probiotics and synbiotics are not strong enough to suggest the routine use of these compounds in patients with thyroid disorders; 3) specific elimination nutrition should not be routine suggested to patients, which, instead have to be checked for possible micronutrients and vitamins deficiency, often owed to gastrointestinal autoimmune comorbidities.

CD20 + T lymphocytes in isolated Hashimoto's thyroiditis and type 3 autoimmune polyendocrine syndrome: a pilot study.

BACKGROUND: CD20+ T cells represent up to 5% of circulating T lymphocytes. These cells have been shown to produce higher levels of IL-17A and IFN-γ than those of CD20- T lymphocytes. Some reports described the role of CD20+ T cells in autoimmune disorders such as multiple sclerosis and rheumatoid arthritis possibly due to their ability to produce these inflammatory cytokines. This study is aimed at describing the behavior of CD20+ T lymphocytes in the most frequent autoimmune disorder, i.e., Hashimoto's thyroiditis (HT), presenting isolated or associated to further autoaggressive disorders in a frame of poly-autoimmunity. METHODS: The study group encompasses 65 HT patients: 23 presenting in isolated form (IT) and 42 with an associated non-endocrine autoimmune disorder [16 with chronic atrophic gastritis (CAG), 15 with nonsegmental vitiligo (VIT), and 11 with celiac disease (CD)]. Twenty healthy donors act as control group (HD). Chronic use of interfering drugs, severe or chronic disorders, and pregnancy and lactation were used as exclusion criteria. Whole blood samples (100 µl) were stained with fluorescent-labeled antibodies (anti-CD45, anti-CD3, anti-CD19, anti-CD16, anti-CD56, anti-CD4, anti-CD8, anti-CD20). Red blood cells were then lysed by adding 1 ml of hypotonic buffer, and samples were acquired on a Flow Cytometer. RESULTS: CD3+CD8+CD20+ T lymphocytes' percentages, were significantly higher in the whole group of autoimmune patients compared to healthy donors (p = 0.0145). Dividing HT patients based on the type of presentation of autoimmune thyroiditis, CAG group showed the highest percentage of these cells as compared to HD and CD (p = 0.0058). IT patients showed higher percentages of CD3+ CD8+CD20+ cells than those of HD patients although not reaching statistical significance. However, dividing IT group based on thyroid function, hypothyroid patients showed higher CD8+CD20+ cell percentages than those of HD and euthyroid patients (p = 0.0111). Moreover, in IT patients, these cells were negatively correlated with FT4 levels (p = 0.0171; r = -0.4921). CONCLUSIONS: These preliminary findings indicate that CD8+CD20+ T cells are activated in patients with autoimmune thyroiditis and may behave differently according to the presence of poly-autoimmunity and hypothyroidism.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

Microbiota and Thyroid Disease: An Updated Systematic Review.

Studies analyzing the relationship between microbiota composition and the thyroid have been increasing rapidly in recent years, and evidence has recently come to light about the involvement of the gut microbiota in various aspects of thyroid pathology. Recently, besides studies analyzing the microbiota composition of different biological niches (salivary microbiota or thyroid tumor microenvironment) in patients with thyroid disorders, some studies have been carried out in peculiar subcategories of patients (pregnant women or obese). Other studies added a metabolomic insight into the characterization of fecal microflora in an attempt to enlighten specific metabolic pathways that could be involved in thyroid disorder pathogenesis. Lastly, some studies described the use of probiotics or symbiotic supplementation aimed at modulating gut microbiota composition for therapeutic purposes. The aim of this systematic review is to analyze the last advancements in the relationship between gut microbiota composition and thyroid autoimmunity, extending the analysis also to nonautoimmune thyroid disorders as well as to the characterization of the microbiota belonging to different biological niches in these patients. The overall results of the present review article strengthen the existence of a bidirectional relationship between the intestine, with its microbial set, and thyroid homeostasis, thus supporting the newly recognized entity known as the gut-thyroid axis.

Ultrasound systems for risk stratification of thyroid nodules prompt inappropriate biopsy in autonomously functioning thyroid nodules.

OBJECTIVE: Ultrasound (US) risk stratification systems (RSSs) have been developed to reduce the number of unnecessary fine-needle aspiration (FNA) biopsies in patients with thyroid nodules. Autonomously functioning thyroid nodules (AFTN) account for 5%-10% of palpable lesions and are very rarely malignant. The present study was undertaken to investigate how RSSs classify AFTNs and whether RSSs are able to avoid unnecessary FNA biopsies in such cases. METHODS: Patients with AFTN who had undergone US, scintigraphy and thyroid function evaluation from December 2016 to December 2017 were selected. US images were retrospectively reviewed and AFTN reclassified according to AACE/ACE/AME, ACR-TIRADS, ATA, BTA, EU-TIRADS, K-TIRADS and TIRADS. Risk class and indication for FNA were assessed. RESULTS: A number of 87 AFTNs from 85 consecutive patients were enrolled. A median diameter of 22 mm (range 10-59) was found, with an ovoid isoechoic nodule being the most frequent US presentation. When AFTNs were reclassified according to US RSSs, the most common categories were low and intermediate risk. AFTNs were assessed as being at high risk/high suspicion/malignant in 1%-9%, with good agreement among AACE/ACE/AME, ATA, EU-TIRADS, K-TIRADS and TIRADS. Remarkably, FNA was indicated in 27%-90% of AFTNs. A statistically significant difference among the systems was found; 8% of cases were nonclassifiable by one or more US RSS. CONCLUSIONS: Ultrasound RSSs prompt inappropriate FNA in a significant number of patients with AFTN.

Performance of contrast-enhanced ultrasound (CEUS) in assessing thyroid nodules: a systematic review and meta-analysis using histological standard of reference.

BACKGROUND: The present study was undertaken to systematically review the literature on the reliability of using contrast-enhanced ultrasound (CEUS) to assess thyroid nodules. To avoid the potential bias in studies using a cytological standard of reference, here we aimed to meta-analyze data from studies adopting histological diagnosis as the gold standard. METHODS: A comprehensive literature exploration of PubMed and Scopus was conducted. The search was updated until June 2018 and references of the retrieved articles screened. Only original articles reporting the histological follow-up of nodules previously undergone CEUS evaluation were eligible for inclusion. Pooled sensitivity, specificity, PPV, and NPV of CEUS were calculated by DerSimonian and Laird method (random-effects model). RESULTS: The literature search retrieved 1885 articles, and 14 were included for the study. There were Chinese, Italian, German, and Austrian authors. All studies used SonoVue. The overall number of reported nodules was 1515, of which 775 were classified as positive at CEUS and 740 as negative. Pooled sensitivity, specificity, PPV, and NPV of CEUS were 85% (95% CI 83-88), 82% (95% CI 77-87), 83% (95% CI 77-88), and 85% (95% CI 81-88), respectively. Moderate inconsistency was present for specificity and PPV. There was publication bias for sensitivity and NPV. CONCLUSIONS: CEUS reaches good performance in discriminating between malignant and benign thyroid lesions.

Dedicated neck 18 F-FDG PET/CT: An additional tool for risk assessment in thyroid nodules at ultrasound intermediate risk.

BACKGROUND: Several ultrasound (US) risk stratification systems have been proposed for the assessment of thyroid nodules, and their performance was shown as good. However, the rate of nodules assessed at intermediate risk is not negligible and whether they should be submitted or not to further examination is still under debate. The present study aimed to evaluate the reliability of 18 F-FDG PET/CT in stratifying the risk of malignancy in these lesions. METHODS: Two institutions participated to this retrospective study in which a dedicated 18 F-FDG PET/CT was proposed to patients having a thyroid nodule with US assessment of EU-TIRADS 4 or 5. 18 F-FDG PET/CT did not influence the diagnostic and therapeutic decision. Histology was the gold standard for all patients. RESULTS: Ninety-three patients were included for the study with 48 EU-TIRADS 4 and 45 EU-TIRADS 5 nodules. Of these, 26 underwent thyroidectomy following FNAC suspicious for or consistent with malignancy, 38 for inconclusive cytology, 27 because of large goitre and 2 for high-risk lesion at US. At histology, 35 carcinomas and 58 benign lesions were found. Cancer prevalence was 16.7% in EU-TIRADS 4 and 60% in EU-TIRADS 5. Overall, 18 F-FDG PET/CT was positive in 33/35 cancers (94.5% sensitivity) and negative in 31/58 benign lesions (53.4% specificity). When considering only EU-TIRADS 4, 18 F-FDG PET/CT was positive in 7/8 cancers and negative in 20/40 benign lesions; among these, there were 36 cases with FNAC indication according to dimensional cut-off (ie >1.5 cm), and 18 F-FDG PET/CT showed 85.7% sensitivity and 41.4% specificity. CONCLUSIONS: 18 F-FDG PET/CT may have a role in stratifying the cancer risk of thyroid nodules with an intermediate ultrasound assessment. More specifically, thyroid lesions classified as EU-TIRADS 4 and with no 18 F-FDG uptake could be ruled out from further examination, similar to other anamnestic and clinical suspicious factors of patients. Further prospective and cost-effectiveness studies are needed.

Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation.

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

Fine-needle aspiration in all thyroid incidentalomas at 18 F-FDG PET/CT: Can EU-TIRADS revise the dogma?

OBJECTIVE: Focal thyroid incidentalomas (TIs) are observed in 2% of 18 F-FDG PET/CT representing malignancy in one-third of cases. Currently, due to the lack of evidence on their optimal management, guidelines suggest fine-needle aspiration cytology (FNAC). The study aim was to evaluate the role of ultrasound evaluation according to EU-TIRADS to assess the risk of TIs and inform FNAC prescriptions. DESIGN: We retrospectively reviewed 18 F-FDG PET/CT TIs recorded during the period 2014-2017. Enrolled were TIs with histological outcome and autonomous nodules. Cases with uncertain matching between 18 F-FDG PET/CT, ultrasound and histology were excluded. RESULTS: According to the selection criteria, 75 TIs, being 13 (17.3%) malignant and 62 (82.7%) benign, were included. Cancers had significantly higher SUVmax and SUVmax ratio (Mann-Whitney P < 0.01) than benign, and the most accurate cut-offs were >7.1 and >3.65, respectively. At ultrasound, the cancer rate was 0% in EU-TIRADS 2, 2.9% in EU-TIRADS 3, 4.2% in EU-TIRADS 4% and 78.6% in EU-TIRADS 5 (chi-squared P < 0.001). Sensitivity, specificity, PPV, NPV and accuracy for malignancy were 92%, 64%, 35%, 98% and 69% for SUVmax; 85%, 68%, 36%, 96% and 71% for SUVmax ratio; and 85%, 95%, 79%, 97% and 93% for EU-TIRADS, respectively. The absence of all these three features reached a specificity of 97.1%. CONCLUSIONS: EU-TIRADS, within a clinical careful approach, can discriminate with significant accuracy lesions at high risk of malignancy from those at low risk among TIs at 18 F-FDG PET/CT. Additionally, a centre-based threshold for SUV parameters should be useful for the initial assessment of these lesions during PET/CT reading and reporting.

Gut microbiota and Hashimoto's thyroiditis.

About two third of the human microbial commensal community, namely the gut microbiota, is hosted by the gastrointestinal tract which represents the largest interface of the organism to the external environment. This microbial community co-evolved in a symbiotic relationship with the human beings. Growing evidence support the notion that the microbiota plays a significant role in maintaining nutritional, metabolic and immunologic homeostasis in the host. Microbiota, beside the expected role in maintaining gastrointestinal homeostasis also exerts metabolic functions in nutrients digestion and absorption, detoxification and vitamins' synthesis. Intestinal microbiota is also key in the correct development of the lymphoid system, 70% of which resides at the intestinal level. Available studies, both in murine models and humans, have shown an altered ratio between the different phyla, which characterize a" normal" gut microbiota, in a number of different disorders including obesity, to which a significant part of the studies on intestinal microbiota has been addressed so far. These variations in gut microbiota composition, known as dysbiosis, has been also described in patients bearing intestinal autoimmune diseases as well as type 1 diabetes mellitus, systemic sclerosis and systemic lupus erythematosus. Being Hashimoto's thyroiditis the most frequent autoimmune disorder worldwide, the analysis of the reciprocal influence with intestinal microbiota gained interest. The whole thyroid peripheral homeostasis may be sensitive to microbiota changes but there is also evidence that the genesis and progression of autoimmune thyroid disorders may be significantly affected from a changing intestinal microbial composition or even from overt dysbiosis. In this brief review, we focused on the main features which characterize the reciprocal influence between microbiota and thyroid autoimmunity described in the most recent literature.

BREG cells in Hashimoto's thyroiditis isolated or associated to further organ-specific autoimmune diseases.

Hashimoto thyroiditis (HT) may occur isolated or associated with other non-endocrine autoimmune disorders (NEAD). No data are available about Breg cells in these disorders and this represented the aim of the study. Th17 and Breg cells subset were characterized on peripheral blood mononuclear cells isolated from 18 healthy donors (HD), 19 patients with isolated HT and 26 patients with HT+NEAD. Th17 were higher in patients with isolated HT than in HD but no further changes were seen in patients with HT+NEAD. CD24hiCD38hi unstimulated Breg cells were similar in HT patients and in HD, but significantly higher in patients with HT+NEAD than in both HT and in HD. CD19+CD24hiCD27+ Breg memory phenotype was similar in HD and in HT patients, but decreased in patients with HT+NEAD (23.4%vs38.5%). Upon CpG-stimulation, CD24hiCD38hi IL-10+ Breg cells were higher in HT patients than in HD (3.9%vs1.8%) but similar in patients with HT+NEAD (2.4%).

Galectin-3 Performance in Histologic a Cytologic Assessment of Thyroid Nodules: A Systematic Review and Meta-Analysis.

The literature on Galectin-3 (Gal-3) was systematically reviewed to achieve more robust information on its histologic reliability in identifying thyroid cancers and on the concordance between Gal-3 test in histologic and cytologic samples. A computer search of the PubMed and Scopus databases was conducted by combinations of the terms thyroid and Gal-3. Initially, 545 articles were found and, after their critical review, 52 original papers were finally included. They reported 8172 nodules with histologic evaluation of Gal-3, of which 358 with also preoperative FNAC Gal-3 assessment. At histology, Gal-3 sensitivity was 87% (95% confidence intervals [CI] from 86% to 88%), and specificity 87% (95% CI from 86% to 88%); in both cases, we found heterogeneity (I2 85% and 93%, respectively) and significant publication bias (p < 0.001). The pooled rate of positive Gal-3 at fine needle aspiration (FNAC) among cancers with histologically proven Gal-3 positivity was 94% (95% CI from 89% to 97%), with neither heterogeneity (I2 14.5%) nor bias (p = 0.086). These data show high reliability of Gal-3 for thyroid cancer at histology, while its sensitivity on FNAC samples is lower. The limits of cytologic preparations and interpretation of Gal-3 results have to be solved.

Liquid liothyronine to obtain target TSH in differentiated thyroid cancer patients.

In the last ten years a liquid formulation of liothyronine (L-T3) became available. To date, no studies on its systematic use have been reported. This study is aimed at assessing the reliability of liquid L-T3 in achieving target TSH in patients with differentiated thyroid cancers (DTC). Twenty-one high risk DTC patients in whom levothyroxine treatment up to 2.0 µg/kg/day did not suppress TSH levels (i.e. >0.1 mIU/L) were selected. Maintaining the same L-T4 dose, they started to assume liquid L-T3 at an initial fixed dose of 3.55 µg (5 drops). Further adjustments of L-T3 dose were tailored according to individual assessment. Initial serum TSH ranged from 0.8 to 12.0 mIU/L, when patients assumed high dose of L-T4 alone. Following the addition of a daily single dose of 3.55 µg L-T3, the target TSH was attained in five patients (23.8%). After increasing L-T3 dose up to a mean of 7.3±3.4 µg/day all patients reached target serum TSH (<0.1 mIU/L). The mean individual L-T3 dose was significantly correlated with the body weight and was 0.11±0.04 µg/kg/day (p=0.013). Mean L-T4:L-T3 ratio was 21:1. No patients showed skewed free-T3 or free-T4 values, neither experienced discomfort nor reported adverse events. Liquid L-T3 can be useful to achieve optimal TSH suppression in high risk DTC with not suppressed TSH on L-T4 alone. This formulation allows an individual tailoring of L-T3, minimizing risks of side effects as well as of overtreatment in these clinical conditions.

Analysis of dose-TSH response effect of levothyroxine soft-gel formulation.

Background: Hypothyroidism is treated with daily levothyroxine (LT4). In recent years, soft gel caps of LT4 (LT4-C) have been commercialized, and their performance has been optimized. Since guidelines recommend dose LT4 according to the tablet preparation efficacy, the present study was undertaken to obtain data about the daily requirement, normalized per body weight, of LT4-C. Methods: Patients undergoing LT4-C after total thyroidectomy and radioiodine treatment for differentiated thyroid carcinoma were selected. There was no specific indication of suppression of TSH (i.e., <0.5 or <0.1 mIU/L). Patients were required to maintain a stable LT4 dose during the study period. Patients with interfering factors were excluded from this study. Results: Thirty patients were enrolled (18 females and 12 males; median age, 50 years; median body weight, 71 kg; median LT4-C dose, 1.71 µg/kg/day). The analysis of patient age did not reveal any differences. The LT4-C dose correlated with free-T4 p = 0.03), but not with TSH (p = 0.42) and free-T3 (p = 0.13). TSH was <1.0 mIU/L in 90% of the cases. The LT4-C dose-TSH response effect was analysed by probit regression model: the probability to achieve TSH <1.0 mIU/l was 99% with a dose of 1.84 (95%CI 1.57-2.12) µg/kg/day, 75% with a dose of 1.38 µg/kg/day (95%CI 1.17-1.59), and 50% with a dose of 1.20 (95%CI 0.96-1.43). At ROC curve analysis, the most accurate cut-off of LT4-C dose to achieve TSH <1.0 mIU/l was 1.53 ug/kg/day with 70% sensitivity and 100% specificity. Conclusions: Athyreotic patients can be initially treated with an LT4-C dose lower than previously stated. Therefore, further prospective studies are warranted.

Lactose intolerance and levothyroxine malabsorption: a review of the literature and report of a series of patients treated with liquid L-T4 without lactose.

In hypothyroid patients needing large doses of levothyroxine (L-T4) (>1.7-2 µg/kg/day) to reach euthyroidism, lactose intolerance (LI) needs to be excluded, owing to the high prevalence in the population. If LI is present, a lactose-free diet decreases the rate of L-T4 malabsorption. However, an increased requirement of L-T4 is described in patients with LI, which can be beneficially treated using lactose-free L-T4 formulation. The lactose-free liquid L-T4 formulation is able to circumvent LI malabsorption leading to the normalization of thyroid-stimulating hormone (TSH) in patients with subclinical hypothyroidism and long-term stable TSH levels.

Iodized Salt May Not Be Sufficient to Guarantee an Adequate Iodine Intake in Pregnant Women.

Adequate iodine intake is of crucial importance in pregnancy to meet the thyroid hormone needs of both mother and fetus. In the present study, undertaken as a part of the surveillance actions following the introduction in Italy of a national salt iodination program in 2005, the iodine intake was investigated in 123 pregnant women and 49 control women living in the same area of central Italy. All the participants were screened for urinary iodine concentration (UIC), serum level of thyrotropin, free-thyroxine, free-triiodothyronine, and thyroid volume. Moreover, they were provided with a questionnaire on the use of iodine-containing salt or supplements. Control women had a median UIC of 102 µg/L, consistent with an iodine sufficiency, while in pregnant women the median UIC value was 108 µg/L, lower than the endorsed UIC of 150 µg/L. In addition, pregnant women showed a significantly increased median thyroid volume compared to controls. Interestingly, the median UIC did not differ between pregnant women not using iodine-containing salt or supplements and those regularly consuming iodized salt alone, while pregnant women with a daily intake of iodine-containing supplements had an adequate median UIC (168 µg/L). In conclusion, the data reported here showed that pregnant women and their fetuses are still exposed to the detrimental effects of iodine deficiency and that the consumption of iodine-containing supplements should be recommended in pregnancy.

[The malabsorption of levothyroxine: a kaleidoscope of comorbidities?] / Il malassorbimento della levotiroxina: un caleidoscopio di comorbilità?

Oral levothyroxine treatment appears to be easy to manage but the hormone absorption can be impaired by several interfering factors, leading to abnormal TSH levels. Therefore, patients can be at risk of both under and over treatment. A 41 years old woman came to our attention for Hashimoto's thyroiditis with refractory hypothyroidism and a malabsorption has been suspected. The patient entered a diagnostic work up which revealed the unusual cause of malabsorption. The patient underwent specific treatment for the disorder with a progressive improvement of the levothyroxine absorption.

What about TSH and Anti-Thyroid Antibodies in Patients with Autoimmune Thyroiditis and Celiac Disease Using a Gluten-Free Diet? A Systematic Review.

The prevalence of celiac disease (CD) in patients with chronic autoimmune thyroiditis (CAIT) is estimated to be between 2 and 7.8%. A gluten-free diet (GFD) in patients with CD is suggested to have a beneficial effect on CAIT. Thus, the present systematic review was undertaken to achieve more robust evidence about the change in thyroid stimulating hormone (TSH) and thyroid-specific antibodies (T-Ab) levels obtained in CD patients following a GFD. A specific search strategy was planned. The last search was performed on March 2022. The following data were mainly searched for in order to be extracted: sample size, mean and/or median with standard deviation (SD), and error (SE), individually, of thyroid hormones and T-Ab at baseline and after GFD, and the duration of the study. The initial search retrieved 297 records and 6 articles met the inclusion criteria. In total, 50 patients with both CD and CAIT and 45 controls were reported. The effects of a GFD on the thyroid hormonal and immunological profile could be extracted only in a part of the studies. Two studies were case reports. A low risk of bias was observed. These findings advise further studies, ideally randomized, in order to better investigate the potential relationship between GFD and thyroid homeostasis. The level of evidence is not still sufficient to recommend GFD to patients with CAIT.

Seeking optimization of LT4 treatment in patients with differentiated thyroid cancer.

Levothyroxine sodium (LT4) is the mainstay treatment to replace thyroid hormonal production in thyroidectomized patients, but, depending on the aggressiveness of the cancer and on the risk of recurrence, patients with differentiated thyroid cancer may also be treated in a TSH-suppressive or semi-suppressive mode. The pathophysiological rationale for this LT4 treatment stems from the role of TSH, considered to be a growth factor for follicular cells, potentially inducing initiation or progression of follicular cell-derived thyroid cancer. Therefore, accurate tailoring of treatment, taking into account both patient characteristics (age and comorbidities) and risk of persistent/recurrent disease, is highly recommended. Furthermore, adjustments to traditional LT4 treatment should be made in thyroidectomized patients due to the lack of thyroidal contribution to whole body triiodothyronine (T3) concentration. Since LT4 exhibits a narrow therapeutic index and the side effects of over- and under-treatment could be deleterious, particularly in this category of patients, caution is required in dose individualization, in the mode of ingestion, and in potential pharmacological and other types of interference as well. Our aim was to analyze the current knowledge concerning LT4 dose requirements in patients with thyroid cancer according to different therapeutic approaches, taking into account a number of factors causing interference with LT4 efficacy. Specific mention is also made about the use of the novel LT4 formulations.