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

The relationship between thyroid disorders and vitamin A. A narrative minireview

: The terms "vitamin A" and "retinoids" encompass a group of fat-soluble compounds essential for human nutrition. Some of them (retinol, retinal, 9-cis-retinoic acid, tretinoin, and 13-cis-retinoic acid) are fully natural, while others are synthetic compounds used mostly for therapeutic purposes. Some evidence indicates that the nutritional status of these retinoids (i.e., the presence or absence of deficiency) is able to modulate thyroid gland metabolism. Vitamin A deficiency is tightly correlated with structural and functional impairment of the thyroid gland and is often associated with iodine deficiency. Furthermore, retinoids are involved in different immune functions, as well as in the process of activation, proliferation, and differentiation of regulatory T cells (Treg). This is particularly significant given the high prevalence of thyroid autoimmune disorders, whose pathogenesis seems to be related to the altered homeostasis of regulatory T cells. Retinoids are also involved in the modulation of gene expression via their interaction with nuclear receptors, and they also act as cofactors in cell growth and differentiation. The ability of retinoic acid to increase iodine uptake and sodium-iodine symporter activity in human thyroid cancer cell lines suggests that some retinoids and their derivatives may be of use in the treatment of different thyroid tumors. This minireview summarizes the current knowledge on the link between nutritional intake of vitamin A and various thyroid disorders

Diagnostic accuracy of ultrasonographic features in detecting thyroid cancer in the transition age: a meta-analysis

Context: Significant uncertainty exists about the diagnostic accuracy of ultrasonographic (US) features used to predict the risk of thyroid cancer in the pediatric population. Moreover, there are no specific indications for thyroid nodule evaluation in patients during the transition age. Objective: The meta-analysis aimed to address the following question: which thyroid nodule US features have the highest accuracy in predicting malignancy in the transition age. Methods: We performed a meta-analysis of observational/cohort/diagnostic accuracy studies dealing with thyroid nodule sonography, reporting US features, and using histology as a reference standard for the diagnosis of malignancy and histology or cytology for the diagnosis of benignity in the transition age (mean/median age 12-21 years). Results: The inclusion criteria were met by 14 studies, published between 2005 and 2020, including 1306 thyroid nodules (mean size 17.9 mm) from 1168 subjects. The frequency of thyroid cancer was 36.6%. The US features with the highest diagnostic odds ratio (DOR) for malignancy were the presence of suspicious lymph nodes (DOR: 56.0 (95% CI: 26.0-119.0)), a 'taller than wide' shape of the nodule (6.0 (95% CI: 2.0-16.0)), the presence of microcalcifications (13.0 (95% CI: 6.0-29.0)) and irregular margins (9.0 (95% CI: 5.0- 17.0)). Heterogeneity among the studies was substantial. Conclusions: Following the diagnosis of a thyroid nodule in the transition age, a thorough US examination of the neck is warranted. The detection of suspicious lymph nodes and/ or thyroid nodules with a 'taller than wide' shape, microcalcifications, and irregular margins is associated with the highest risk of malignancy in the selection of nodules candidates for biopsy

Unilateral thyroid-associated orbitopathy as the only sign of occult celiac disease. Effective treatment with a gluten-free diet

Unilateral thyroid-associated orbitopathy may be the only sign of an occult celiac disease. Here we presented evidence that a treatment with a gluten-free diet may represent an effective treatment for extraintestinal manifestations of celiac disorders

Gut microbiome and thyroid autoimmunity

Intestinal microbiota gained attention due to its pleiotropic effect on intestinal barrier, nutrients metabolism and on immune system development and functions. Recent evidence pointed out a possible role of an altered gut microbiota composition in the pathogenesis and progression of several autoimmune disorders, occurring at gastrointestinal level or far apart. In thyroid autoimmune disorders, encompassing Hashimoto's thyroiditis, Graves’ disease and thyroid-associated orbitopathy, the combined effect of environmental triggers and genetic predisposing background, lead to the loss of self-tolerance and to auto-aggressive damage, involving both cellular and humoral networks of immune system. This review is aimed at assessing the current knowledge about the studies published on the fecal microbiota composition in patients bearing thyroid autoimmune diseases. We further examined the reciprocal interaction between gut microbiota composition and the most used treatments for thyroid disorders

CHARACTERIZATION OF CD4+TH17 AND B REGULATORY CELLS IN HASHIMOTO’S THYROIDITIS

In the last years, Th17 lymphocytes and regulatory B lymphocytes (Breg) seem to play a promising role in understanding the pathogenesis of autoimmune disorders. In isolated Hashimoto’s thyroiditis (HT), increased Th1 and Th17 activation has been described but little is known about Breg which allegedly suppress the pro-inflammatory response. Aim of this study was to compare Th17 and Breg subpopulation in healthy subjects and in patients affected by HT. A total of 19 patients (17 women and 2 men, mean age 48 – 10 years) affected by HT and 18 age- and sex-matched healthy donors (16 women and 2 men, mean age 42 – 12 years) were enrolled in this study. Effector Th17 lymphocytes were obtained from overnight stimulated PBMCs, then stained, fixed, permeabilized and stained intracellularly with anti-IL-17A. For Breg detection, freshly PBMCs were surface stained with anti-CD19, anti-CD24, anti-CD38, and anti-CD27. Cells were then acquired on a FACS ARIA II. Increased percentage (2.6% – 1.6 versus 1.6% – 0.9; p = 0.0337) of Th17 cells in HT patients as compared with healthy controls were observed. Instead, we found similar percentage of non stimulated CD24hiCD38hi Breg cells between isolated HT patients and healthy donors (2.4% – 0.9 versus 2.0% – 0.7; p = ns). Also, mature CD24intCD38int and memory CD24hiCD38neg B subsets, were similar in HT patients and healthy controls (30.8 vs. 25.1% and 49.5 vs. 56.0%, respectively; p = ns). Following CpG oligonucleotide stimulation (functional assay of B cells), small but not significant differences were seen in total CD19+ cells subset and total B lymphocytes producing IL-10 between HT patients and healthy donors (2.9% – 1.9 and 1.9% – 1.1; p = ns). However, a significant increase was recognized in the percentage of IL10-producing Breg cells in HT patients as compared to healthy controls (3.9% – 1.8 and 2.4% – 1.1; p = 0.0303). These preliminary findings confirmed activation of proinflammatory Th17 pathway but described for the first time an upregulation of IL-10 producing Breg cells in Hashimoto’s thyroiditis which may oppose to Th17 activation

Levothyroxine treatment and gastric juice pH in humans. The proof of concept

Purpose: Despite the absorption of oral thyroxine (T4) occurs in the small bowel, several patients with gastric disorders show an increased need for T4. In vitro evidence suggested that medium pH variations interfere with T4 dissolution. This study was aimed at finding the proof of concept of a direct relationship between the minimal effective dose of T4 and the actual gastric juice pH. Patients and methods: Among 311 consecutively thyroxine-treated patients, 61 bearing Hashimoto’s thyroiditis (52 F/9 M; median age = 51 years) who complained persistent dyspepsia and/or upper abdominal symptoms following a noninvasive workup for gastrointestinal disorders, underwent EGDS with multiple biopsies and gastric juice pH measurement. All patients accepted to take thyroxine in fasting conditions, abstaining from eating or drinking for one hour. Results: Thyroxine requirement increased along with the rising gastric pH (ρ = 0.4229; p = 0.0007). A multivariate analysis revealed that gastric pH was, beside body mass index, the far more important independent variable in determining the effective dose of T4 (p = 0.001). The ROC curve revealed that the pH threshold for an increased thyroxine requirement was at 2.28, being the AUC by 78%. Subdividing patients by the histologic findings, it appeared a significant increase (p = 0.0025) along with the progressive damage of gastric mucosa. Conclusion: The in vivo measurement of gastric pH highlighted its key role in determining the minimal effective dose of oral T4 and may explain the interference of food, of some drugs and gut disorders on levothyroxine treatment

The potential role of hypochlorhydria in the development of duodenal dysbiosis. A preliminary report

In recent years, the role of gastric and duodenal microbiota has acquired increasing importance in the homeostasis of the host, although, to date, most evidence concern the faecal microbiota. Indeed, the gastric, and duodenal microbiota are challenging to study, due to gastric acid, bile, digestive enzymes, and rapid transit time. Specifically, the gastric acid environment may influence their bacterial composition since the acid barrier protects against orally ingested microorganisms and leads to their inactivation before reaching the intestine. The aim of this study was to assess a correlation between intragastric pH and gastric as well as intestinal microbiota of patients with histologic gastric alterations. pH was measured in the gastric juice and the bacterial composition in gastric and duodenal biopsies and faecal samples, was investigated via 16s rRNA gene sequencing. The main result is the direct correlation of duodenal microbiota biodiversity, via alpha diversity measures, with intragastric pH values. In particular, patients with hypochlorhydria showed increased duodenal microbiota biodiversity, higher intragastric pH values being prevalent in patients with chronic atrophic gastritis. Lastly, the latter was also strongly associated to the presence of oral bacteria, like Rothia mucilaginosa, Streptococcus salivarius and Granulicatella adiacens, in the duodenal microbiota. In conclusions, our results suggest a low-acid gastric environment as a contributive factor for duodenal dysbiosis, potentially leading to the development of pathological conditions of the gastrointestinal tract