Thyroxine treatment with softgel capsule formulation. Usefulness in hypothyroid patients without malabsorption

Background: Levothyroxine sodium (LT4) is the therapy of choice for hypothyroidism. In the last decade, new LT4 formulations, such as liquid and softgel capsules, became available. Even if some evidence has been reached in the efficacy of liquid LT4 in patients with suboptimal TSH on tablet LT4, the usefulness of softgel LT4 has been rarely studied. This study aimed at evaluating the effect of switching from tablet to softgel LT4 patients without increased need for LT4. TSH was used as proxy of LT4 bioavailability and effectiveness. Methods: During the period from April to August 2017, 19 patients on tablet LT4 treatment for hypothyroidism, mostly due to autoimmune thyroiditis, were enrolled. Subjects with causes of malabsorption or increased requirement of LT4 were previously excluded. Patients finally included were asked to switch from tablet to softgel LT4 formulation at unchanged dose and ingestion fashion (30 min before breakfast). TSH was measured with chemiluminescence immunoassays. results: According to exclusion and inclusion criteria, 19 patients were finally selected. One of these had headache 4 days later and come back to tablet LT4, and 18 of them (16W/2M; mean age = 55 years; BMI 22.7 kg/m2) completed the study. They were treated with a median LT4 dose of 88 μg/day and showed a median TSH value of 3.33 mIU/L. The rate of cases with TSH ≤ 4.0 mIU/L was 61.1% (11/18 cases). When patients were re-evaluated after 3 months of softgel LT4, we observed that TSH reached levels under 4.0 mIU/L in 16/18 (88.9%) patients, TSH was lower in 11 cases, and in 6 out of 7 patients with pre-switch TSH values over the normal range. Overall, TSH values on softgel LT4 (median 1.90 mIU/L) was significantly lower from that observed during tablet LT4 (p = 0.0039). conclusion: These data show that hypothyroid patients with no proven malabsorption may have an improved TSH following 3 months from the switch from tablet to softgel LT4 preparation at unchanged dose

Pregnancy outcome in poly-autoimmune disorders. The case of APECED syndrome

Autoimmune polyendocrinopathy-candidiasis–ectodermal dysplasia (APECED) or PAS I is a rare monogenic disorder affecting 10 people/million characterized by different loss of-function mutations on the AIRE gene (1). The AIRE gene encodes a protein representing a nonconventional transcrip tion factor, predominantly expressed in the thymus, which localizes to chromatin encompassing the target genes and activates, through histones binding, the complexes involved in the initiation of gene transcription (2). It induces ectopic expression of self-antigens in thymus cells that are other wise silenced and restricted to other tissues. Ultimately, the AIRE gene determines the central tolerance through the deletion of autoreactive thymocytes and modulates the per ipheral tolerance through the positive selection of regula tory T cells (Tregs) (1). Its loss of function seems to enable the escape of autoreactive T clones from the thymus to cir culation, where poorly efficient Tregs may not ensure per ipheral tolerance (3). Almost all developmental tissues are expressed in the thymus under the control of AIRE (3), and therefore pregnancy represents a primary event for human immune system

Galectin-3 performance in histologic and 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 (I285% 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 (I214.5%) 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

Iodine status in schoolchildren and pregnant women of Lazio, a central Region of Italy

The inhabitants of Lazio, similarly to those of other Italian regions, have been historically exposed to the detrimental effects of an inadequate intake of iodine. The latter is a micronutrient essential for the biosynthesis of thyroid hormones (TH). Iodine deficiency is responsible for a number of adverse effects on human health known as iodine deficiency disorders (IDD), the most common of which worldwide are goiter and hypothyroidism. In order to reduce IDD, a national salt iodination program was started in Italy in 2005. In this article we reviewed the available data regarding iodine intake in the Lazio population before and after the introduction of the national salt iodination program, in order to evaluate its efficacy and the eventual problem(s) limiting its success. On the whole, the information acquired indicates that, following the introduction of the program, the dietary iodine intake in the Lazio population is improved. There is, however, still much work ahead to ameliorate the iodine prophylaxis in this region. In fact, although a generally adequate iodine intake in school-age children has been observed, there are still areas where a mild iodine insufficiency is present. Moreover, two independent epidemiological surveys on pregnant women evidenced a low urinary iodine concentration with respect to the reference range conceived by the World Health Organization. These findings demonstrate the need for greater attention to the iodine prophylaxis by health care providers (i.e., obstetricians, gynecologists, pediatricians, etc.), and the implementation of effective advertising campaigns aimed at increasing the knowledge and awareness of the favorable effects of iodine supplementation on population health

Hashimoto's thyroiditis and autoimmune gastritis

The term "thyrogastric syndrome" defines the association between autoimmune thyroid disease and chronic autoimmune gastritis (CAG), and it was first described in the early 1960s. More recently, this association has been included in polyglandular autoimmune syndrome type IIIb, in which autoimmune thyroiditis represents the pivotal disorder. Hashimoto's thyroiditis (HT) is the most frequent autoimmune disease, and it has been reported to be associated with gastric disorders in 10-40% of patients while about 40% of patients with autoimmune gastritis also present HT. Some intriguing similarities have been described about the pathogenic mechanism of these two disorders, involving a complex interaction among genetic, embryological, immunologic, and environmental factors. CAG is characterized by a partial or total disappearance of parietal cells implying the impairment of both hydrochloric acid and intrinsic factor production. The clinical outcome of this gastric damage is the occurrence of a hypochlorhydric-dependent iron-deficient anemia, followed by pernicious anemia concomitant with the progression to a severe gastric atrophy. Malabsorption of levothyroxine may occur as well. We have briefly summarized in this minireview the most recent achievements on this peculiar association of diseases that, in the last years, have been increasingly diagnosed

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

Early detection of biochemically occult autonomous thyroid nodules

Objective: Autonomously functioning thyroid areas may be associated with subclinical or overt hyperthyroidism, but may exist even in the presence of normal TSH. This study was aimed at comparing the rate of autonomously functioning areas and their cardiac sequelae in patients with nodular goitre studied with the usual and a novel approach. Design and methods: In total 490 adult outpatients with thyroid nodular goitre, living in a mild iodine-deficient area, were selected in our referral centre for thyroid diseases from 2009 to 2014 on the basis of a suspicion of thyroid functional autonomy. They were divided in three groups according to a non-conventional approach (excessive response to thyroxine treatment: group 1) or conventional approach (low/normal TSH with clinical suspicion or low TSH: groups 2 and 3). All patients of the study with the suspicion of thyroid functional autonomy underwent thyroid scan with radioactive iodine (I131) uptake (RAIU). Results: The percentage of confirmed thyroid functional autonomy was 319/490, being significantly higher in group 3 than in groups 1 and 2 (81.5 vs 64.7 vs 52.6%; chi-square P < 0.0001). However, the diagnosis with non-conventional approach was made at a significant earlier age (P < 0.0001). Cardiac arrhythmias as well as atrial fibrillation were similarly detected by conventional and non-conventional approaches (chi-square test: P = 0.2537; P = 0.8425). Conclusions: The hyper-responsiveness to thyroxine treatment should induce the suspicion of thyroid functional autonomy at an early stage, allowing to detect autonomous functioning areas in apparently euthyroid patients

Serum thyroid hormone antibodies are frequent in patients with polyglandular autoimmune syndrome type 3, particularly in those who require thyroxine treatment

Polyglandular autoimmune syndrome (PAS) type 3 consists of autoimmune thyroid disease (AITD) coexisting with ≥1 non-thyroidal autoimmune disease (NTAID) other than Addison’s disease and hypoparathyroidism. We evaluated the prevalence and repertoire of thyroid hormones antibodies (THAb) in PAS-3 patients. Using a radioimmunoprecipation technique, we measured THAb (T3IgM, T3IgG, T4IgM, and T4IgG) in 107 PAS-3 patients and 88 controls (patients with AITD without any NTAID). Based on the selective coexistence of AITD with one NTAID (chronic autoimmune gastritis, non-segmental vitiligo or celiac disease), patients were divided into group 1 (chronic autoimmune gastritis positive, n = 64), group 2 (non-segmental vitiligo positive, n = 24), and group 3 (celiac disease positive, n = 15). At least one of the four THAb was detected in 45 PAS-3 patients (42.1%) and 28 controls (31.8%, P = 0.14), with similar rates in the three PAS-3 groups. The rates of T3Ab, T4Ab, and T3 + T4Ab were similar in groups 1 and 2, while in group 3, T3Ab was undetected (P = 0.02). In PAS-3 patients, the rate of levothyroxine treatment was greater in THAb-positive patients compared to THAb-negative patients (76.7 vs. 56.1%, P = 0.03, RR = 1.4, 95% CI 1.03–1.81). Not unexpectedly, levothyroxine daily dose was significantly higher in group 1 and group 3, namely in patients with gastrointestinal disorders, compared to group 2 (1.9 ± 0.4 and 1.8 ± 0.3 vs. 1.5 ± 0.2 μg/kg body weight, P = 0.0005 and P = 0.004). Almost half of PAS-3 patients have THAb, whose repertoire is similar if chronic autoimmune gastritis or celiac disease is present. A prospective study would confirm whether THAb positivity predicts greater likelihood of requiring levothyroxine treatment

Gastrointestinal Malabsorption of Thyroxine

Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of thyroxine may be marred by behavioral, pharmacologic and pathologic issues acting as interfering factors. Despite a continuous search for an optimal thyroxine treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of thyroxine. Gastrointestinal malabsorption of oral thyroxine represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed.In this review article we aimed at examining the pharmacologic features of thyroxine preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of thyroxine and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on thyroxine absorption at gastric and intestinal level. The impact of gastrointestinal disorders on thyroxine treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and, often hidden, gastrointestinal diseases impairing thyroxine absorption

Systemic Lupus Erythematosus and Thyroid Autoimmunity

Most of the studies present in the literature show a high prevalence, and incidence, of new cases of hypothyroidism and autoimmune thyroiditis (AT) in systemic lupus erythematosus (SLE) patients, overall in female gender. A limited number of cases of Graves' disease have been also reported in SLE patients, in agreement with the higher prevalence of thyroid autoimmunity. It has been also demonstrated that a Th1 predominance is associated with AT in SLE patients. Furthermore, a higher prevalence of papillary thyroid cancer has been recently reported in SLE, in particular in the presence of thyroid autoimmunity. However, studies in larger number of SLE patients are needed to confirm findings about thyroid cancer. On the whole, data from literature strongly suggest that female SLE patients, with a high risk (a normal but at the higher limit thyroid-stimulating hormone value, positive antithyroid peroxidase antibodies, a hypoechoic pattern, and small thyroid), should undergo periodic thyroid function follow-up, and appropriate treatments when needed. A careful thyroid monitoring would be opportune during the follow-up of these patients