Lipoprotein alterations in endocrine disorders - a review of the recent developments in the field.

Dyslipidemia is one of the most common disorders worldwide, which, if left untreated, results in a multitude of complications. Thus proper diagnostics, which includes identifying of secondary causes of dyslipidemia is crucial. Endocrine disorders are an important cause of secondary dyslipidemia. This paper aims to review the publications on lipoprotein alterations in endocrine disorders from the past two years and provide an overview of the recent discoveries in this dynamically developing and large field. Significant changes in lipoprotein serum concentrations are present in most endocrinological diseases and can be modified with proper treatment. Some lipoproteins have also been proposed as markers in some endocrine diseases, e.g., thyroid carcinoma. From the scope of endocrine disorders, the largest number of studies explored the lipoprotein changes in polycystic ovary syndrome and in women during the menopausal and peri-menopausal period. Even though the association of thyroid disorders with dyslipidemia is already well studied, new research has delivered some exciting findings about lipoprotein alterations in euthyroid patients with either positive antithyroid peroxidase antibodies or reduced sensitivity to thyroid hormones. The problem of the adverse metabolic profile, including dyslipidemia in hypoprolactinemia has been recognized. Moreover, this review describes other significant discoveries encompassing lipoprotein alterations in disorders of the adrenals, thyroid, parathyroid glands, pituitary, and gonads. The up-to-date knowledge of the influence of endocrine disorders and hormonal changes on serum lipoproteins is prudent as it can significantly impact therapeutic decisions.

Standard therapy or additionally radioactive iodine (131I) therapy; which will stop the recurrence of glioblastoma multiforme (GBM)?

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. The average survival time for a patient diagnosed with GBM, using standard treatment methods, is several months. Authors of the article pose a direct question: Is it possible to treat GBM solely with radioactive iodine (¹³¹I) therapy without employing the sodium iodide symporter (NIS) gene? After all, NIS has been detected not only in the thyroid but also in various tumours. The main author of this article (A.C.), with the assistance of her colleagues (physicians and pharmacologists), underwent ¹³¹I therapy after prior iodine inhibition, resulting in approximately 30% reduction in tumour size as revealed by magnetic resonance imaging (MRI). Classical therapy for GBM encompasses neurosurgery, conventional radiotherapy, and chemotherapy (e.g. temozolomide). Currently, tyrosine kinase inhibitors (imatinib, sunitinib, and sorafenib) are being used. Additionally, novel drugs such as crizotinib, entrectinib, or larotrectinib are being applied. Recently, personalised multimodal immunotherapy (IMI) based on anti-tumour vaccines derived from oncolytic viruses has been developed, concomitant with the advancement of cellular and molecular immunology. Thus, ¹³¹I therapy has been successfully employed for the first time in the case of GBM recurrence.

Are Twin Pregnancies at Higher Risk for Iron and Calcium Deficiency than Singleton Pregnancies?

The aim of this study was to compare the iron and calcium status in singleton and twin pregnancies and to assess whether there is an increased risk for iron and calcium deficiency in twin gestation. The study included 105 singleton and 9 twin pregnancies at or above 35 weeks of gestation. Information on prenatal supplementation with iron or calcium was acquired, and adverse perinatal outcomes were recorded. Biosamples from all 114 mothers and 73 newborns (61 singleton and 12 twin newborns) were finally analyzed. Total iron and calcium concentrations in serum were measured through total reflection X-ray fluorescence analysis. The results indicated no significant differences in maternal serum iron and calcium concentrations between singleton and twin pregnancies. Similarly, iron and calcium concentrations in newborn umbilical cord serum samples were not different between singleton and twin pregnancies. The comparison of total iron and calcium between mothers and umbilical cord serum indicated significantly lower concentrations in the mothers, with the differences being not homogenous but rather pair-specific. A significant positive correlation between maternal serum and umbilical cord serum calcium concentration was noticed. Prenatal iron supplementation was associated with higher iron concentrations in both mothers and newborns, supporting the efficiency of supplementation and the quality of the study methods. Collectively, the data indicate no significant differences in serum iron and calcium concentrations with regard to singleton or twin pregnancies and the efficiency of iron supplementation during pregnancy for increasing iron status.

Iodine deficiency and real-life supplementation ineffectiveness in Polish pregnant women and its impact on thyroid metabolism.

Introduction: Iodine is a pivotal component of thyroid hormones, and its deficiency leads to negative pregnancy outcomes. Therefore, during gestation, additional iodine supplementation is recommended. Objectives: By evaluating a group of women from western Poland, the study updated on iodine status during pregnancy and the effectiveness of iodine supplementation in relation to the maternal and neonatal thyroid function. Patients and methods: A total of 91 women were recruited before the delivery between 2019 and 2021. During the medical interview, the patients declared their dietary supplements intake. Thyroid parameters (TSH, ft3, ft4, a-TPO, a-Tg, and TRAb) were measured in the serum of mothers and in the cord blood of newborns after birth. Urinary iodine concentration (UIC) and urine/creatinine (UIC/crea) ratio were assessed in single urine samples using a validated high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Neonatal TSH screening from dried blood spot was analyzed. Results: Pregnant women showed a median (interquartile range) UIC of 106 (69-156) µg/liter and UIC/crea ratio of 104 (62-221) µg/g, whereas approximately 20% had UIC/crea below 50 µg/g, indicating iodine deficiency. The iodine supplementation ratio was 68%. No significant differences in UIC, UIC/crea and thyroid parameters were found between iodine supplemented and non-supplemented groups; however, the highest ioduria was detected when iodine was supplemented in addition to levothyroxine in comparison with both substances administered separately. Patients with UIC/crea within 150-249 µg/g demonstrated the lowest TSH and a-TPO levels. Screening TSH was above 5 mIU/liter in 6% of children. Conclusions: Despite the national salt iodization and the recommendation to supplement iodine during gestation, the status of the abovementioned microelement and real-life intake revealed the ineffectiveness of the current iodine-deficiency prophylaxis model in pregnancy.

Clinical, Biochemical, and Sonographic Factors Influencing Performance of Parathormone Washout Measurement vs. 99mTc-MIBI Scintigraphy in the Preoperative Diagnostics of Parathyroid Adenomas.

The purpose of the study was to assess the clinical, biochemical, and sonographic factors influencing the performance of parathormone washout measurement (PTHw) vs. MIBI in the preoperative localization of parathyroid adenoma (PA). The studied group consisted of 39 patients with primary or tertiary hyperparathyroidism. The measurement of PTH concentrations was performed using an electro-chemiluminescence immunoassay. Scintigraphic localization of PA was carried out using dual-tracer planar neck scintigraphy, using 74 MBq 99mTc-pertechnetate and 740 MBq of 99mTc-MIBI. MIBI was unambiguously positive in 74% of patients. Among patients with negative or inconclusive MIBI, 90% had a positive PTHw result. Among patients with negative PTHw, two out of three had a positive MIBI result. The PTHw of lesions <10 mm in their largest diameter yielded positive results in 95%, compared to 75% for MIBI. For lesions ≥10 mm in largest diameter, 88% were visualised using MIBI. In conclusion, PTHw is a highly effective, easy, quick, safe, and relatively cheap procedure which might be considered for PA localisation, especially in patients with lesions presenting typical ultrasound features and a size below 10 mm. MIBI remains a useful procedure in specialized centres, particularly for patients in whom PTHw failed, larger lesions, and in cases of the ectopic location of PA.

High IgG4 serum concentration is associated with active Graves orbitopathy.

Background: The aim of the study was to evaluate the differences in clinical profile, laboratory parameters, and ophthalmological signs, and symptoms between patients with high IgG4 Graves orbitopathy and patients with normal IgG4 Graves orbitopathy. Methods: This was a prospective observational study. We recruited adult patients with Graves Orbitopathy(GO) referred to our clinic for further diagnostics and treatment. Eventually, 60 patients with GO were enrolled in the study. All patients underwent ophthalmological assessment, magnetic resonance imaging (MRI) of the orbits, and laboratory tests, including IgG4 serum concentration measurement. High IgG4 GO was diagnosed if the IgG4 concentration exceeded 135 mg/dl. We used both the clinical activity score (CAS) and magnetic resonance imaging (MRI) to assess the activity of GO. Eventually, active GO was defined according to MRI results. Results: Among 60 GO patients, 15 (25%) patients had elevated IgG4 levels. Patients in the high IgG4 group had a higher prevalence of active GO by MRI than patients with normal IgG4 (100% vs. 64.44%, P=0.006). They also had a higher eosinophile count in peripheral blood, a lower bilirubin level, a more frequent lower eyelid retraction, and a lower prevalence of glaucoma. There were no statistically significant differences between the groups in CAS. Patients with active GO, had higher median IgG4 level [89.95 (55.48; 171.1) vs 43.45 (32.48; 49.68) mg/dl, P<0.001]. The receiver operating characteristic (ROC) analysis for IgG4 as a marker of active GO revealed the following results: AUC 0.848 for the cut-off value of 54.2 mg/dl, sensitivity 79.5%, specificity 87.5%, positive predictive value 94.6%, negative predictive value 59.1%. Conclusions: We demonstrated that IgG4 is a marker of GO activity. Certain differences in the clinical profile of patients with high IgG4 GO, and normal IgG4 GO were observed. More data is needed to establish whether patients with high IgG4 GO are GO patients with particularly active disease or actually represent a distinct clinical entity related to IgG4-Related Disease.

Follicular Thyroid Adenoma and Follicular Thyroid Carcinoma-A Common or Distinct Background? Loss of Heterozygosity in Comprehensive Microarray Study.

Pre- and postsurgical differentiation between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC) represents a significant diagnostic challenge. Furthermore, it remains unclear whether they share a common or distinct background and what the mechanisms underlying follicular thyroid lesions malignancy are. The study aimed to compare FTA and FTC by the comprehensive microarray and to identify recurrent regions of loss of heterozygosity (LOH). We analyzed formalin-fixed paraffin-embedded (FFPE) samples acquired from 32 Caucasian patients diagnosed with FTA (16) and FTC (16). We used the OncoScan™ microarray assay (Affymetrix, USA), using highly multiplexed molecular inversion probes for single nucleotide polymorphism (SNP). The total number of LOH was higher in FTC compared with FTA (18 vs. 15). The most common LOH present in 21 cases, in both FTA (10 cases) and FTC (11 cases), was 16p12.1, which encompasses many cancer-related genes, such as TP53, and was followed by 3p21.31. The only LOH present exclusively in FTA patients (56% vs. 0%) was 11p11.2-p11.12. The alteration which tended to be detected more often in FTC (6 vs. 1 in FTA) was 12q24.11-q24.13 overlapping FOXN4, MYL2, PTPN11 genes. FTA and FTC may share a common genetic background, even though differentiating rearrangements may also be detected.

[131I]I-MIBG-negative metastases of a recurrent sporadic paraganglioma in a female with achondroplasia.

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Cushing's syndrome is associated with altered adipokine profile.

Introduction: Adipokines are signaling molecules involved in the integration of metabolism. Changes in their concentrations were observed in obesity, metabolic syndrome, diabetes mellitus and cardiovascular diseases, as well as endocrine disorders. Cushing's syndrome is associated with metabolic dysregulation, but the significance of adipokines in this entity and related complications is largely unknown. The aim of our study was to determine the concentrations of adipokines: fetuin A, fatty acid binding protein 4 (FABP4) and retinol binding protein 4 (RBP4) in Cushing's syndrome and to assess their relation to established cardiovascular and diabetes risk markers. Methods: We examined 21 subjects with Cushing's syndrome and 24 healthy controls in a cross-sectional manner. Venous blood samples were analysed for adipokines, cortisol, adrenocorticotrophin, glucose, insulin, glycated haemoglobin (HbA1c), triglycerides, cholesterol fractions, thyrotropin and free thyroid hormones concentrations. Patients' body mass index (BMI) was evaluated, homeostatic model assessment-insulin resistance and Systematic Coronary Risk Evaluation (SCORE) were calculated. Results: We found that the concentration of fetuin A was lower, while FABP4 and RBP4 concentrations were higher in Cushing's syndrome compared to controls [156.4 ± 60.0 µg/ml vs 260.7 ± 49.6 µg/ml; 79.8 (35.2-156.1) ng/ml vs 27.9 (17.1-36.7) ng/ml and 34 (30-37.7) mg/l vs 25.8 (23.6-27.7) mg/l, respectively]. Fetuin A correlated inversely, while FABP4 and RBP4 positively, with the concentrations of urinary free cortisol and adrenocorticotrophin. Fetuin A was positively related to LDL-cholesterol, and negatively to SCORE and HbA1c. FABP4 was associated positively with BMI, HbA1c and triglycerides, while RBP4 correlated positively with triglycerides and systolic blood pressure. Conclusions: Adipokines' concentrations change in hypercortisolism. Further research is needed to ascertain whether adipokines are involved in the development of metabolic complications accompanying Cushing's syndrome or secondarily reflect metabolic dysregulation.

Thyroid diseases and fertility disorders - Guidelines of the Polish Society of Endocrinology [Choroby tarczycy a zaburzenia plodnosci - rekomendacje Polskiego Towarzystwa Endokrynologicznego].

Thyroid hormones influence female fertility, directly stimulating oocyte maturation and regulating prolactin and sex hormone binding globulin (SHBG) concentrations. Hyperthyroidism affects 1-2%, overt hypothyroidism 0.3%, and subclinical hypothyroidism up to 15% of women of childbearing age. Approximately 10% of euthyroid women have elevated concentrations of anti-thyroid peroxidase antibodies (aTPO) and/or anti-thyroglobulin (aTg) antibodies. Hypothyroidism can cause menstrual and ovulation disorders, and impact fertility. Studies carried out to date have not conclusively demonstrated that subclinical hypothyroidism or elevated aTPO/aTg concentrations make it harder to conceive, but they do increase the risk of pregnancy loss. Subclinical hypothyroidism and elevated aTPO/aTg concentrations without thyroid disorders are more common in polycystic ovary syndrome, premature ovarian insufficiency, and idiopathic infertility. Fertility problems are therefore an indication for screening for thyroid diseases (in females as well as in some males). A thyroid disorder diagnosed in subfertile couples should be treated appropriately, especially before attempting assisted reproductive techniques. These recommendations are intended as a guide for the management of thyroid diseases associated with infertility.

Selenium Status and Supplementation Effects in Pregnancy-A Study on Mother-Child Pairs from a Single-Center Cohort.

The demand for selenium (Se) increases during pregnancy since this element supports child growth, proper neuronal development and maternal thyroid function. The issue is particularly relevant for populations living in areas with a limited selenium supply, where many pregnant women opt for Se supplementation. The efficiency of this measure is unknown, although it seems vital in the prevention of severe Se deficiency. In order to evaluate this hypothesis, an observational study was conducted in Poland, where Se deficiency is prevalent. Pregnant women were invited to participate in the study and provided serum samples at the end of pregnancy (n = 115). Information on the supplemental intake of micronutrients was recorded in a face-to-face interview. In addition, serum samples were isolated from the cord blood of newborns at delivery (n = 112) and included in the analyses. Thyroid hormone status was evaluated by routine laboratory tests, and Se status was determined by total Se and selenoprotein P (SELENOP) concentrations and extracellular glutathione peroxidase (GPX3) activity. The three parameters of Se status correlated strongly within the group of mothers and within the group of newborns, with an additional significant correlation found among mother-child pairs. One-third of mothers reported additional Se intake, mainly as a component of multi-micronutrient supplements, at a mean (±SD) dosage of 42 ± 14 µg Se/day. Despite this regime, most of the women presented an insufficient Se status, with 79% of mothers displaying serum Se concentrations below 70 µg/L (indicating Se deficiency) and 22% showing levels below 45.9 µg/L (severe Se deficiency). The inadequate Se supply was also reflected in relatively low SELENOP concentrations and GPX3 activity. Neither total Se nor SELENOP or GPX3 levels were significantly higher in the group of mothers reporting the intake of supplements than in the non-supplementing group. Nevertheless, elevated SELENOP concentrations were observed in the subgroup receiving supplements with more than 55 µg/day. We conclude that the self-administered supplementation of small Se dosages was not sufficient to achieve replete Se status in the micronutrient scant area. However, the maternal Se deficit measured by either Se, SELENOP or GPX3 was transferred from mothers to the newborns, as the parameters correlated strongly in the mother-newborn pairs of samples. It is vital to re-evaluate the guidelines concerning pregnancy care and monitoring of micronutrient status during pregnancy, in particular in areas where deficiencies are present.

Lipid profile abnormalities associated with endocrine disorders.

Nearly 30% of patients with lipid profile abnormalities suffer from secondary dyslipidaemias. Endocrine disorders are one of the most important causes of dyslipidaemia. Dyslipidaemia can be observed in the pathologies of a variety of endocrine glands, including the thyroid, the pituitary, the adrenals, and the gonads. The most common endocrinopathy causing dyslipidaemia is hypothyroidism. In this paper, we review the lipid profile alterations observed in endocrinopathies. We describe changes in classic lipid profile parameters, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. However, we also focus on the influence of endocrine disorders on relatively new cardiovascular markers such as apolipoprotein B, apolipoprotein A1, and lipoprotein(a). While almost all endocrinopathies cause detrimental changes to the lipid profile, hyperthyroidism seems to be a disorder in which lowering of such parameters as total cholesterol, low-density cholesterol, and triglycerides can be observed. Comprehensive screening for endocrine disorders should always be included in the differential diagnostic process of secondary causes of dyslipidaemia. Early detection and treatment of endocrinopathy have a considerable impact on a patient's health. Proper treatment of those disorders plays a crucial role in modifying the cardiovascular risk and improving the lipid profile of those patients. Even though lipid-lowering therapy is usually still needed, in some cases restoration of hormonal balance might be sufficient to normalize the lipid profile abnormalities.

Summary of Meta-analyses of Studies Involving TIRADS Classifications (EU-TIRADS, ACR-TIRADS, and K-TIRADS) in Evaluating the Malignant Potential of Focal Lesions of The Thyroid Gland.

Numerous scientific societies around the world have published their TIRADS (Thyroid Imaging Reporting and Data System) classifications that evaluate the risk of malignancy of focal thyroid lesions, presenting different ultrasound features for each category and lesion size thresholds to determine eligibility for biopsy. The use of such risk estimation systems in focal thyroid lesions facilitates the reporting of thyroid ultrasound findings and improves the qualification of focal lesions for fine-needle aspiration biopsy (FNAB). In this publication, the three most popular TIRADS classifications, European - EU-TIRADS, Korean - K-TIRADS, and developed by the American Society of Radiology - ACR-TIRADS, are presented and discussed based on a literature review. The results of available head-to-head statistical analyses comparing the classifications are also presented. The advantage of the EU-TIRADS and K-TIRADS systems is that they include only the most important ultrasound features, so their application is not time-consuming, and the scores are easy to incorporate into clinical practice. ACR-TIRADS, unlike other scales, is based on a unique classification system and represents the most comprehensive classification. Each of the five categories of ultrasound features - morphology, echogenicity, shape, margins, microcalcifications - are evaluated and assigned a score from 0 to 3, with a higher score being associated with a higher risk of cancer. Based on the available data, the greatest benefit has been demonstrated for the ACR-TIRADS classification, which also has implications for minimising the number of unnecessary FNABs. However, limitations related to the heterogeneity of the groups analysed in the study, including differences in the populations studied, inclusion criteria, proportions of patients of either sexes, and the number of malignant lesions analysed, should also be taken into account.

Summary of Meta-analyses of Studies Considering Lesion Size Cut-off Thresholds for The Assessment of Eligibility for FNAB and Sonoelastography and Inter- and Intra-observer Agreement in Estimating the Malignant Potential of Focal Lesions of The Thyroid Gland.

Thyroid cancer is a tumour with a steadily increasing incidence. It accounts for 7% to 15% of focal lesions detected by ultrasound, depending on age, gender and other factors affecting its occurrence. Fine-needle aspiration biopsy is an essential method to establish the diagnosis but, in view of its limitations, sonoelastography is seen as a non-invasive technique useful in differentiating the nature of lesions and monitoring them after fine-needle aspiration biopsy. This paper presents a literature review on the role of both sonoelastographic techniques (relative strain sonoelastography, shear wave sonoelastography) to assess the deformability of focal thyroid lesions. Ultrasound examination is a relatively subjective method of thyroid imaging, depending on the skills of the examiner, the experience of the centre, and the quality of equipment used. As a consequence, there are inconsistencies between the results obtained by different examiners (inter-observer variability) and by the same examiner (intra-observer variability). In this paper, the authors present a review of the literature on inter-observer and intra-observer variability in the assessment of individual features of ultrasound imaging of focal lesions in the thyroid. In addition, the authors report on an analysis of cut-off thresholds for the size of lesions constituting the basis for fine-needle aspiration biopsy eligibility assessment. The need to diagnose carcinomas up to 10 mm in diameter is highlighted, however a more liberal approach is recommended in terms of indications for biopsy in lesions associated with a low risk of malignancy, where, based on consultations with patients, active ultrasound surveillance might even be considered.

Interplay between Fatty Acid Binding Protein 4, Fetuin-A, Retinol Binding Protein 4 and Thyroid Function in Metabolic Dysregulation.

Signalling between the tissues integrating synthesis, transformation and utilization of energy substrates and their regulatory hormonal axes play a substantial role in the development of metabolic disorders. Interactions between cytokines, particularly liver derived hepatokines and adipokines, secreted from adipose tissue, constitute one of major areas of current research devoted to metabolic dysregulation. The thyroid exerts crucial influence on the maintenance of basal metabolic rate, thermogenesis, carbohydrate and lipid metabolism, while its dysfunction promotes the development of metabolic disorders. In this review, we discuss the interplay between three adipokines: fatty acid binding protein type 4, fetuin-A, retinol binding protein type 4 and thyroid hormones, that shed a new light onto mechanisms underlying atherosclerosis, cardiovascular complications, obesity, insulin resistance and diabetes accompanying thyroid dysfunction. Furthermore, we summarize clinical findings on those cytokines in the course of thyroid disorders.

NKX2-5 Variant in Two Siblings with Thyroid Hemiagenesis.

Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis. The aim of the study was to reveal genetic factors responsible for thyroid maldevelopment in two siblings with THA. None of the family members presented with congenital heart defect. The samples were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Enrichment Kit, San Diego, CA 92121, USA). An ultra-rare variant c.839C>T (p.Pro280Leu) in NKX2-5 gene (NM_004387.4) was identified in both affected children and an unaffected father. In the mother, the variant was not present. This variant is reported in population databases with 0.0000655 MAF (GnomAD v3, dbSNP rs761596254). The affected amino acid position is moderately conserved (positive scores in PhyloP: 1.364 and phastCons: 0.398). Functional prediction algorithms showed deleterious impact (dbNSFP v4.1, FATHMM, SIFT) or benign (CADD, PolyPhen-2, Mutation Assessor). According to ACMG criteria, variant is classified as having uncertain clinical significance. For the first time, NKX2-5 gene variants were found in two siblings with THA, providing evidence for its potential contribution to the pathogenesis of this type of thyroid dysgenesis. The presence of the variant in an unaffected parent, carrier of p.Pro280Leu variant, suggests potential contribution of yet unidentified additional factors determining the final penetrance and expression.