Ante Punda

Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis

Abstract Hashimotos thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development. A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study. Diagnosis of HT cases was based on clinical examination, measurement of thyroid hormones (TSH and fT4) and antibodies (TgAb, TPOAb) and ultrasound examination. We selected and genotyped 14 known TPOAb-associated genetic variants. Case–control logistic regression model was used to test the association of selected genetic variants with HT. Additionally, we tested association of the same genetic variants with thyroid related quantitative traits (TPOAb levels, TgAb levels and thyroid gland volume) using linear regression. Three genetic variants showed nominal association with HT; rs10774625 in ATXN2 gene (p = 0.0149, OR = 0.73, CI = 0.56–0.94), rs7171171 near RASGRP1 gene (p = 0.0356, OR = 1.4, CI = 1.02–1.92) and rs11675434 in TPO gene (p = 0.041, OR = 1.31, CI = 1.01–1.69). Two of these SNPs (rs1077462, rs11675434) also showed association with TPOAb levels (p = 0.043, β = −0.39; p = 0.042, β = 0.40, respectively) and one (rs7171171) was associated with thyroid gland volume (p = 0.0226, β = −0.21). Our findings suggest that variants inside or near TPO, ATXN2 and RASGRP1 genes are associated with HT. Identified loci are novel to HT and represent good basis for further exploration of HT susceptibility.

Association of Established Thyroid-stimulating Hormone and Free Thyroxine Genetic Variants with Hashimoto’s Thyroiditis

ABSTRACT Hashimoto’s thyroiditis (HT), the most frequent autoimmune thyroid disease (AITD), is characterized by chronic inflammation of the thyroid gland that usually results in hypothyroidism. Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels are used as clinical determinants of thyroid function. The main aim of this study was to explore the association of established TSH and FT4 genetic variants with HT. We performed a case–control analysis using 23 genetic markers in 200 HT patients and 304 controls. Additionally, we tested the association of selected variants with several thyroid-related quantitative traits in HT cases only. Two genetic variants showed nominal association with HT: rs11935941 near NR3C2 gene (p = 0.0034, OR = 0.57, 95% CI = 0.39–0.83) and rs1537424 near MBIP gene (p = 0.0169, OR = 0.72, 95% CI = 0.55–0.94). Additionally, three SNPs showed nominal association with thyroglobulin antibody (TgAb) levels: rs4804416 in INSR gene (p = 0.0073, β = −0.51), rs6435953 near IGFBP5 gene (p = 0.0081, β = 0.75), and rs1537424 near MBIP gene (p = 0.0117, β = 0.49). GLIS3 genetic variant rs10974423 showed nominal association with thyroid peroxidase antibody (TPOAb) levels (p = 0.0465, β = −0.56) and NRG1 genetic variant rs7825175 was nominally associated with thyroid gland volume (p = 0.0272, β = −0.18). All detected loci were previously related to thyroid function or pathology. Findings from our study suggest biological relevance of NR3C2 and MBIP with HT, although these loci require additional confirmation in a larger replication study.

Association of established hypothyroidism-associated genetic variants with Hashimoto’s thyroiditis

PurposeHashimoto’s thyroiditis (HT) as a chronic autoimmune disease of the thyroid gland is the most common cause of hypothyroidism. Since HT and hypothyroidism are closely related, the main aim of this study was to explore the association of established hypothyroidism single-nucleotide polymorphisms (SNPs) with HT.MethodsThe case–control dataset included 200 HT cases and 304 controls. Diagnosis of HT cases was based on clinical examination, measurement of thyroid antibodies (TgAb, TPOAb), hormones (TSH and FT4) and ultrasound examination. We genotyped and analysed 11 known hypothyroidism-associated genetic variants. Case–control association analysis was performed in order to test each SNP for the association with HT using logistic regression model. Additionally, each SNP was tested for the association with thyroid-related quantitative traits (TPOAb levels, TgAb levels and thyroid volume) in HT cases only using linear regression.ResultsWe identified two genetic variants nominally associated with HT rs3184504 in SH2B3 gene (P = 0.0135, OR = 0.74, 95% CI = 0.57–0.95) and rs4704397 in PDE8B gene (P = 0.0383, OR = 1.32, 95% CI = 1.01–1.74). The SH2B3 genetic variant also showed nominal association with TPOAb levels (P = 0.0163, β = −0.46) and rs4979402 inside DFNB31 gene was nominally associated with TgAb levels (P = 0.0443, β = 0.41).ConclusionsSH2B3 gene has previously been associated with susceptibility to several autoimmune diseases, whereas PDE8B has been associated with TSH levels and suggested to modulate thyroid physiology that may influence the manifestation of thyroid disease. Identified loci are novel and biologically plausible candidates for HT development and represent good basis for further exploration of HT susceptibility.

Izražajnost ciklina D1, RET i p27 u papilarnom mikrokarcinomu štitne žlijezde

Th e aim of the study was to determine the influence of RET, p27 and cyclin D1 on regional lymph node metastases in papillary microcarcinoma. The analysis included 70 patients with papillary thyroid microcarcinoma that underwent surgery at Split University Hospital Center between 1999 and 2001. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue by the RET, p27 and cyclin D1 antibodies. Quantification was based on the intensity and distribution of nuclear staining, dividing tumors into those that showed expression (expressors) and those that showed no expression (non-expressors). Univariate analysis using χ²-test and Fisher exact test was performed with the level of statistical significance set at p<0.05. There was no statistically significant difference in the incidence of metastases according to the expression or non-expression of RET mutation (χ²-test: p=0.459; Fisher exact test: p=0.672). Among 25 cases with cyclin D1 expression, 6 had metastases, whereas only 2 of 45 cases with no cyclin D expression had metastases (χ²-test: p=0.014; Fisher exact test: p=0.021), indicating that the expression of cyclin D1 is not crucial for the development of metastases in lymph nodes. In contrast, analysis of p27 expression showed it to be significantly associated with lymph node metastasis because 3 of 45 patients with p27 expression had metastases, indicating a statistically significant correlation between p27 expression and lymph node metastases (χ²-test: p=0.093; Fisher exact test: p=0.124). This study confirmed the importance of the evaluation of RET, p27 and cyclin D1 expression and demonstrated the validity of their application in the assessment of microcarcinoma behavior.

Are we estimating the adverse effects of shock-wave lithotripsy on a faulty scale?

The adverse effect of shock-wave lithotripsy (SWL) for renal stones on blood pressure is currently defined as its post-treatment increase. On the contrary, we hypothesize that even mild, unilateral renal obstruction initiates an increase in blood pressure. Then, in absence of treatment-induced injury, the stone removal should decrease the blood pressure. We derived the formula to assess the expected change in the mean arterial pressure following relief of renal obstruction without affecting the kidney functions. The predictions were well replicated in the cohort of patients with renal stone treated with parenchyma-saving open surgery, with 6.4 mmHg decrease at 3 months. On the contrary, in SWL cohort, instead of the expected 4.7 mmHg decrease, the blood pressure was unchanged. In conclusion, the absence of decrease in blood pressure is a very common adverse effect of SWL, leading to an epidemiologically significant increase in the risk of arterial vascular events.

Dual ectopic thyroid gland: sonography and scintigraphy of lingual and sublingual thyroid.

Dual ectopic lingual and sublingual thyroid gland is an extraordinarily rare condition. We present 1 patient with subclinical hypothyroidism. The clinical examination revealed that the thyroid gland was not palpable in its usual cervical location, whereas ultrasonography confirmed an empty thyroid bed without any ectopic thyroid tissue in the rest of the neck. The final diagnosis of dual ectopic lingual and sublingual thyroid was established by ultrasound examination through the mouth floor and confirmed by scintigraphy and CT thereafter.

Preoperative Tc-99m-pertechnetate scan visualization of gross neck metastases from microcarcinoma papillare and another papillary carcinoma of tall cell variant scintigraphically presented like small warm nodule in Graves disease patient.

Purpose: Preoperative scintigraphic visualization of metastases from well-differentiated thyroid microcarcinoma in patients with Graves disease is extremely rare, as is the scintigraphic visualization of poorly differentiated thyroid carcinoma as a warm nodule. We present a patient with Graves disease and both of these rare entities. Case Report: A 47-year-old woman complained of a growing left-side neck mass and symptoms of thyrotoxicosis. On clinical examination, the thyroid was palpable without discernible nodularity, while the left side of the neck was occupied by 3 gross, painless nodules. She also had signs of thyrotoxicosis and biochemical parameters of Graves hyperthyroidism. Ultrasound examination showed moderately hypoechogenic thyroid with a small hypoechogenic nodule in the upper pole of the left lobe and 3 gross, almost normoechogenic nodules on the left side of the neck. On Tc-99m-pertechnetate pinhole scintigraphy there was a small, warm nodule in the upper pole of the left lobe and 3 gross metastatic nodules on the left side of the neck. Fine needle aspiration of the neck nodules was consistent with metastases from thyroid papillary carcinoma. After thyrostatic preparation a total thyroidectomy with left modified radical neck dissection was done. Results and Conclusion: Histopathologic examination disclosed 2 carcinomas in the left thyroid lobe. One of them was a tall cell variant of papillary carcinoma in the upper pole of the left lobe that measured 5 mm and corresponded to the small warm nodule, and the second one was a classic form of papillary microcarcinoma that measured 2 mm. Metastases accrued from the classic form of papillary microcarcinoma. Although the patient had 2 thyroid carcinomas, one with metastases and the other of more aggressive form, which is consistent with advanced stage and aggressiveness, she is now disease-free, 4 years after the operation and radioiodine ablation.

Determinants of 131I radiation dose to thyroid follicular cells

We argued that modeling the thyroid as composed of identical follicles, packed as inside the cubes that are aligned side to side is unrealistic since this leaves too much space between diagonal neighbors and in reality these spaces are occupied by relatively small follicles. This assumption leads to underestimation of self-absorption of 131I radiation in coloidal lumens of the thyroid follicles. We conclude that the degree of intrathyroidal inhomogeneity of 131I beta radiation dose may be larger than estimated by Hindie et al. due to close packing of follicles, which is especially important in cases of relatively large follicles.

Evaluation of Correlations Between Food-Specific Antibodies and Clinical Aspects of Hashimoto’s Thyroiditis

Abstract Objective: We have comprehensively evaluated an immunologic response to food antigens, mediated by immunoglobulin G (IgG) antibodies, on clinical aspects of Hashimoto’s thyroiditis (HT). Methods: IgG antibodies to 125 food antigens were measured in serum samples of 74 HT patients and 245 controls using microarray-based enzyme-linked immunosorbent assay (ELISA) test. We analyzed differences in IgG levels between two groups and evaluated correlations between food-specific IgG levels and HT-related clinical phenotypes (thyroid hormones/antibodies, symptoms of hypothyroidism, measures of body size and blood pressure) and food consumption in HT patients. Results: We observed increased IgG levels to 12 different food antigens in either HT cases or controls, of which plum-specific IgG antibodies were significantly higher (p = 1.70 × 10−8), and almond-specific IgG antibodies were significantly lower (p = 8.11 × 10−5) in HT patients in comparison to controls, suggesting their possible roles in HT etiology or symptomatology. There was no significant correlation between any of 12 increased food-specific IgG antibodies, along with gluten-specific IgG, with clinically important phenotypes, such as thyroid hormones/antibodies or symptoms. Among other tested correlations, the most interesting is the negative correlation between coffee and tea combined IgG levels and number of symptoms, suggesting possible beneficial effect of tea and coffee on disease symptoms. We also found that food consumption is not correlated with IgG levels. Conclusions: Distribution of food-specific IgG antibodies is comparable between HT patients and controls, with the exception of plum and almond. There is no evidence that increased food-specific IgG antibodies are associated with clinical aspects of HT. Clarification of biology behind formation of these antibodies is needed.

Thyroglobulin Antibodies are Associated with Symptom Burden in Patients with Hashimoto’s Thyroiditis: A Cross-Sectional Study

ABSTRACT Background: Hashimoto’s thyroiditis (HT) is the most common form of autoimmune thyroid disorders characterized by lower production of thyroid hormones and positivity to autoantibodies to thyroglobulin (TgAb) and/or thyroid peroxidase (TPOAb). We performed a comprehensive phenotypic characterization of patients with HT, with specific focus on thyroid autoimmunity, to get better understanding of disease manifestation. Methods: We collected information on thyroid-specific phenotypes (TSH, T3, T4, fT4, TgAb, TPOAb, thyroid volume) and other clinical phenotypes (age, body surface area, number of hypothyroidism symptoms, blood pressure) from 290 patients with HT without levothyroxine (LT4) therapy with the aim to test for correlations between thyroid-specific and clinical phenotypes. Results: Our key and novel finding is the existence of significant positive correlation between TgAb levels and the number of symptoms (r = 0.25, p = 0.0001) in HT patients without LT4 therapy that remained significant after adjustment for TPOAb, T3, TSH levels and thyroid volume (β = 0.66, SE = 0.3, p = 0.0299). Increased TgAb levels are significantly associated with fragile hair (p = 0.0043), face edema (p = 0.0061), edema of the eyes (p = 0.0293) and harsh voice (p = 0.0349). Conclusions: Elevated TgAb levels are associated with symptom burden in HT patients, suggesting a role of thyroid autoimmunity in clinical manifestations of HT. Based on these results, we recommend screening for TgAb antibodies in HT patients with symptom burden. We also suggest that further work on understandings of symptoms appearance due to their autoimmune or hypothyroid causation is needed.