Anti-C1q autoantibodies are linked to autoimmune thyroid disorders in pregnant women.

Anti-C1q antibodies (anti-C1q) have been implicated in the pathogenesis of autoimmune diseases, including autoimmune thyroid disorders (AITD). The aim of this study was to evaluate the association between anti-C1q and thyroid function in pregnancy-associated AITD. In 96 pregnant women screened positive for AITD (thyroid dysfunction and/or antibodies against thyroperoxidase - TPOAb), anti-C1q were measured during the 9-11th gestational week and after delivery (median 16 months after delivery), and compared to the corresponding serum levels of thyroid hormones. As controls, 80 healthy pregnant women, 72 non-pregnant AITD patients and 72 blood donors were included. In the non-pregnant AITD group, two serum samples ≥ 6 months apart were analysed. Compared to blood donors, anti-C1q levels were substantially higher in all pregnant women analysed. In pregnancy, anti-C1q levels were higher in the TPOAb-positive women than in controls (37 versus 17·5%, P < 0·0001). Anti-C1q-positive pregnant women screened positive for AITD had higher thyroid-stimulating hormone (TSH) levels than anti-C1q-negative women (2·41 versus 1·94 mU/l, P = 0·01), and TSH correlated positively with anti-C1q (r = 0·226, P = 0·045) in the TPOAb-positive women. After delivery, serum levels of anti-C1q decreased in the positively screened TPOAb-negative women (8·8 versus 5·9 U/l, P = 0·002), but not in the TPOAb-positive ones, and they no longer correlated with TSH. Anti-C1q antibody levels increase during pregnancy in general and even more in the context of AITD, where they correlate with thyroid stimulating hormone levels.

Thyroid nodules: pathophysiological insight on oncogenesis and novel diagnostic techniques.

Thyroid nodules are a very frequent pathology among common population. Despite the vast majority of them are of benign origin, the incidence of thyroid cancer is currently rather rising. Although there are several risk factors of thyroid cancer and several clinical, ultrasound, biochemical and molecular diagnostic markers, the exact mechanisms of thyroid oncogenesis and the linkage between thyroid nodule ultrasound appearance and its biological character remain unclear. While ionizing radiation is the only one well-known risk factor for thyroid cancer, the significance of some others remains unclear. The aim of our review was to discuss some not completely known pathophysiological mechanisms involved in thyroid oncogenesis as hypothyroidism, mutations of genes regulating cell proliferation, thyroid autoimmunity and pregnancy and to describe pathophysiological background of some ultrasound markers of thyroid cancer (size, echogenicity, vascularization, calcifications and stiffness). Better knowledge in this field is crucial for development of novel diagnostic techniques and therapeutic approaches. For example, the analysis of BRAF, RAS and other mutations in cytological samples may help to distinction between follicular thyroid carcinoma and follicular thyroid adenoma and may significantly decrease the number of unnecessary surgery among patients with thyroid nodules. Alternatively, the different malign cells growth, angiogenesis, destructions of thyroid follicles, reparative changes, growth retardation, fibrosis and increased interstitial fluid pressure implicate the typical ultrasound appearance of papillary thyroid cancer (hypoechogenicity, irregular vascularization, microcalcifications, stiffness) which is essential to catch the suspicious nodules on the basis of their ultrasound appearance among large amount of benign nodules.

Low prevalence of clinically high-risk women and pathological thyroid ultrasound among pregnant women positive in universal screening for thyroid disorders.

BACKGROUND: It is controversial whether screening program for thyroid disorders in pregnancy should be universal or targeted case-finding. To evaluate the relationship between history, laboratory parameters and thyroid ultrasound (TUS) in pregnant women positive in universal screening. SUBJECTS AND METHODS: The screening included investigation of serum TSH (thyroid stimulating hormone) and TPOAb (antithyroperoxidase antibodies) in 5,520 unselected pregnant women in the 9-11th gestational week. In 822 the screening was positive: abnormal TSH (> 3.67 or < 0.06 mIU/l) and/or positive TPOAb (> 143 kIU/l). 200 consecutive women with positive screening were included it the study. RESULTS: 41 women (21%) had transient gestational hyperthyroidism (TGH) and 159 (79%) had a thyroid pathology: 10 (5%) overt hypothyroidism; 76 (38%) subclinical hypothyroidism, 7 (3.5%) overt hyperthyroidism and 66 (33%) euthyroid TPOAb positivity. After exclusion of TGH, only 74/159 (47%) women were classified as high-risk for thyroid disease according to their history. There were no significant clinical and laboratory differences between the high- vs. low-risk women, except for higher proportion of FT4<75th percentile (P=0.008) and larger thyroid volume in the high-risk group (P=0.04). Finally, only 66/126 (52%) of TPOAb-positive pregnant women had autoimmune pattern in TUS in comparison with 41/49 (84%) TPOAb-positive non-pregnant control women of comparable age (P<0.001). CONCLUSIONS: Less than half of the positively screened pregnant women can be classified as high-risk and almost half of them had not autoimmune pattern in TUS. High- and low-risk pregnant women have similar clinical and laboratory characteristics.

[The thyroid gland-running the show behind the scenes--1st part]. / Sedá eminence v medicíne--stítná zláza: 1. cást.

Diseases of the thyroid gland involve many areas of medicine. The impairment of thyroid gland function affects 4-5% of younger population and more than 10% of the senior population (in ratio of 6-8 women to every man). Thyroid gland defects are mostly of autoimmune origin. The development of various kind of autoimmune disease in specific cases can be anticipatedd or diagnosed in their early stages. This article emphasizes certain connections of autoimmune thyroid gland diseases with diabetology, dermatology, and .. hematology.

The relationship between thyroid function, serum monokine induced by interferon gamma and soluble interleukin-2 receptor in thyroid autoimmune diseases.

Interactions between cytokines play an important role in the development of thyroid autoimmunity. Using enzyme-linked immunosorbent assay we investigated serum concentrations of soluble interleukin-2 receptor (sIL-2R), interferon-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, CD30, monokine induced by interferon-gamma (MIG), cytotoxic T lymphocyte antigen-4 and markers of apoptosis decoy receptor 3 and Bcl-2 in 28 patients with hyperthyroid Graves' disease (GD), 24 patients with untreated Hashimoto's thyroiditis (HT) and 15 healthy controls. TNF-alpha, IL-10 and sIL-2R were higher in GD compared with HT and controls (TNF-alpha: 8.79 in GD versus 2.54 pg/ml in HT, P = 0.01; IL-10: 10.00 versus 3.10 versus 3.10 pg/ml, P(1) < 0.001, P(2) = 0.005; sIL-2R: 1.26 versus 0.64 versus 0.46 ng/ml, P < 0.001). MIG and CD30 were higher in HT compared with controls (649.22 +/- 262.55 versus 312.95 +/- 143.35 pg/ml, P = 0.037, 6.57 +/- 2.35 versus 3.03 +/- 1.04 U/ml, P = 0.036 respectively). In GD sIL-2R decreased when the euthyroid state was achieved (1.31 +/- 0.64 versus 0.260 +/- 0.11, n = 12, P < 0.001). sIL-2R correlated positively with free thyroxine (FT4) (R = 0.521, P = 0.000) and negatively with thyroid stimulating hormone (TSH) (R = -0.472, P = 0.00132). MIG correlated negatively with FT4 (R = -0.573, P = 0.00234) and positively with TSH (R = 0.462, P = 0.0179). The results suggest that serum concentrations of sIL-2R and MIG are related to thyroid function rather than to activation of autoimmunity.

Autoantibodies against complement C1q correlate with the thyroid function in patients with autoimmune thyroid disease.

Autoantibodies against complement C1q (anti-C1q) have been well described in patients with systemic lupus erythematosus, where they correlate with the occurrence of severe lupus nephritis. However, data on anti-C1q in organ-specific autoimmune diseases are scarce. In order to determine the prevalence of anti-C1q in patients with autoimmune thyroid disorders (AITD) and a possible association with thyroid function, we measured prospectively anti-C1q in 23 patients with Graves' disease (GD) and 52 patients with Hashimoto's thyroiditis (HT). Anti-C1q levels were correlated with parameters of thyroid function and autoantibodies against thyroperoxidase, thyroglobulin and thyroid stimulating hormone (TSH) receptor. Twenty-one patients with multi-nodular goitre and 72 normal blood donors served as controls. We found elevated concentrations of anti-C1q more frequently in patients with AITD than in controls: seven of 23 (30%) patients with GD and 11 of 52 (21%) patients with HT, compared with one of 21 (5%) patients with multi-nodular goitre and six of 72 (8%) normal controls. Anti-C1q levels did not correlate with thyroid autoantibodies. However, in GD absolute levels of anti-C1q correlated negatively with TSH and positively with free thyroxine (FT4) and triiodothyronine (FT3). In contrast, in HT, anti-C1q correlated positively with TSH levels. No correlation between TSH and thyroid autoantibodies was found. In conclusion, we found an increased prevalence of anti-C1q in patients with AITD and their levels correlated with the thyroid function in both GD and HT. This correlation seems to be independent of thyroid autoantibodies. Therefore, anti-C1q might point to a pathogenic mechanism involved in the development of AITD that is independent of classical thyroid autoantibodies.

[The importance of screening for thyroid dysfunction during pregnancy: pathophysiological background and practical implications]. / Význam skríninku tyreopatií u tehotných zen: patofyziologický podklad a praktické aspekty.

Thyroid hormones are essential both for the physiological course of pregnancy and for the optimal differentiation of the embryonic tissues and foetal brain development. Overt and subclinical hypothyroidism constitutes a frequent cause of infertility, it carries along an increased risk of spontaneous abortion and premature birth, and it may lead to an impaired foetal brain development resulting in a worse psychoneurological outcome in the progeny. The repeatedly documented high prevalence of thyroid diseases in pregnancy warrants a realization of systematic screening for thyroid dysfunction during early stage of pregnancy or better before conception whenever possible. The Czech Endocrine Society attempts to implement such a systematic screening in the Czech Republic, although the particular aspects of the screening are still discussed.

[Thyroid diseases, dyslipidemia and cardiovascular risk]. / Tyreopatie, dyslipidemie a kardiovaskulární rizika.

By affecting the metabolism of lipids, hypothyroidism accelerates the process of atherogenesis and increases cardiovascular risk. In manifest hypothyroidism the number of LDL receptors in the liver decreases and there is an increase in levels of overall cholesterol, LDL-cholesterol and apolipoprotein B in the blood. Levels of HDL particles remain normal or even rise slightly as a result of reduced activity of the Cholesterol ester transfer protein (CETP) and hepatic lipase. This leads to a reduction in the transport of cholesterol esters from HDL-(2) to VLDL and IDL. Subclinical hypothyroidism also has a negative effect on the lipid profile, but is more likely to lead to pro-atherogenic changes in the proportion of lipid particles than to a reduction in overall cholesterol. Subclinical hypothyroidism leads to the manifestation of certain risk factors of atherosclerosis. Although studies of overall mortality and cardiovascular morbidity have not been completely unanimous in their conclusions, increased cardiovascular risk can be considered likely in subclinical hypothyroidism. It remains an open question whether the treatment of subclinical hypothyroidism with levothyroxine. At present we have only indirect proof from studies that assessed the effect of levothyroxine treatment on risk factors of atherosclerosis. Starting treatment with lipid lowering agents (especially statins) for (sub)clinical hypothyroidism is extremely risky though due to the risk of the development or worsening of myopathy, which is a further cogent argument for the active screening and treatment of(sub)clinical hypothyroidism for all patients with dyslipidemia.

[The role of complement in autoimmune thyroid disorders]. / Vztah komplementu a autoimunitnich onemocnení stítné zlázy.

The complement system is a crucial part of the innate immune system. In systemic autoimmune disorders, its effects tend to be protective. On the contrary, in the autoimmune thyroid disorders (AIT) the complement actively attacks thyrocytes, which express a number of complement components as well as complement inhibitory molecules. According to the experimental studies different ways of complement activation might occur in the thyroid tissue. All ensue via the classical pathway that is started either by immune complexes containing complement activating autoantibodies against thyroid autoantigens, or by direct binding of C4 to the molecule of thyroid peroxidase (TPO); or by direct complement activation by reactive oxygen radicals. Thyrocytes are relatively resistant to the complement attack. However, sublethaly injured thyrocytes release proinflammatory cytokines and reactive oxygen radicals and thus promote the inflammatory process in the thyroid. So far, the clinical significance of the complement in the thyroid has been studied only in postpartum thyroiditis. The exact role of complement in the pathogenesis of AIT remains to be elucidated.

[Thyroid malfunction in pregnancy]. / Poruchy stítné zlázy v tehotenství--souhrn výsledku nezávislých studií.

CONTEXT: Over the past 15 years there have been discussions about advisability of thyroid gland function screening in pregnant women, recommendations are being defined at least ten years. The reasoning is based on fact, that not only complications in pregnancy or after delivery were proved, but also problems in mental development of children, the mothers of which suffered impairement of thyroid gland function. OBJECTIVE: We are presenting thyroid parametres TSH, TPOAb, in part also FT4, in 1st trimestr of pregnancy. Examination were performed in three Czech centers and included 4500 pregnant women. RESULTS: The TSH suppression was proved in 3.6%, mostly without link to thyroid gland function, the increased TSH concentration in connection with (sub)clinical hypothyroidism was found in 5% of women, the low FT4 concentration under 9.8 pmol/I, which endangers fetal intellectual development, was found in 17 of 120 investigated woman with TSH higher than 4.00 mU/l. Thus exists a risk of minimum 1 to 170 in all group, that insufficient fetal brain development occurs. TPOAb were positive in 15% women. Increased risk of thyroid malfunction progress in women with positive TPOAb in pregnancy (and up to 50% after delivery) was repeatedly proved. CONCLUSION: Based on the results (5% hypothyroidism, 15% with TPOAb pregnant women) we would like to commence discussion concerning screening in pregnancy in CR, preferably before the planned conception, or at latest just before the actual pregnancy. Systematic cooperation among gynecologists, endocrinologists, general practitioners and laboratories should be established to solve the problems, as laboratory normal range, pregnancy timing for examination, unification of diagnostic procedures and correct interpretation of the results.

[Contemporary theories concerning chronic lymphocytic thyroiditis]. / Soucasné názory na vznik chronické lymfocytární tyroiditidy.

Review of contemporary theories and hypothesis concerning chronic lymphycytic thyroiditis is presented. The origin of the disease depends on various factors: genetics, immunological conditions, cytokins, iodine supply, hormones, TSH and its receptors, apoptosis activation and inhibition. The environmental conditions include goitrogens, selenium, polutants and other still unknown factors. Whether the disease will be accompanied with goiter, nodules or thyroid atrophy with functional disorder is still not evident.

[Thyroid diseases in oncological patients]. / Onemocnení stítné zlázy u onkologicky nemocných.

The authors review the most common situation concerning oncological patients with concomitant thyroid disease. In case of unknown origin of metastasis and nodular goitre the ultrasound examination with fine needle aspiration biopsy confirms or excludes the thyroid origin. The euthyroid sick syndrome is often diagnosed in oncological patient as a consequence of oncological disease and it doesn't mean hypothyroidism. If oncological patients prove to have a thyroid functional failure the endocrinologist must correct the function as fast as possible to enable oncological treatment. There is no evidence that chemotherapy can influence the thyroid function, but radiotherapy can cause thyroiditis with later hypofunction. The interferon therapy causes thyroid dysfunction in 10% of patients and the recommendation to examine not only TSH and FT4 but also thyroid antibodies is warranted. Lymphoma of the thyroid gland occurs most often on the basis of lymphocytic thyroiditis and lymphocytic thyroiditis may be a risk factor for papillary carcinoma of the thyroid as well. Women with breast carcinoma were proved to have lymphocytic thyroiditis with minor thyroid hypofunction more often than the corresponding group of women with colon cancer or control group of healthy women. In case of renal tumor (Grawitz), breast or lung carcinoma the thyroid can be attacked with metastasis, and ultrasound with fine needle biopsy can reliably differentiate between primary or secondary thyroid involvements. The thyroid can be involved in some diseases: multiple endocrine neoplasia, Carney, Cowden and Gardner's syndromes.

Screening for associated autoimmunity in type 1 diabetes mellitus with respect to diabetes control.

As an autoimmune disease, type 1 diabetes mellitus (DM) can be associated with other autoimmune disorders. The aim of this study was to detect subclinically associated autoimmune thyroid disease, coeliac disease, and Addison's disease. The presence of autoantibodies was evaluated with special regard to the control of diabetes and to the clinical status of the patient. Fifty-one type 1 diabetic patients (22 men, 29 women, mean age 37+/-11 years, mean duration of diabetes 16+/-13 years) were included into this study. Specific antibodies to islet antigens--glutamic acid decarboxylase (GAD65), protein thyrosine phosphatase IA-2alpha, and to thyroid autoantigens--thyroid microsomal peroxidase (TPO) and thyroglobulin (TG) and also thyroid stimulating hormone (TSH) were measured by RIA. Autoantigens of the small intestine--tissue transglutaminase autoantibodies (ATTG), IgA and IgG antibodies to gliadin (AGA-IgA, AGA-IgG) were evaluated by ELISA. Endomysial autoantibodies (EMA) and adrenal cortex antibodies (ACA) were detected by indirect immunofluorescence microscopy. Eleven new cases of thyreopathy (22 % of patients) were detected by the assessment of thyroid autoantibodies and TSH. Two new cases of thyreotoxicosis were diagnosed during the study. Coeliac disease was diagnosed in at least two cases. Addison's disease was not diagnosed, although the ACA were positive in two patients. No influence of single or combined autoantibody positivity on the control of diabetes was found if normal organ function was preserved. In both patients with thyreotoxicosis the control of diabetes was worsened and improved after treatment. The screening of autoantibodies in type 1 diabetic patients could reveal subclinical cases of AITD or coeliac disease. Subclinical forms of these disorders have no influence on diabetes control. However, impaired organ function may be associated with the worsened control of diabetes as we demonstrated on two newly diagnosed cases of thyreotoxicosis. We suggest the need for the follow-up of patients with positive autoantibodies because further deterioration of the respective organs can be expected.

Serum levels of antibodies to thyroid peroxidase correlate with quantitative descriptors of thyroid ultrasound images in patients with breast cancer.

The aim of the study was to compare the structural changes in ultrasound image of the thyroid tissue in 12 women with breast cancer (BC) and 8 women with colorectal cancer (CC). MATLAB software was used to analyse the digitised images. As quantitative descriptors of thyroid ultrasound images (QDTI) were used raw grey scale values of individual image pixels (RAW) and the optimal one-dimensional discriminative texture features (F2, F6, F7). The possible relations between QDTI and thyroid laboratory parameters were tested. In the BC group serum levels of antibodies to thyroid peroxidase negatively correlated with feature RAW (multiple regression, beta coefficient -0.75, p=0.004) and positively with feature F2 (multiple regression, beta coefficient 1.44, p=0.04). In the BC group RAW negatively correlated with serum levels of tumour marker CA 15-3 (Pearson's correlation coefficient, r=-0.714, p=0.00917). No such correlations were found in CC group. The correlations between QDTI and serum levels of antibodies to thyroid peroxidase in patients with BC show that the positivity of antibodies to thyroid peroxidase is probably accompanied with structural changes in the thyroid tissue.

Autoimmune thyroid diseases in women with breast cancer and colorectal cancer.

The aim of the study was to compare the prevalence of autoimmune thyroid diseases in three groups of women (66 with breast cancer (CaB), 68 with colorectal cancer (CaC) and 49 without oncological diseases as a control group). Serum levels of thyroid-stimulating hormone (TSH), free thyroxin (fT4), antibodies to thyroglobulin (TGB-ab) and thyroperoxidase (TPO-ab) and tumor markers CEA, CA 15-3 and CA 19-9 were investigated in all subjects by using the chemiluminiscence method. In contrast to Graves' disease (no observed case), autoimmune thyroiditis was diagnosed in 24.2 % women with CaB (4.5 % euthyroid and 19.7 % with subclinical or overt hypothyroidism), compared to 16.7 % in women with CaC (2.0 % euthyroid and 14.7 % with subclinical or overt hypothyroidism) and 16.2 % controls (4.0 % euthyroid and 12.2 % with subclinical or overt hypothyroidism). Serum levels of TGB-ab were higher in the group with breast cancer as compared to those with colorectal cancer and the control group (medians: 35.80 vs. 31.75 vs. 27.70, p<0.001). Similarly, the percentage of positive TGB-ab and TPO-ab serum levels was higher in women with breast cancer as compared to those with colorectal cancer and the control group. The results of the study support the controversial theory that there is an increased prevalence of autoimmune thyroiditis in women with breast cancer.

[Subclinical hypothyroidism with emphasis on the cardiovascular system]. / Subklinická hypotyreóza se zamerením na kardiovaskulární systém.

Subclinical hypothyroidism is comparatively frequent disorder with incidence between 3 to 7% in the general population; in females over 60 it can exceed 10%. There is no unequivocal view on the clinical significance of the syndrome; however, it may correspond with increased risk of atherosclerosis and its complications. Especially in elderly women, screening for subclinical hypothyroidism is recommended with possible hormone replacement according to given criteria. Decision about the therapy of subclinical hypothyroidism should be done together with cardiologist, psychiatrist or neurologist in order to correct possible clinical impacts and prevent further manifestations.

IgA and IgG antigliadin, IgA anti-tissue transglutaminase and antiendomysial antibodies in patients with autoimmune thyroid diseases and their relationship to thyroidal replacement therapy.

Celiac disease is a chronic illness of the small bowel caused by gliadin intolerance in genetically predisposed subjects. The aim of this study was to investigate serum levels of IgA and IgG antigliadin antibodies, IgA antiendomysial antibodies, and IgA anti-tissue transglutaminase antibodies in 169 patients with autoimmune thyroid diseases, i.e. chronic thyroiditis and Graves' disease. Antiendomysial antibodies were positive in 2 out of 169 persons (1.18%), IgA antigliadin antibodies in 15.98%, IgG antigliadin antibodies in 51.48%, and IgA anti-tissue transglutaminase in 14.79%. The prevalence of positivity was higher compared to the 1312 control blood donors described in our previous study (Vancíková et al. 2002) (p<0.05). Patients with chronic thyroiditis treated with a high replacement dosage of levothyroxin (125-200 microg daily) had higher serum levels of IgA antigliadin antibodies in comparison with patients treated with a lower dosage (50-100 microg daily) (medians: 13.00 vs. 19.69, p=0.033). We found a negative correlation of IgA anti-tissue transglutaminase antibodies and total calcium serum levels (r = -0.480, p=0.0236, n=22). We can conclude that in persons with autoimmune thyropathy there is a high prevalence of positive antigliadin, anti-tissue transglutaminase and antiendomysial antibodies. Latent celiac disease may lead to impaired resorption of therapeutically administered levothyroxine, calcium, or other substances.