Thyroid autoimmunity in the current iodine environment.

Iodine is essential for thyroid function. Thyroid disorders related to iodine deficiency decreased progressively with the continuous iodine prophylaxis and the increased iodine intake. An adverse effect resulting from iodine prophylaxis may be the induction of thyroid autoimmunity. Although experiments performed in animal models suggest that iodine could initiate or exacerbate thyroid autoimmunity, the role of iodine in humans remains controversial. Several observational studies in areas with adequate or high iodine intake suggest that there is an increase in the incidence of thyroid autoimmune disease. Moreover, intervention studies suggest that increased iodine intake may enhance thyroid autoimmunity too. However, not all studies generated the same findings, probably because of genetic, racial, and environmental differences. It seems that autoimmune exacerbation is a transient phenomenon. Studies have shown that in persons presenting thyroid antibodies, the levels of these antibodies progressively decrease when the majority of them react against a nonspecific pattern of thyroglobulin (Tg) epitopes. However, in a small number of these persons, the anti-Tg antibodies are similar to those in patients with patent thyroid autoimmune disease, reacting against specific immunodominant Tg epitopes, and their levels persist. One possible attractive explanation is that enhanced iodine intake increases the antigenicity of Tg through the incorporation of iodine into its molecule and the formation of iodinated Tg epitopes or even the generation of noniodinated pathogenetic Tg epitopes that are normally cryptic.

Arterial stiffness is increased in subjects with hypothyroidism.

BACKGROUND: The association between hypothyroidism and increased vascular resistance, arterial wall thickening and endothelial dysfunction is well recognized. The aim of the present study was to examine if hypothyroid subjects have increased arterial stiffness, a risk factor for cardiovascular morbidity and mortality. METHODS: Sixty-five subjects (59 females and 6 males) with normal thyroid function or hypothyroidism of varying degree were investigated by radial artery applanation tonometry and pulse wave analysis, for evaluation of arterial stiffness. RESULTS: Serum TSH values were positively correlated with central systolic blood pressure (r=0.258, p=0.037), central pulse pressure (r=0.316, p=0.010), augmentation pressure (r=0.299, p=0.015) and negatively with reflection time index (RTI), which indicates the pressure wave velocity (r=-0.311, p=0.012). Hypothyroid patients presented higher central systolic pressure and pulse pressure, higher augmentation pressure and lower RTI, indicating increased arterial stiffness in these subjects. RTI was independently related to age, central systolic pressure and TSH. Mild changes of arterial stiffness were observed even in subjects with TSH range 2.01-4.0 muU/ml suggesting that this group may have an early stage of mild thyroid failure. CONCLUSIONS: Hypothyroidism, even in the subclinical stage, is associated with changes in arterial stiffness. The observed abnormalities in arterial stiffness may have detrimental effects on left ventricular function and coronary perfusion in hypothyroid subjects.

Regulation of vascular endothelial growth factor expression by insulin-like growth factor I in thyroid carcinomas.

Vascular endothelial growth factor (VEGF) produced by tumor cells potently stimulates endothelial cell proliferation and angiogenesis and plays a key role in the pathophysiology of several neoplasias. Hypoxia activates the VEGF promoter via response elements that bind the transcription factors hypoxia-inducible factor-1 alpha (HIF-1 alpha) and activator protein-1 (AP-1). Yet, the paracrine signaling pathways regulating VEGF production and angiogenesis in thyroid cancer have not been fully elucidated. In this study, we, therefore, investigated the regulation of VEGF production by the thyroid carcinoma cell line SW579. We found that IGF-I up-regulated VEGF mRNA expression and protein secretion. Furthermore, transfection of SW579 cells with vector expressing a constitutively active form of Akt, a major mediator of IGF-I signaling, also stimulated VEGF expression. The IGF-I-induced up-regulation of VEGF production was associated with activation of AP-1 and HIF-1 alpha and was abrogated by phosphatidylinositol 3-kinase inhibitors (wortmannin and LY294002); Jun kinase inhibitor (SP600125); HIF-1 alpha antisense oligonucleotide; or geldanamycin, an inhibitor of the heat shock protein 90 molecular chaperone, which regulates the three-dimensional conformation and function of IGF-I-receptor and Akt. These data indicate that IGF-I stimulates VEGF synthesis in thyroid carcinomas in an Akt-dependent pathway via AP-1 and HIF-1 alpha and provide the framework for clinical use of small-molecule inhibitors, including geldanamycin analogs, to abrogate proangiogenic cascades in thyroid cancer.

Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis.

OBJECTIVE: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). DESIGN AND METHODS: Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. RESULTS: In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. CONCLUSIONS: Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress.

Hypothalamic-pituitary-adrenal axis and interleukin-6 activity in children with head trauma and syndrome of inappropriate secretion of antidiuretic hormone.

OBJECTIVE: Arginine vasopressin (AVP; anti-diuretic hormone) and corticotropin-releasing hormone are the two major secretagogues of hypophyseal adrenocorticotropin (ACTH). Interleukin-6 (IL-6) is a potent stimulator of the human hypothalamic-pituitary-adrenal axis (HPA) and a secretagogue of both parvocellular and magnocelullar AVP. We have previously suggested that IL-6-stimulated AVP secretion may be the origin of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in inflammatory conditions. STUDY DESIGN: To further elucidate the relationship between IL-6 and SIADH as well as IL-6 and HPA axis activity, we studied eight previously healthy children (age 6.3 +/- 4.8 [mean +/- SD] years, weight 23.8 +/- 10.5 kg) who--after sustaining head trauma--presented SIADH during hospitalization (for 7.1 +/- 3.8 days) in the pediatric intensive care unit (P-ICU). Routine blood samples were taken twice daily at 08:00 and 20:00 hours. All children but one survived. Measurements included blood and urine osmolality (BlOsm and UrOsm, respectively), serum cortisol (F) and IL-6, plasma ACTH and AVP. Correlations were assessed with linear regression among the areas under the curve (AUC) of BlOsm, UrOsm, ACTH, F, IL-6 and AVP, separately for BlOsm values <280 mOsm (SIADH phase) and > or = 280 mOsm (non-SIADH phase). RESULTS: During the SIADH phase AVP-AUC correlated positively with IL-6-AUC (r = +0.96, p<0.05), BlOsm-AUC correlated positively with AVP-AUC and F-AUC (r = +0.95 and +0.98, p<0.05, respectively) and F-AUC correlated positively with ACTH-AUC (r = +0.99, p<0.05). During the non-SIADH phase ACTH-AUC correlated positively with BlOsm-AUC (r = +0.96, p<0.05). CONCLUSION: IL-6 secreted during an aseptic inflammatory state, such as sustaining head trauma with SIADH, is quantitatively correlated to AVP, indicating that this cytokine is directly and/or indirectly involved in the pathogenesis of SIADH.

Circulating levels of oxidized low-density lipoprotein in overt and mild hypothyroidism.

The increased low-density lipoprotein cholesterol (LDL-C) levels in hypothyroidism may enhance the formation of oxidized LDL (oxi-LDL) that may consequently generate foam cells by their uptake by the macrophages. The goal of this study was to investigate whether plasma circulating oxi-LDL levels are elevated in mild and in overt hypothyroidism, if the concentration of oxi-LDL is influenced in a short-term treatment period by thyroid hormone, and whether correlations exist between serum concentration of thyrotropin (TSH), thyroid hormone, and cholesterol. Thirty-nine patients with overt hypothyroidism (OH), 41 patients with mild thyroid failure (MTF), and 57 controls (CNTR) were investigated. Serum TSH concentrations were increased in OH (18 +/- 6 mU/L) and in MTF (6 +/- 2 mU/L), whereas in CNTR the levels were 1.6 +/- 0.3 mU/L. Plasma circulating levels of oxi-LDL were measured by a new enzyme-linked immunosorbent assay (ELISA) kit (normal range, 40-75 mU/L) and they were found statistically significantly increased in OH compared to MTF (86 +/- 16 mU/L vs. 73 +/- 13 mU/L; p < 0.01) and to CNTR (62 +/- 11 mU/L; p < 0.001). Smokers in all groups exhibited statistically significant higher plasma oxi-LDL levels compared to nonsmokers. The percentage of increase amounted to 17.7% in OH, to 9.8% in MTF, and to 8% in CNTR. Replacement treatment with levothyroxine over a period of 3 months in 12 of 39 patients with OH and in 14 of 41 patients with MTF resulted in a statistically significant decrease of oxi-LDL only in the OH group. Thus, plasma oxi-LDL decreased in OH from 82 +/- 12 mU/L to 73 +/- 10 mU/L (p < 0.05), to the upper normal level, and in MTF from 68 +/- 5 mU/L to 64 +/- 5 mU/L, respectively. In conclusion, we can state that circulating oxi-LDL levels are elevated in untreated overt hypothyroidism, they tend to be higher in mild thyroid failure, they are severely affected by smoking, however, they need a longer time course to decrease via thyroxine treatment.

Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand selectively kills neoplastic cells, including thyroid carcinoma cells (Mitsiades et al: Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2000, 60:4122-41299). We investigated the mechanisms regulating Apo2L/TRAIL-induced apoptosis in thyroid carcinoma cells, as well as the impact of insulin-like growth factor (IGF)-1, interferon-gamma, and TNF-alpha. We found that the emergence of resistance to Apo2L/TRAIL, after prolonged incubation with this cytokine, was associated with increased levels of FLICE inhibitory protein (FLIP), and was overcome by cycloheximide and bisindolylmaleimide, that specifically down-regulated FLIP expression, as well as by transfection of a FLIP anti-sense oligonucleotide. IGF-1 activated Akt; up-regulated the caspase inhibitors FLIP, cIAP-2, XIAP, and survivin; and attenuated Apo2L/TRAIL-induced apoptosis. This effect was inhibited by the IGF-1 receptor neutralizing antibody aIR3, the PI-3K inhibitor wortmannin, and the heat shock protein-90 chaperone inhibitor geldanamycin. Transfection of constitutively active Akt protected from TRAIL. Conversely, interferon-gamma and TNF-alpha had a sensitizing effect. We conclude that FLIP may negatively regulate Apo2L/TRAIL-induced apoptosis in thyroid carcinomas. Microenvironmental paracrine survival factors, such as IGF-1, up-regulate caspase inhibitors, including FLIP, and protect from Apo2L/TRAIL in a PI-3K/Akt-dependent manner. T helper-1 cytokines and compounds that selectively abrogate the IGF-1 signaling pathway may be helpful adjunct agents in Apo2L/TRAIL-based anti-cancer therapeutic regimens.

Pitutaty insufficiency. Diagnosis masked by a toxic thyroid adenoma.

A patient with undiagnosed pituitary insufficiency who also had a toxic thyroid adenoma is presented. The T3 secreted by the adenoma apparently corrected the secondary thyroid failure, but also aggravated the secondary adrenal failure and almost precipitated adrenal crisis. The diagnostic work-up in such an unusual co-existence is discussed, in particular since the clinical diagnosis of pituitary insufficiency in the elderly is not easily established.