Elevated Thyroid Autoantibodies Aggravate Stroke Severity in Euthyroidism with Acute Ischemic Stroke.

Introduction: Studies have indicated that immune reactions contribute to endothelial dysfunction and atherosclerosis. It is unclear whether thyroid dysfunction or elevated thyroid autoantibodies are associated with atherosclerosis. Therefore, we investigated the influence of thyroid autoimmunity related to elevated thyroid autoantibodies on functional outcome in euthyroidism with acute ischemic stroke (AIS). Methods: All patients with AIS underwent tests for thyroid function and thyroid antibodies (thyroid peroxidase antibody and thyroglobulin autoantibody). We divided the patients suffering from euthyroidism and AIS into positive thyroid autoantibody and negative thyroid autoantibody groups. Demographic profiles, risk factors, and functional outcomes were compared between the two groups. Results: Out of the total 422 patients, 50 (11.8%) were included in the positive thyroid autoantibody group. The National Institutes of Health Stroke Scale (NIHSS) score at admission and discharge was higher in the positive thyroid autoantibody group than the negative thyroid autoantibody group (P < 0.05). In addition, there was significant difference in the mortality during hospitalizations between the two groups (P < 0.01). Conclusion: This study showed that thyroid autoantibodies aggravate stroke severity in euthyroidism with AIS. We speculate that vascular damage related to thyroid autoimmunity may aggravate the increased risk of unfavorable outcomes, independent of thyroid function.

The Association of TSH and Thyroid Hormones With Lymphopenia in Bacterial Sepsis and COVID-19.

CONTEXT: Lymphopenia is a key feature of immune dysfunction in patients with bacterial sepsis and coronavirus disease 2019 (COVID-19) and is associated with poor clinical outcomes, but the cause is largely unknown. Severely ill patients may present with thyroid function abnormalities, so-called nonthyroidal illness syndrome, and several studies have linked thyrotropin (thyroid stimulating hormone, TSH) and the thyroid hormones thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to homeostatic regulation and function of lymphocyte populations. OBJECTIVE: This work aimed to test the hypothesis that abnormal thyroid function correlates with lymphopenia in patients with severe infections. METHODS: A retrospective analysis of absolute lymphocyte counts, circulating TSH, T4, free T4 (FT4), T3, albumin, and inflammatory biomarkers was performed in 2 independent hospitalized study populations: bacterial sepsis (n = 224) and COVID-19 patients (n = 161). A subgroup analysis was performed in patients with severe lymphopenia and normal lymphocyte counts. RESULTS: Only T3 significantly correlated (ρ = 0.252) with lymphocyte counts in patients with bacterial sepsis, and lower concentrations were found in severe lymphopenic compared to nonlymphopenic patients (n = 56 per group). Severe lymphopenic COVID-19 patients (n = 17) showed significantly lower plasma concentrations of TSH, T4, FT4, and T3 compared to patients without lymphopenia (n = 18), and demonstrated significantly increased values of the inflammatory markers interleukin-6, C-reactive protein, and ferritin. Remarkably, after 1 week of follow-up, the majority (12 of 15) of COVID-19 patients showed quantitative recovery of their lymphocyte numbers, whereas TSH and thyroid hormones remained mainly disturbed. CONCLUSION: Abnormal thyroid function correlates with lymphopenia in patients with severe infections, like bacterial sepsis and COVID-19, but future studies need to establish whether a causal relationship is involved.

Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyroiditis is increasingly recognized. The role of thyroid autoimmunity and SARS-CoV-2 viral load in SARS-CoV-2-related thyroid dysfunction is unclear. We evaluated the thyroid function of a cohort of coronavirus disease 2019 (COVID-19) patients, in relation to their clinical features, and biochemical, immunological, and inflammatory markers. METHODS: Consecutive adult patients, without known thyroid disorders, admitted to Queen Mary Hospital for COVID-19 from July 21 to August 21, 2020, were included. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine (fT3), and antithyroid antibodies were measured on admission. RESULTS: Among 191 patients with COVID-19 (mean age 53.5 ±â€…17.2 years; 51.8% male), 84.3% were mild, 12.6% were moderate, and 3.1% were severe. Abnormal thyroid function was seen in 13.1%. Ten patients had isolated low TSH, suggestive of subclinical thyrotoxicosis due to thyroiditis, although the contribution of autoimmunity was likely in 2 of them. Autoimmune thyroiditis probably also contributed to subclinical hypothyroidism in another patient. Ten patients had isolated low fT3, likely representing nonthyroidal illness syndrome. Lower SARS-Cov-2 polymerase chain reaction cycle threshold values and elevated C-reactive protein were independently associated with occurrence of low TSH (P = .030) and low fT3 (P = .007), respectively. A decreasing trend of fT3 with increasing COVID-19 severity (P = .032) was found. Patients with low fT3 had more adverse COVID-19-related outcomes. CONCLUSION: Around 15% of patients with mild to moderate COVID-19 had thyroid dysfunction. There may be a direct effect of SARS-CoV-2 on thyroid function, potentially leading to exacerbation of pre-existing autoimmune thyroid disease. Low fT3, associated with systemic inflammation, may have a prognostic significance.

The relationship between inflammatory factors, oxidative stress and DIO-1 concentration in patients with chronic renal failure accompanied with or without euthyroid sick syndrome.

Objective To investigate the relationship between inflammatory factors, oxidative stress and type 1 deiodinase (DIO-1) concentration in patients with chronic renal failure (CRF) with or without euthyroid sick syndrome (ESS). Methods This study recruited patients with CRF and divided them into two groups: group 1 had low free triiodothyronine (FT3) levels; and group 2 had normal FT3 levels. Group 3 consisted of healthy volunteers. Serum levels of interleukin (IL)-6, IL-1ß, tumour necrosis factor (TNF)-α, 8-isoprostane and DIO-1 were measured using enzyme-linked immunosorbent assays. Multiple regression analysis was used to analyse correlations between parameters. Results Sixty patients were enrolled into each group and the groups were comparable in terms of vital signs, white blood cell count, free thyroxine and thyroid stimulating hormone concentrations. The serum DIO-1 concentration was significantly higher in group 2 than in groups 1 and 3. Multivariate regression analysis revealed that the DIO-1 concentration was inversely correlated with the TNF-α concentration. Conclusions Patients with CRF without ESS showed higher concentrations of DIO-1 than patients with ESS. The DIO-1 concentration was inversely correlated with the TNF-α concentration, which might indicate that the inflammatory response was milder in the patients with CRF without ESS than in those with ESS.

The molecular basis of the non-thyroidal illness syndrome.

The 'sick euthyroid syndrome' or 'non-thyroidal illness syndrome' (NTIS) occurs in a large proportion of hospitalized patients and comprises a variety of alterations in the hypothalamus-pituitary-thyroid (HPT) axis that are observed during illness. One of the hallmarks of NTIS is decreased thyroid hormone (TH) serum concentrations, often viewed as an adaptive mechanism to save energy. Downregulation of hypophysiotropic TRH neurons in the paraventricular nucleus of the hypothalamus and of TSH production in the pituitary gland points to disturbed negative feedback regulation during illness. In addition to these alterations in the central component of the HPT axis, changes in TH metabolism occur in a variety of TH target tissues during NTIS, dependent on the timing, nature and severity of the illness. Cytokines, released during illness, are known to affect a variety of genes involved in TH metabolism and are therefore considered a major determinant of NTIS. The availability of in vivo and in vitro models for NTIS has elucidated part of the mechanisms involved in the sometimes paradoxical changes in the HPT axis and TH responsive tissues. However, the pathogenesis of NTIS is still incompletely understood. This review focusses on the molecular mechanisms involved in the tissue changes in TH metabolism and discusses the gaps that still require further research.

Clinical features of thyroid-associated ophthalmopathy in clinically euthyroid Korean patients.

AIM: To compare clinical characteristics and thyroid-stimulating hormone receptor antibodies (TRAbs) in thyroid-associated ophthalmopathy (TAO) in euthyroid Korean patients with those in hyperthyroid patients. METHODS: Clinical activity scores (CASs), modified NOSPECS scores, exophthalmometry values, prevalence of optic neuropathy, restrictive myopathy and lid retraction, and the positivity and levels of TRAb (thyrotropin-binding inhibitor immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSI)) were compared in 24 euthyroid (group A) and 139 clinical/subclinical hyperthyroid TAO patients (group B). RESULTS: Group A presented more clinically unilateral involvement than group B (79.2% vs 27.3%, P<0.001), less active (CAS 1.50 vs 2.26, P=0.014) and less severe clinical course (NOSPECS 3.38 vs 4.13, P=0.037). Lid retraction was more prevalent in group A than group B (91.7% vs 66.2%, P=0.014). Prevalence of optic neuropathy and restrictive myopathy, and the mean value of exophthalmometry were not different. Mean TBII levels were lower (7.20 IU/l) in group A than in group B (44.58 IU/l, P<0.001). A similar difference was found in the TSI bioassay (201.40% vs 425.19%, P=0.001). The positive rate of TBII in group A (34.8%) was significantly lower than in group B (90.8%, P<0.001). The positive rate of TSI was high in both group A (83.3%) and B (91.7%), with no significant difference (P=0.337). CONCLUSIONS: Patients with euthyroid TAO showed a less active and severe clinical course, more unilateral involvement, and lower levels of TRAb than those in patients with hyperthyroid TAO. These distinct clinical and biochemical characteristics might be useful in assessment of euthyroid TAO, and the TSI might be more sensitive for diagnosing these patients.

Serum CXCL10 levels and neuromuscular manifestations in patients with autoimmune thyroid diseases.

OBJECTIVE: Serum C-X-C motif chemokine 10 (CXCL10) levels have been shown to be elevated in autoimmune thyroid diseases (AITD). This study sought to determine whether newly diagnosed AITD patients with neuromuscular findings had higher levels of CXCL10 than those without neuromuscular manifestations. DESIGN: A total of 80 patients were recruited to the study, which included treatment-naive hypothyroid Hashimoto's thyroiditis (n = 19) and hyperthyroid Graves' disease (GD; n = 21), euthyroid thyroid autoantibody-positive (n = 20) and -negative (n = 20) patients. METHODS: All patients underwent a thorough sensorimotor and neuromuscular examination. Serum samples were kept in - 20°C for further CXCL10 measurements with ELISA. RESULTS: There was a significant difference with regard to serum CXCL10 levels only between GD and euthyroid thyroid autoantibody-negative patient groups [187(12-418) vs. 37.5(2-542) pg/ml, p < 0.05]. However, a comparison of newly diagnosed AITD patients with and without neuromuscular manifestations in terms of serum CXCL10 levels yielded no significant difference. When a correlation of existence of a neuromuscular manifestation and serum CXCL10 levels was evaluated, a significantly positive correlation was noted between carpal tunnel syndrome (CTS) and serum CXCL10 levels [207 (95-748) pg/ml in CTS-positive vs. 117 (2-977) pg/ml in CTS-negative patients, p < 0.05]. CONCLUSIONS: In this study, from a number of neuromuscular manifestations, only the existence of CTS correlated with significantly higher CXCL10 levels in the whole study group. Further studies with larger numbers of patients with autoimmune-based hyper- and hypothyroidism may better clarify the hypothesis regarding a relationship between serum CXCL10 levels and neuromuscular manifestations of AITD.

Th1 polarization and low-T3 syndrome are correlated with hyperleptinemia in hemodialysis patients.

BACKGROUND: Patients undergoing chronic hemodialysis (HD) have an impaired immune response with a dysregulated Th1/Th2 cytokine network and altered the levels of thyroid hormone (TH) in euthyroid sick syndrome. Leptin, an adipocyte-secreted hormone, is considered to be a proinflammatory adipocytokine, with multiple effects on several tissues acting on the intermediate and energy metabolism. The aims of the present study were to assess the changes in serum levels of leptin and their correlation with Th1/Th2 cytokine and TH production in HD patients. METHODS: Fifty-three uremic patients with hemodialysis were evaluated; 30 healthy volunteers served as controls. Baseline serum concentrations of interleukin-2 (IL-2), sIL-2R, interferon-gamma (IFN-gamma), IL-4 and IL-10 were analyzed using ELISA. Serum levels of leptin, total triiodothyronine (TT3), free triiodothyronine (FT3), total thyroxine (TT4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined by radioimmunoassay (RIA). Other metabolic variables were measured in all patients and control subjects. Multiple correlation analysis was performed among variables. RESULTS: Mean serum leptin concentration was significantly higher in HD patients than that in controls (p<0.01), especially in women (p<0.001). While the fasting serum levels of sIL-2R and Th1-type cytokines including IL-2 and IFN-gamma were significantly higher in HD patients compared with controls, Th2-type cytokine, including IL-4 and IL-10, levels did not differ between patients and controls. The serum TT3 and FT3 levels were lower in patients than controls, but TT4, FT4 and TSH were no different. Serum leptin levels in HD patients were significantly positively correlated with IL-2, IFN-gamma, sIL-2R and TSH; and negatively correlated with IL-4, IL-10, TT3 and FT3. Serum IL-2 levels correlated positively with serum IL-4, sIL-2R, TT3 and FT3. A negative correlation was observed between serum IFN-gamma and IL-4 levels in the patients. CONCLUSIONS: These data suggest that hyperleptinemia in HD patients correlated with cytokine dysregulation with a high level of Th1-type cytokines, and euthyroid sick syndrome with low T3 levels which might be involved in Th1 polarization and low-T3 syndrome in dialysis patients.

Thyroid hormone and insulin-like growth factor-I in patients with multiple myeloma treated with melphalan and prednisone.

BACKGROUND: The relationship between endocrine regulation and immune system has recently become the subject of intense investigations. The aim of this study was the comparative assessment of serum levels of selected hormones and insulin-like growth factor-I (IGF-I) in patients with multiple myeloma (MM) during applied therapy. METHODS: The levels of prolactin, hGH, TSH, fT3, fT4 and IGF-I in serum of 13 untreated patients with MM and in 16 healthy controls were determined. The patients were treated in cyclic courses with melphalan plus prednisone, and investigations were carried out in the first four courses of this therapy. The results were compared in the following manner: (1) at entry between studied MM group and healthy subjects, and (2) during the therapy intragroup-intracyclic comparisons were made in paired serum samples collected from patients before and after every therapeutic course. RESULTS: At entry, significantly lower levels of TSH and fT3 were obtained in MM patients. The means remained within low normal reference range. Slightly increasing levels of TSH and fT3 during treatment with lower concentrations of these hormones after every therapeutic course and a statistically significant difference of fT3 level in the fourth therapy course were revealed. The levels of fT4 were within the normal reference values and showed a tendency to decrease during therapy with significant differences in the first therapeutic course. After the third and the fourth therapy courses, concentrations of IGF-I were statistically significantly higher than initially. CONCLUSIONS: Euthyroid sick syndrome can exist in MM patients, and the therapy with melphalan plus prednisone is accompanied by slightly expressed serum changes of thyroid hormone concentrations and IGF-I levels.

[Dilated cardiomyopathy associated with autoimmune disease of thyroid gland].

Congestive heart failure is the main cause of cardiovascular morbidity and mortality with more than one million hospitalizations per year. Dilated cardiomyopathy is one of the main causes of congestive heart failure characterized by diminished function of the left, right or both ventricles and ejection fraction less than 40%. Numerous studies reported that the diseases of thyroid gland among the patients with dilated cardiomiopathy were very frequent: with prevalence from 18% to 49%. The impaired thyroid gland function was found as primary cause of cardiomyopathy in 1% of patients. At the same time, among patients with terminal dilated cardiomyopathy, euthyroid sick syndrome was very frequent with low values of T3. According to our results, 29.4% of patients with dilated cardiomyopathy also had autoimmunity disorder of thyroid gland with present antithyroglobin and antimicrosomal antibodies. These patients had lower ejection fraction and worse prognosis. In American College of Cardiology/American Heart Association guidelines for the evaluation and treatment of the congestive heart failure, evaluation of thyroid gland function was recommended; but the evaluation of antitireoglobulin antibodies and free T3 and free T4 was also essential, as was calculation of their ratio. This is the way to discover the autoimmunity disorder of thyroid gland and/ or "euthyroid sick syndrome". In patients with dilated cardiomyopathy and low-T3 syndrome, short-term administration of thyroid hormones resulted in improvement of ejection fraction, diminishing of symptoms and better survival.

Autoantibodies to thyroperoxidase (TPOAb) in a large population of euthyroid subjects: implications for the definition of TPOAb reference intervals.

OBJECTIVE: Measurement of autoantibodies against thyroperoxidase (TPOAb) plays an important role in the diagnosis of autoimmune thyroid disease. The assessment of reference intervals for TPOAb, however, is a controversial issue since elevated TPOAb values are sometimes found in subjects without other evidence of thyroid disease. METHODS: TPOAb were measured in 1,295 euthyroid individuals using a highly sensitive, fully automated chemiluminescence assay (Advantage A-TPO, Nichols Institute Diagnostics, CA, USA). The study subjects participated in a population study on the prevalence of thyroid disorders in the German federal state of Saxony, an area of mild iodine deficiency. RESULTS: TPOAb above the detection limit of 0.45 IU/ml were found in 1,277/1,295 euthyroid individuals. TPOAb values in the low measurable range below 1.1 IU/ml followed a normal distribution, and this was independent of age and sex. When using a cut-off value of 1.1 IU/ml, which corresponds to a sensitivity of 79% and a specificity of 95% resulting from the receiver-operator characteristic plot for discrimination between a main type and other types with a higher mean value of TPOAb, elevated TPOAb were found in 14.4% of euthyroid men and in 25.8% of euthyroid women. CONCLUSIONS: The results demonstrate for the first time that TPOAb are detectable in nearly all euthyroid individuals and that TPOAb values in the low measurable range are normally distributed. The distribution of TPOAb values in the low range is independent of age and sex. Based on these data, reference intervals for TPOAb can be defined that are independent of the population investigated. The clinical significance of slightly elevated TPOAb, however, has still to be defined by prospective studies.

Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseases--implications for the euthyroid sick syndrome.

OBJECTIVE: To determine whether cytokine release or activation of the hypothalamo-pituitary-adrenal (HPA) axis is predominantly involved in the development of the euthyroid sick syndrome (ESS). DESIGN: Prospective observational study. SETTING: Intensive care unit at a tertiary care medical center in Germany. PATIENTS: Nine patients with sepsis of different causes and eight patients with acute myocardial infarction. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Immediately on admission and on day 7 the following parameters were determined: total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), thyrotropin (TSH), interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), serum cortisol and plasma adrenocorticotropin (ACTH). On admission, concentrations of all thyroid hormones and TSH were significantly lower in septic patients compared to non-septic patients, whereas all cytokines except IL-2 were significantly elevated in the sepsis group. By contrast, there was no difference in serum cortisol and plasma ACTH levels between the two groups. On day 7, T4 and T3 were still lower in the septic group, whereas IL-1 beta, sIL-2R and IL-6 were still elevated. Again, no differences were found with regard to cortisol and ACTH levels. CONCLUSIONS: Euthyroid sick syndrome occurs very early during the course of septic diseases. Significantly decreased levels of total T4, FT4, T3 and TSH in septic patients suggest central suppression of TSH as well as inhibition of thyroid hormone release in ESS. The HPA axis is activated in septic patients and in non-septic patients and does not contribute to the development of ESS.

[Euthyroid sick syndrome: recent physiopathologic findings]. / Les dyshormonémies des affections non thyroïdiennes: données physiopathologiques nouvelles.

INTRODUCTION: Patients with nonthyroidal disease frequently exhibit abnormal thyroid function tests; this is referred to as euthyroid sick syndrome. The clinical significance of this syndrome is unknown: abnormal endocrine reaction with reduced triiodothyronine (T3) at the tissue level, or adaptation to stress protecting the body against exaggerated catabolism. CURRENT KNOWLEDGE AND KEY POINTS: Recent advances in the underlying mechanisms concern the role of deiodinase and of the transport of thyroid hormone in tissues. Various factors acting on deiodinase or on transport system, such as medications and nutritional factors, have been implicated. Considerable interest has raised concerning the role of cytokines. Some cytokines may act at every level of the thyrotropic axis, but their real action in vivo remains unclear. Nutritional factors have a great impact on thyroid hormone metabolism, but the mechanism of the decrease in T3 induced by starvation is not identified. The role of the decrease in type I hepatic deiodinase has been recently challenged. FUTURE PROSPECTS AND PROJECTS: Despite its complexity, euthyroid sick syndrome is a model for the study of thyroid hormone metabolism regulation. Characterisation of the thyroid hormone transport proteins will lead to significant advances in the understanding of the syndrome.

Influence of antithyroid antibodies in euthyroid women on in vitro fertilization-embryo transfer outcome.

PROBLEM: To investigate whether antithyroid antibodies (ATAs) affect the pregnancy outcome in euthyroid women undergoing in vitro fertilization-embryo transfer (IVF-ET). METHOD OF STUDY: Thyroid peroxidase antibody (TPOA) and thyroglobulin antibody (TGA) were measured by radioligand assay kits that were used as ATAs in 79 patients with tubal or unexplained infertility who were enrolled in an IVF-ET program. Women who were positive for antinuclear antibody, lupus anticoagulant, anticardiolipin antibody, and rheumatoid factor were excluded from our study. The study group comprised 28 (29.1%) euthyroid women who were positive for TPOAs, TGAs, or both. Fifty-one euthyroid women without ATAs served as control subjects. The results were analyzed with linear regression analysis, Student's t-test, Mann-Whitney U test, Kruskal-Wallis analysis of variance, chi 2 test, and Fisher's exact test. RESULTS: There were no significant differences between the study group and the control group in patient characteristics such as age, infertility duration, and hormonal profile. There were also no significant differences between the two groups with respect to the number of retrieved oocytes, the fertilization rate, the number of embryos frozen, and the number of embryos transferred. There were no correlations between ATA (TPOA and TGA) titers and the fertilization rate. The clinical pregnancy rate per cycle was significantly lower in the study group, with 26.3% (10/38), compared with 39.3% (35/89) in the control group. The biochemical pregnancy rate per cycle and the miscarriage rate were significantly higher in the study group, 18.4% (7/38) and 40.0% (4/10), respectively, compared with 5.6% (5/89) and 11.4% (4/35), respectively, in the control group. In the study group, both TPOA and TGA titers were significantly higher in the biochemical pregnancy group than in the clinical pregnancy group or the nonpregnancy group. In 10 women with ATAs who achieved pregnancy after IVF-ET, both TPOA and TGA titers were significantly higher in the miscarriage group than in the ongoing pregnancy/delivery group. CONCLUSION: ATAs in euthyroid women with tubal or unexplained infertility have an association with a poor pregnancy outcome after IVF-ET treatment.

Immunoneutralization of interleukin-1, tumor necrosis factor, interleukin-6 or interferon does not prevent the LPS-induced sick euthyroid syndrome in mice.

The sick euthyroid syndrome is a state of altered thyroid hormone metabolism which occurs during illness. The pathogenesis is incompletely understood but recent studies indicate a role of cytokines. It is unknown if cytokines released during illness are directly responsible for the changes in thyroid hormone metabolism. Therefore we studied if previous immunoneutralization of cytokines can prevent endotoxin (lipopolysaccharide LPS), induced sick euthyroid syndrome. LPS administration resulted in systemic illness, an increase in serum tumor necrosis factor (TNF alpha) and interleukin (IL)-6 and a decrease in serum triiodothyronine (T3) and thyroxine (T4). Immunoneutralization of the effects of cytokines was accomplished by administration of monoclonal antibodies against mouse IL-1 type-1 receptor (IL-1R), TNF alpha, IL-6 or interferon (IFN gamma) prior to LPS. The LPS-induced release of cytokines was affected by previous immunoneutralization as compared with control experiments with normal immunoglobulin (IgG): anti-IL-1R did not affect serum TNF alpha but decreased serum IL-6, anti-TNF alpha decreased serum TNF alpha but not IL-6, anti-IL-6 did not affect serum TNF alpha but hugely increased IL-6 and anti-IFN gamma decreased both serum TNF alpha and IL-6. Specific immunoneutralization of IL-1, TNF alpha or IFN gamma did not prevent the LPS-induced decrease in serum T3, T4 and liver 5'-deiodinase mRNA. However, immunoneutralization of IL-6, although not preventing the fall in serum T3 and T4, did mitigate the LPS-induced decrease in liver 5'-deiodinase mRNA. In view of possible non-specific effects of the huge dose of immunoglobulins (1 mg), used only in the immunoneutralization of IL-6, we repeated the experiment with F(ab')2 fragments of anti-IL-6 antibodies. Compared with F(ab')2 fragments of control IgG, anti-IL-6 F(ab')2 did not affect the LPS-induced rise in serum TNF alpha or the decrease in serum T3 and T4 and liver 5'-deiodinase mRNA. Serum IL-6 levels induced by LPS were, however, cleared more rapidly from the circulation when anti-IL-6 F(ab')2 fragments rather than intact anti-IL-6 were administered. In conclusion, immunoneutralization of IL-1, TNF alpha or IFN gamma did not prevent the LPS-induced sick euthyroid syndrome in mice; immunoneutralization of IL-6, however, transiently inhibits the LPS-induced decrease of liver 5'-deiodinase mRNA.

The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice.

To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNF alpha), interleukin-1 (IL-1 alpha), interleukin-6 (IL-6) and interferon-gamma (IFN gamma). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNF alpha and IL-6 and (c) a decrease of liver 5'-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T3) and thyroxine (T4) at 8 h and of serum free T3 (fT3) and free T4 (fT4) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1 alpha, TNF alpha, IL-6 or IFN gamma could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1 alpha caused systemic illness, and IL-1 alpha was the only cytokine that decreased liver 5'-deiodinase mRNA transiently. IL-1 alpha, TNF alpha or IL-6 did not decrease serum T3, T4 and TSH, but administration of IFN gamma decreased serum T4, T3 and fT3 in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS. The following conclusions were reached.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid disorders in Korean patients with systemic lupus erythematosus.

Although autoimmune thyroid diseases have been associated with systemic lupus erythematosus (SLE), the prevalence of thyroid disorder is controversial. To clarify the prevalence of thyroid disorder in Korean patients with SLE, thyroid functions and diseases were evaluated in 63 SLE patients. Of these patients, Hashimoto's thyroiditis (9.5%) as well as euthyroid sick syndrome (14.3%) were more common than Graves' disease (4.8%). The prevalence of antithyroid autoantibodies (antimicrosomal and/or antithyroglobulin autoantibodies) in SLE was 27.0%. High titers of these autoantibodies were mainly detected in Hashimoto's thyroiditis. These results suggested that thyroid diseases are not uncommon in SLE and autoimmune thyroid diseases are possible manifestations in some patients with SLE. Antithyroid autoantibodies may be good predictors for the detection of Hashimoto's thyroiditis developing in SLE.

Artifactual elevation of thyroid-stimulating hormone.

A clinically euthyroid patient was found to have a normal serum thyroxine level and an elevated plasma thyrotropin (TSH) level measured by fluoroimmunoassay. Thyroid hormone therapy failed to suppress the TSH level. The TSH level was unresponsive to thyrotropin-releasing hormone (TRH) administration, alpha-subunits of pituitary glycoproteins were undetectable in her plasma, and imaging of the pituitary-hypothalamic region was normal. Measurement of TSH with an assay containing sheep antibody to TSH failed to reveal TSH in the patient's plasma. Addition of mouse IgG to the TSH fluoroimmunoassay reduced the patient's TSH to an undetectable level. These observations are consistent with a spurious elevation of TSH due to the presence of an anti-mouse antibody. Artifactual elevations of TSH have not been identified commonly, but this possibility should be considered when the TSH level is inappropriate for the apparent state of thyroid function.

Euthyroid infiltrative ophthalmopathy: clinical-immunological characteristics.

The thyroid hormone titres of the sera of 25 euthyroid infiltrative ophthalmopathic patients was examined, TRH test was performed, and thyroid-stimulating antibodies were studied by membrane receptor assay and TRAK assay. Previously, other diseases causing exophthalmos could be excluded by ophthalmological, radiological examinations, orbital ultrasonography and/or CT. Following TRH administration, 18 out of 25 patients showed abnormal TSH response, 16 of them were TSI - positive. Five of them became hyperthyroid 2-2.5 years later. After TRH administration 7 patients produced normal TSH response, none of them became hyperthyroid in the subsequent 2-4 years follow-up period. In the 7 TRH-negative patients, four were found to have higher hTG and an antithyroid microsome antibody titre. In those patients the fine needle biopsy verified chronic lymphocytic thyroiditis. In three patients there was no evidence of a pathological change of the thyroid gland. Based on our results, the patients could be divided into three groups. The prognostic and therapeutic differentiation of these groups seems to be justified.