Impact of Thyroid Autoantibodies on Functional Outcome in Patients with Acute Ischemic Stroke Han-Jin Cho, MD,* Sang-Soo Kim, MD,† Sang-Min Sung, MD,* and Dae-Soo Jung, MD*
Background: Recent studies have shown that thyroid autoantibodies contribute to the development of cerebrovascular diseases, including atherosclerosis, moyamoya disease, and even arterial dissection, induced by immune-mediated endothelial dysfunction on the cerebral vasculature. The aim of this study was to investigate the impact of thyroid autoantibodies on functional outcome in patients with acute ischemic stroke. Methods: We reviewed the patients with acute ischemic stroke who consecutively underwent thyroid autoantibody tests. We divided the patients into positive thyroid autoantibody (PAB) and negative thyroid autoantibody (NAB) groups. Demographic profiles, risk factors, stroke subtypes, laboratory results, and functional outcomes were compared between the 2 groups. We performed the multivariate analysis to determine whether thyroid autoantibodies were independently associated with functional outcome. Results: Of the 763 patients, 121 (15.9%) were of the PAB group. Compared with the NAB group, higher baseline National Institutes of Health Stroke Scale score (P 5.001) and prevalence of large-artery atherosclerosis (P 5 .014) were found in the PAB group. The PAB group had significantly higher proportion of unfavorable outcome at 3 months (modified Rankin Scale score $ 3) than the NAB group (P 5 .002). On multiple regression analysis, lower tri-iodothyronine level (odds ratio [OR] .985, 95% confidence interval [CI] .976-.995, P 5.002) and PABs (OR 1.661, 95% CI 1.013-2.724, P 5.044) were significant and independent predictors of unfavorable outcome. Conclusions: This study showed that elevated thyroid autoantibodies were independently associated with unfavorable outcome in patients with acute ischemic stroke. We speculate that immune-mediated vascular damage may contribute to the increased risk of unfavorable outcome by providing insufficient cerebral blood flow to the ischemic area. Key Words: Cerebral infarction—stroke—thyroid gland—autoantibodies— prognosis. Ó 2014 by National Stroke Association
Introduction Several studies have provided the evidences for the relationship between thyroid autoimmunity and vascular diseases.1-4 Apart from the histopathologic data reporting From the *Department of Neurology, Pusan National University Hospital, Pusan National University Graduate School of Medicine and Biomedical Research Institute, Busan; and †Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital, Pusan National University Graduate School of Medicine, Busan, Korea. Received December 16, 2013; revision received January 29, 2014; accepted February 5, 2014. Grant support: None.
cerebral vasculitis in autoimmune thyroiditis patients,5,6 a recent study showed higher prevalence of elevated thyroid autoantibodies in stroke patients with intracranial stenosis than those without.4 In other studies,
Conflict of interest: The authors have no conflict of interest to report. Address correspondence to Han-Jin Cho, MD, Department of Neurology, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 602-739, Korea. E-mail: [email protected] 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.02.008
Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2014: pp 1-6
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thyroid autoantibodies were associated with moyamoya disease and even arterial dissection.7-9 Although the exact mechanism is not fully understood, these findings have been ascribed to immune-mediated inflammatory reaction and resultant endothelial dysfunction on the cerebral vasculature, based on the fact that vascular tissues share some antigenic properties with thyroid tissues.1-3 Given the association between thyroid autoimmunity and endothelial dysfunction, the previous studies that showed impaired cerebral perfusion in patients with autoimmune thyroiditis arouse concerns as to whether thyroid autoimmunity may contribute to the unfavorable cerebrovascular prognosis.10,11 However, until now, there have been few considerations of the possibility that thyroid autoantibodies may affect functional outcome in acute ischemic stroke patients. Thus, we investigated the impact of thyroid autoantibodies on functional outcome in these patients.
Methods Patient Selection From November 2010 to April 2013, we reviewed 1035 patients with acute ischemic stroke who were admitted to the stroke center and registered in a prospectively collected stroke registry. Eligible for this study were patients who had acute cerebral infarction demonstrated by diffusion-weighted imaging within 7 days of symptom onset and underwent thyroid function tests accompanied with thyroid autoantibody tests. We excluded patients with pre-existing thyroid disease except for benign thyroid nodules, use of levothyroxine or antithyroid medication during admission, or administration of thrombolytic treatment. This study was approved by the hospital’s institutional review board.
Clinical Information We collected baseline demographics, laboratory results, and vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and cigarette smoking. Hypertension was defined as high blood pressure (systolic $ 140 mm Hg or diastolic $ 90 mm Hg) or the taking of antihypertensive agents. Diabetes mellitus was diagnosed by a high fasting plasma glucose level ($7.0 mmol/L) or the taking of hypoglycemic agents. Hyperlipidemia was defined by a high level of fasting serum total cholesterol ($6.2 mmol/L), low-density lipoprotein cholesterol ($4.1 mmol/L), or treatment with antihyperlipidemic agents after a diagnosis of hyperlipidemia. Patients were considered as smokers if they smoked within the 3-month period before admission. Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score at admission and discharge. Functional outcome was evaluated using the modified Rankin Scale (mRS) and unfavorable
outcome was defined as an mRS score of 3 or more at 3 months after symptom onset. Stroke subtypes were established using the Trial ORG 10172 in Acute Stroke Treatment classification system.12 Both high and medium risk cardiac sources were considered as potential sources of cardioembolism.
Thyroid Function and Autoantibody Tests During the study period, we performed the laboratory tests for thyroid function and autoantibodies in the consecutive patients with acute ischemic stroke presenting within 7 days of symptom onset. Blood samples were taken in the morning after admission. Thyroid function was evaluated by measuring serum levels of tri-iodothyronine (T3), free thyroxine (FT4), and thyroidstimulating hormone (TSH). The reference ranges for T3, FT4, and TSH were 80-170 ng/dL, .75-2.0 ng/dL, and .3-5.0 mIU/mL, respectively. For the assessment of thyroid autoimmunity, serum concentrations of thyroperoxidase (TPO-Ab) and thyroglobulin (TG-Ab) autoantibodies were measured using radioimmunoassay with a commercial kit (Brahms, Hennigsdorf, Germany). The analytic sensitivities of the assays for TPO-Ab and TG-Ab were 5.5 and 5.5 U/mL, respectively, and the ranges for intra-assay coefficients of variation were 2.9%-4.5% and 2.0%-7.5%, respectively. The normal ranges for TPO-Ab and TG-Ab were of 60 U/mL or less each according to the manufacturer’s reference. Thyroid function was categorized into 3 groups based on the level of TSH, which consisted of hyperthyroidism (TSH , .3 mIU/L), euthyroidism (TSH .3-5.0 mIU/L), and hypothyroidism (TSH . 5.0 mIU/L). We divided the patients into 2 groups according to the levels of thyroid autoantibodies. Positive thyroid autoantibody (PAB) group was defined as either TPO-Ab or TG-Ab greater than 60 U/mL. Negative thyroid autoantibody (NAB) group was defined as TPO-Ab and TG-Ab of 60 U/mL or less concurrently. We evaluated the association of functional outcome and thyroid autoantibody levels with tertiles of TPO-Ab and TG-Ab titers.
Statistical Analysis Categorical variables were compared using Pearson chi-square or Fisher exact test, where appropriate. Continuous variables were compared using Mann–Whitney test because the values of T3, FT4, and TSH were not normally distributed. Descriptive data were given as frequencies (percentage) or median (interquartile range [IQR]). Multiple logistic regression analysis was used to determine the independent predictors associated with unfavorable outcome, in which variables with P less than .1 on univariate analysis were included. The results were expressed as odd ratios (OR) and 95% confidence intervals (CIs). Values of P less than .05 were considered statistically significant. All statistical analyses
THYROID AUTOANTIBODIES IN ACUTE ISCHEMIC STROKE
Table 1. Comparison of demographic, laboratory, and clinical features in patients with and without elevated thyroid autoantibodies PAB (n 5 121) Male Age NIHSS score at admission Hypertension Diabetes Hyperlipidemia Cigarette smoking Stroke subtypes Large-artery atherosclerosis Cardioembolism Small-artery occlusion Other determined Undetermined Laboratory results T3 (ng/dL) FT4 (ng/dL) TSH (mIU/mL) ESR (mm/h) hs-CRP (mg/dL) Fibrinogen (mmol/L) Clinical outcomes NIHSS score at discharge Unfavorable outcome at 3 mo Mortality at 3 mo
Abbreviations: ESR, erythrocyte sedimentation rate; FT4, free thyroxine; hs-CRP, high-sensitivity C-reactive protein; NAB, negative thyroid autoantibodies; NIHSS, National Institutes of Health Stroke Scale; PAB, positive thyroid autoantibody; T3, tri-iodothyronine; TSH, thyroidstimulating hormone. Values are number (column %) or median (interquartile range). *P , .05.
were performed with SPSS software 18.0 for Windows (SPSS, Inc., Chicago, IL).
Results Of the 1035 patients, 272 were excluded because of known thyroid disease (n 5 21, 2.0%), use of levothyroxine or antithyroid medication during admission (n 5 25, 2.4%), administration of thrombolytic therapy (n 5 191, 18.5%), unperformed thyroid function or autoantibody tests (n 5 11, 1.1%), and unavailable data for mRS at 3 months (n 5 24, 2.3%). Finally, a total of 763 patients were eligible for this study. The median age was 68 (IQR 58-75) years, and 480 (62.9%) patients were men. The median time interval from symptom onset to hospital arrival was 12.9 (IQR 3.6-38.6) hours. Of the 763 patients, 121 (15.9%) were of the PAB group. Hypothyroidism was found in 36 patients (4.7%), euthyroidism in 655 (85.9%), and hyperthyroidism in 72 (9.4%). The patients with elevated thyroid autoantibodies were the most commonly found in those with hyperthyroidism in 20 (27.8%), followed by hypothyroidism in 9 (25.0%) and euthyroidism in 92 (14.0%). The baseline demographics, laboratory results including thyroid function test, and clinical outcomes of
the PAB and NAB groups are shown in Table 1. The age, sex distribution, and vascular risk factors were not significantly different between the 2 groups. Higher NIHSS score at admission was observed in the PAB group than the NAB group (5 [2-14] vs 4 [1-9], P 5.001). Analysis of the frequency of stroke subtypes showed that the largeartery atherosclerosis was more frequent in the PAB group than in the NAB group (35.5% vs 24.8%, P 5 .014). The serum T3, FT4, and TSH levels did not differ between the groups. In the PAB group, NIHSS score at discharge (3 [1-11] vs 2 [0-6], P 5.007) and percentage of unfavorable outcome at 3 months (49.6% vs 34.4%, P 5 .002) were significantly higher compared with the NAB group, with no difference in mortality rate at 3 months. In univariate analysis for the factors associated with functional outcome, male gender, hyperlipidemia, cigarette smoking, and small-artery occlusion were more frequently observed in patients with favorable outcome. Higher levels of hemoglobin, T3, and TSH were also related with favorable outcome. In contrast, older age, higher NIHSS score at admission, hypertension, diabetes mellitus, cardioembolism, higher levels of fasting glucose and FT4, and PABs were significantly associated with
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Table 2. Univariate analysis for the factors associated with functional outcome Outcome Favorable (n 5 482) Male Age NIHSS score at admission Hypertension Diabetes Hyperlipidemia Cigarette smoking Stroke subtypes Large-artery atherosclerosis Cardioembolism Small-artery occlusion Other determined Undetermined Laboratory results Hemoglobin (g/dL) Platelet count (103/mL) Total cholesterol (mmol/L) Fasting glucose (mmol/L) T3 (ng/dL) FT4 (ng/dL) TSH (mIU/mL) Positive thyroid autoantibodies
Abbreviations: FT4, free thyroxine; NIHSS, National Institutes of Health Stroke Scale; T3, tri-iodothyronine; TSH, thyroid stimulating hormone. Values are number (column %) or median (interquartile range). *P , .05. yP , .1.
unfavorable outcome (Table 2). After adjusting for confounders, multivariate analysis showed that male gender (OR 1.641, 95% CI 1.066-2.526, P 5 .024), older age (OR 1.034, 95% CI 1.017-1.052, P , .001), higher NIHSS score at admission (OR 1.205, 95% CI 1.165-1.247, P , .001), higher fasting glucose level (OR 1.131, 95% CI 1.0331.237, P 5 .007), lower T3 level (OR .985, 95% CI .976.995, P 5 .002), and PABs (OR 1.661, 95% CI 1.013-2.724, P 5 .044) were significant and independent predictors of unfavorable outcome. The values of FT4 and TSH were not associated with functional outcome (Table 3). Functional outcomes according to the levels of TPO-Ab and TG-Ab did not reach statistical differences in tertile analysis (P 5 .141 and .611). However, patients with higher levels of thyroid autoantibodies tended to have higher prevalence of unfavorable outcome in both autoantibody groups (Fig 1).
Discussion This study showed that elevated thyroid autoantibodies were independently associated with unfavorable outcome in patients with acute ischemic stroke. As far as we can ascertain, this is the first report to suggest a
possible impact of thyroid autoimmunity on functional outcome. Although the precise mechanism cannot be drawn from this study, the most likely speculation is that immune-mediated vascular damage may contribute to the increased risk of unfavorable outcome in ischemic stroke patients, by providing insufficient cerebral blood flow throughout the ischemic area. Various researchers demonstrated the presence of antigenic sites for thyroid autoantibodies on the cerebral vasculature,1,2 which may lead to cross-reactivity between thyroid gland and vascular tissues. This pathogenesis was supported by 2 reports showing cerebral vasculitis because of the deposition of immune complexes in patients with Hashimoto thyroiditis.5,6 In addition, the previous study showed impairment of endothelial-dependent arterial dilatation in Hashimoto thyroiditis patients, indicating that immune response is associated with endothelial dysfunction.3 Both immune-mediated inflammatory reaction and endothelial dysfunction may be the crucial steps in the development of atherosclerosis,13,14 and recent evidences have demonstrated that thyroid autoantibodies were in association with the occurrence of intracranial arterial stenosis.4 Our result that the patients with elevated thyroid autoantibodies were more
THYROID AUTOANTIBODIES IN ACUTE ISCHEMIC STROKE
Table 3. Multivariate analysis for the predictors determining functional outcome Unfavorable outcome
Male Age NIHSS score at admission Fasting glucose T3 (ng/dL) FT4 (ng/dL) TSH (mIU/mL) Positive thyroid autoantibodies
Abbreviations: CI, confidence interval; FT4, free thyroxine; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; T3, tri-iodothyronine; TSH, thyroid-stimulating hormone.
likely to suffer from large-artery atherosclerosis than those without may be in line with such a pathomechanism. Endothelial dysfunction and resultant impairment of cerebral perfusion have the prognostic significance in the acute stage of ischemic stroke.15,16 Therefore, the previous studies that revealed decreased brain perfusion in patients with autoimmune thyroiditis may strengthen the hypothesis of a possible relationship between thyroid autoantibodies and unfavorable functional outcome in acute ischemic stroke patients.10,11 Several studies have investigated that thyroid dysfunction may involve short-term and long-term cerebrovascular consequences. This study demonstrated that lower level of T3 was an independent predictor of unfavorable outcome 3 months after ischemic stroke. Low T3 syndrome is known as nonthyroidal illness syndrome or sick euthyroid syndrome, in which the hormonal condition is a reduction of serum T3 without the elevation of serum TSH. The most commonly cited mechanism is a decrease in the peripheral production of T3 because of
Figure 1. Tertile analysis for functional outcomes according to serum concentrations of thyroperoxidase and thyroglobulin autoantibodies.
alterations in the activity of the enzyme responsible for extrathyroidal conversion of T4 into T3.17 Consistent with our result, these hormonal changes have been described as being associated with worse clinical severity at presentation and a prognostic risk factor for poor outcome and mortality in stroke patients.18-20 However, further studies are warranted to determine whether low T3 syndrome is just an index representing the severity of ischemic stroke or a factor with the causal relationship to functional outcome because limited and controversial data regarding the efficacy of the correction for low T3 state are available.21 In acute phase of ischemic stroke, we found that hyperthyroidism was more frequently observed compared with hypothyroidism. This finding is supported by a previous study, which showed that TSH value in acute stroke patients admitted within 12 hours after symptom onset remained low through day 5 and began to increase on day 7. Conversely, FT4 level was initially high and had a decreasing tendency during the first 7 days.22 Hyperthyroidism has been investigated as a risk factor for poor functional outcome in ischemic stroke patients.23 Although the actual mechanisms contributing to this relationship have not been elucidated, some putative explanations include changes in coagulation factors, increased sympathetic nervous activity, and impaired ischemic tolerance because of an increase in oxygen consumption.24,25 This study showed that neither TSH nor FT4 level was not associated with functional outcome. Interestingly, the patients with elevated thyroid autoantibodies were the most commonly observed in those with hyperthyroidism, accounting for 27.8%. Therefore, based on the deleterious influence of thyroid autoantibodies on functional outcome, we assume that thyroid autoantibodies may affect unfavorable outcome in acute ischemic stroke patients with hyperthyroidism. Our findings should be interpreted with caution. First, elevated thyroid autoantibodies in the acute stage of ischemic stroke may be an epiphenomenon of severe stroke, as in the previous study that showed elevated inflammatory markers were associated with poor outcome.26 However, in this study, the levels of serum biomarkers representing systemic inflammatory response, such as erythrocyte sedimentation rate and highsensitivity C-reactive protein, were not different between the PAB and the NAB groups, which may suggest that thyroid autoantibodies have direct relationship with functional outcome. Second, many patients (n 5 191, 18.5%) who underwent the thrombolytic treatment were excluded because reperfusion therapy has great effect on functional outcome. Therefore, a potential bias might be skewing our results toward recruitment of less severely affected patients among those admitted within the therapeutic time window for thrombolysis. Finally, we included the patients who presented within 7 days from symptom onset. This
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time window could be so broad in view of the fact that thyroid function is continuously changed in acute stage of ischemic stroke. However, in this study, 488 patients (63.9%) presented to our hospital on the day of symptom onset and 652 (85.5%) within 3 days, which makes our study somewhat homogenous. In conclusion, this study showed that elevated thyroid autoantibodies were independently associated with unfavorable outcome in patients with acute ischemic stroke. We suggested that endothelial dysfunction implicated by vascular autoimmune reaction could affect functional outcome, reducing cerebral perfusion throughout the ischemic area. Future study is needed to determine whether the regulation of thyroid autoimmunity can improve functional outcome in ischemic stroke patients, which may help to support the possibility raised by this study.
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Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke
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Although National Institutes of Health Stroke Scale (NIHSS) is a known predictor of outcome in acute ischemic stroke, there are other factors like age, ambulatory status, and ability to swallow that may be predictors of outcome but are not assessed b
The aim of this study was to examine the association between MI and PNA in the setting of acute ischemic stroke and patient outcome. Eligible patients were identified from a prospectively collected stroke registry and included if transthoracic echoca