Authored by Dmytro Filimonov*
Abstract
Background: According to recent studies, thyroid hormones may have various effects on stroke severity, course and outcome, but underlying mechanisms of this association are still unclear.
Objective: The aim was to determine the relationship of thyroid hormones during stroke onset with stroke severity and outcome in clinical study.
Methods: In this study 168 adult patients with acute ischemic stroke were enrolled. Concentrations of free T3 (fT3), free T4 (fT4), TSH and basic stroke risk factors were assessed during 24h from symptoms onset. Neurological deficit was assessed by Scandinavian Stroke Scale (SSS). Disabling deficit was defined as mRs score ≥3 at 6 months after stroke.
Results: ANOVA showed that SSS scores were significantly higher in patients with fT3 level in 4th quartile (≥5.35 pmol/l) compared to 2-3rd quartile (SSS median 48 vs. 37, p=0,0481) and especially to 1st quartile (≤3,4050 pmol/l, SSS median 48 vs. 30, p=0,0018). In patients without prior stroke (n=124) baseline SSS-score was independently affected by fT3 (corrected R2 = 0.49, p < 0.0001). According to ROC-analysis, fT3 level <4,44 pmol/l was a predictor of disabling deficit (AUC = 0.727, specificity - 96.4%, sensitivity - 66.8%, p = 0.003). Univariate analysis showed association between poor outcome and low fT3, in multiple regression this association became insignificant only after correction for baseline SSS-score, but no other stroke risk factors
Conclusion: The study showed that a low serum free triiodothyronine level during stroke onset negatively affects the stroke severity in firsttime stroke patients and may be predictor of its unfavorable outcome. There was a trend for association between low free triiodothyronine and unfavorable stroke outcome after 6 months. Beneficial effects of additional fT3 supplement during stroke should be assessed in future studies.
Keywords: Ischemic stroke; Outcome; Thyroid hormones; Triiodothyronine
Abbreviations: AIS: Acute Ischemic Stroke; fT3: Free Triiodothyronine; fT4: Free Thyroxine; TSH: Thyroid-Stimulating Hormone; CRP: C-Reactive Protein; CI: Confidential Interval; ATP: Adenosine Diphosphate; SSS: Scandinavian Stroke Scale; mRs: Modified Rankin Scale
Introduction
Currently, in most countries, stroke is one of the leading causes of death and disability [1]. Despite certain advances in the treatment and prevention of cerebrovascular diseases, stroke remains in second place in the world among the diseases leading to death. According to numerous clinical studies, the most effective treatment for acute ischemic stroke is the restoration of cerebral blood flow by reperfusion methods, such as intravenous or selective thrombolysis, or mechanical thrombectomy [2,3]. However, reperfusion therapy is possible only within a relatively narrow therapeutic window [4]. In cases where thrombolysis or thrombectomy is not indicated or there are no opportunities for its implementation, modern approaches to patient management during the acute period of stroke include both secondary prevention of cerebrovascular disease and an attempt to reduce the severity of neurological deficit by protecting ischemic (but potentially viable) brain tissue in penumbra zone [5]. Nevertheless, despite the diversity of neuroprotective drugs, different in their mechanism of action and effective in preclinical studies, none of them has enough clinical efficacy. In this regard, the search for new approaches of neuroprotection remains one of the most important tasks of modern neuropharmacology [5].
The survival of the brain tissue under ischemia depends on the intensity of metabolism, oxygen demand, as well as the ability to maintain the redox potential and support the synthesis of highenergy compounds (ATP, etc.). The mechanism of action of most neuroprotectors is based on the effects on these processes [6,7]. Over the past decades, special attention had been paid to the neuroprotective properties of endogenous molecules such as VEGF, erythropoietin, brain neurotrophic factor, etc. It is known that triiodothyronine, an active form of the thyroid hormone thyroxin, separates tissue respiration and oxidative phosphorylation. This process leads to disruption of the Krebs cycle, reduced ATP production, hyperthermia, and has a potentially negative effect in acute cerebral ischemia [8]. On the other hand, it is known that triiodothyronine has several neuroprotective effects - it contributes to the capture of neurotoxic glutamate by astrocytes, stimulation of the Na + / K + membrane channels in neurons, the restoration of intracellular pH [9]. Thus, selective therapeutic effect on thyroid metabolism (stimulation or inhibition of the function of thyroid hormones) may be promising potential target for new approaches in the treatment of stroke.
In recent years, more publications appeared in the literature about the possible effect of thyroid hormones on the risk of development, severity and outcome of acute ischemic stroke. Nevertheless, the results of the published works are rather contradictory [10]. Finally, the nature of the influence of hyperor hypothyroidism on the course and outcome of a stroke is still unclear.
Aims
Aim of this study was to determine the relationship between markers of thyroid function and the severity of neurological and functional deficit in acute ischemic stroke.
Materials and Methods
This study was conducted at the single clinical and research center – V.K. Gusak Institute of Urgent and Reparative Surgery (Donetsk). 168 patients (women – 71, men – 97) aged 42 to 78 years with acute ischemic heterogeneous stroke were enrolled in this study. Patients with verified autoimmune thyroiditis or a malignancy were excluded from the study. Within 24 hours from stroke onset basic risk stroke factors were analyzed. Serum free triiodothyronine (fT3), free thyroxine (fT4) and the thyroid stimulator hormone (TSH) were determined using ELISA method (CHEMWELL EIA-analyzer with DRG-international assay kits). Blood sampling was performed during 24 hours from stroke onset. Neurological deficit was assessed using Scandinavian Stroke Scale (SSS). Poor stroke outcome was assumed as 3 or more points on the modified Rankin Scale (mRs) after 6 months from stroke onset. Thyroid hormones and TSH levels below 25 and above 75 percentiles were assumed as “low” and “high”, respectively.
Statistical analysis
Statistical analysis was performed using MedCalc v14 software. Continuous data with non-normal distribution is presented as median and 95% CI. For analysis of variation of neurological deficit ANOVA method was used and patients were divided to subgroups according to T3 levels: “hypothyroid” (T3 below 25-percentile), “euthyroid” (T3 in 25-75 percentile), “hyperthyroid” (T3 above 75 percentile). For determining impact of thyroid hormones on stroke outcome using logistic regression patient were dichotomized in subgroups with good outcome (mRs 0-2) and poor outcome (mRs 3-6).
Results
Strokes in the carotid territory were the most frequent (79% of all patients), with the atherothrombotic subtype being the most common (64%). The leading basic risk factors were arterial hypertension (65%), smoking (42%), coronary heart disease (29%), atrial fibrillation (27%). 49 patients (28%) had previously history of TIA or ischemic stroke, 119 patients had the ischemic stroke developed for the first time. Demographic characteristics of the examined patients are presented in Table 1.
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