|Year : 2017 | Volume
| Issue : 1 | Page : 32-37
Thyroid dysfunction in patients of ischemic cerebrovascular accidents
Apurva Pande, Vijay Kumar Goel, Amit Rastogi, Abhinav Gupta
Department of Medicine, Subharti Institute of Medical Sciences, Meerut, Uttar Pradesh, India
|Date of Web Publication||20-Feb-2017|
Department of Medicine, Subharti Institute of Medical Sciences, Subhartipuram, NH-58, Delhi-Haridwar Bypass Road, Meerut - 250 001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Thyroid dysfunction has been associated with cerebrovascular accidents (CVAs) and is an area of active research in the present times. Materials and Methods: In the present study we tried to establish a relation between the variation in thyroid profile and ischemic CVAs in 75 patients who were admitted to our hospital within 48 hours of the event. Results: Of the 75 patients, 43 had nonthyroidal illness syndrome (NTIS), 13 were euthyroid, 6 were hyperthyroid, 9 were subclinical hypothyroid, and 4 were hypothyroid. Conclusion: In ischemic cases, high mortality rates were observed in euthyroid patients followed by patients with NTIS. A low FT3 level was associated with unfavorable outcome as accessed by the Glasgow Coma Scale and the Scandinavian Stroke Scale scoring.
Keywords: Cerebrovascular accident, euthyroid, nonthyroidal illness syndrome, thyroid dysfunction
|How to cite this article:|
Pande A, Goel VK, Rastogi A, Gupta A. Thyroid dysfunction in patients of ischemic cerebrovascular accidents. Thyroid Res Pract 2017;14:32-7
|How to cite this URL:|
Pande A, Goel VK, Rastogi A, Gupta A. Thyroid dysfunction in patients of ischemic cerebrovascular accidents. Thyroid Res Pract [serial online] 2017 [cited 2017 May 25];14:32-7. Available from: http://www.thetrp.net/text.asp?2017/14/1/32/200568
| Introduction|| |
At present, cerebrovascular accidents (CVAs) are the leading cause of morbidity and mortality. It is a form of acute stress and has a detrimental effect on various neurophysiological pathways. Conditions such as hypertension, atherosclerosis, diabetes mellitus, and thyroid dysfunction are identified as risk factors in the etiology of stroke. It is not known till date as to what extent each one of these risk factors contribute to the pathophysiology of CVA.
Thyroid hormones have an important role in regulating cellular metabolic activity and neural development. Circulating thyroid hormone levels seems to modulate the outcome of ischemic reperfusion injury. A number of comorbidities have been associated with increased mortality in acute stroke patients. Hypothyroidism is a possible risk factor for stroke although there are very few studies to prove this. It is not known whether hypothyroidism (either clinical or subclinical) affects outcome in patients with acute cerebrovascular disease.
A neuroprotective role of hypothyroidism has been shown in acute stroke patients. In a detailed study on 744 acute stroke patients with a median age of 70 years, they observed that hypothyroid patients had a better survival at follow-up. Similarly, Baek et al. also concluded that acute ischemic patients with subclinical hypothyroidism (SCH) were more likely to show functional outcomes than those without SCH. On the other hand, there are reports suggesting that hypothyroidism alters several traditional risk factors for cardiovascular disease. These studies support a biologically possible role for hypothyroidism increasing the risk of atherosclerotic cardiovascular diseases, via increases in circulating levels of highly atherogenic low-density lipoprotein cholesterol particles, induction of diastolic hypertension, altered coagulability, and direct effects on vascular smooth muscle. Furthermore, some evidence suggests that hypothyroidism may exacerbate the cardiovascular risks associated with cigarette smoking and insulin resistance.
Cappola and Ladenson  showed a link between hypothyroidism and atherosclerosis which in turn may lead to stroke. In such patients, adequate thyroid hormone replacement therapy protects disease progression. The nonthyroidal illness syndrome (NTIS or “euthyroid sick syndrome” or low triiodothyronine [T3] syndrome) is frequently encountered in hospitalized patients, especially those in Intensive Care Units (ICUs) and describes abnormalities in thyroid function tests in the absence of obvious thyroid disease. The most common abnormality is a decrease in T3 levels. In the presence of more severe illness, a fall in the level of thyroxin (T4) occurs while the thyroid-stimulating hormone (TSH) levels do not show the expected pituitary-thyroid axis reactivity. These changes are associated with disease severity and have been connected with poor short-term prognosis. Alevizaki et al. conducted a study on 737 consecutive patients with acute first-ever stroke who presented within 24 h from symptom onset and concluded that a high proportion of these patients had low T3 values. The low T3 syndrome is an independent predictor of early and late survival in patients with acute stroke and predicts handicap at 1 year.
During critical illness, changes in circulating hormone levels are a common phenomenon. These alterations are correlated with the severity of morbidity and the outcomes of patients in ICUs. Thyroid hormones play a key role in the maintenance of body growth by modulating metabolism and the immune system. In a recent study by Wang et al., it was found that FT3 was the most powerful predictor of ICU mortality among the complete thyroid hormone indicators, thereby highlighting the importance of FT3 as a predictor of ICU mortality.
Review of literature shows that there is no common consensus regarding the precise role of thyroid hormones in CVA patients. The present study aims to establish a link between the thyroid hormones dysfunction in patients of ischemic stroke.
| Materials and Methods|| |
Patients of ischemic stroke who were admitted to Subharti Medical College and Associated Chhatrapati Shivaji Subharti Hospital, Meerut, were included in this study. We studied 75 patients who suffered from ischemic stroke and were admitted to the institution from November 2010 to July 2012.
Every patient was subjected to a detailed clinical history and neurological examination. Two neurological scores, namely, the Glasgow Coma Scale (GCS) and the Scandinavian Stroke Scale (SSS) were used to access the neurological outcome. A history of hypertension was defined as systolic blood pressure >140 mmHg or diastolic blood pressure of >90 mmHg, or both diagnosed at least twice before the stroke or treatment of hypertension has been given. The presence of Type 2 diabetes mellitus was defined as use of oral hypoglycemic agents or insulin before the occurrence of CVA or an HbA1c level >7. Current smoking was considered as present when the patient had smoked daily before the CVA. In each patient, a thyroid profile was done which included FT3, FT4, TSH, and anti-thyroid peroxidase antibody.
The thyroid hormones (FT3, FT4, and TSH) were done on VIDAS automated analyzer using dry chemistry by enzyme-linked fluorescent assay technique. The range, mean ± standard deviation (SD) of FT3, FT4, and TSH were 3.47–8.81, 4.8 ± 1.17, 7.49–19.77, 13 ± 3.23, and 0.25–4.36, 1.2 ± 1.2, respectively. Any value of FT3, FT4, and TSH <3.47, <7.49, and >4.36, respectively, were taken as hypothyroid. The value of FT3, FT4, and TSH >8.81, >19.77, and <0.25, respectively, were taken as hyperthyroid.
On the basis of thyroid profile, the patients were divided into five categories: NTIS/euthyroid sick syndrome, euthyroid, hyperthyroid, hypothyroid, and subclinical hypothyroid.
- NTIS was diagnosed as a low FT3, low or normal, and low or normal TSH
- Euthyroid was diagnosed as normal FT3, FT4, and TSH
- Hyperthyroid was diagnosed as high FT3, high FT4, and low TSH
- Hypothyroid was diagnosed as low FT3, low FT4, and high TSH
- Subclinical hypothyroid was diagnosed as low or normal FT3, normal FT4, and high TSH.
All the values were expressed in terms of mean and SD, and statistical analysis was carried out using Z-test at 5% and 1% level of significance, respectively. Further, Karl Pearson correlation coefficient was calculated between low profile group and high profile group. Analysis of variance F- test was applied to the study population at 5% level of significance.
Patients included in the study were the ones who had a hemorrhagic stroke and those who presented to the hospital within 48 h of the event. Exclusion criteria included those patients who presented to the hospital after 48 h of the event; those who had head injury, subarachnoid hemorrhage, tumors, and central nervous system infections; patients with sepsis, renal, hepatic dysfunction and drugs known to alter thyroid profile; and those with known prior thyroid dysfunction.
| Results|| |
Analysis of the age and sex distribution showed that in the age group <49, 50–59, 60–69, and >70 years, the males and females were 12 (16%) and 5 (7%), 7 (9%) and 4 (5%), 9 (12%) and 11 (15%), and 14 (19%) and 13 (17%), respectively [Figure 1].
Analysis of the GCS score with the thyroid profile showed that of 75 patients, 64 (85.3%) had a GCS score of <8, of these 43 (57%) patients had FT3 <4 pmol/L, 10 (13%) had FT4 <9 pmol/L, and 10 (13%) had TSH >5 µIU/L. Eleven (12.9%) patients had a GCS score of >8, of these 7 (9%) had FT3 <4 pmol/L, 3 (4%) had FT4 <9 pmol/L, and 4 (5%) had TSH >5 µIU/L [Figure 2]. Analysis of the SSS score with the thyroid profile showed that of 75 patients, 58 (74.35%) had a SSS score <15, of these 40 (53%) had FT3 <4 pmol/L, 10 (13.3%) had FT4 <9 pmol/L, and 7 (9.3%) had a TSH >5 µIU/L. Seventeen (22.6%) patients had a SSS score of >15, of these 10 (13.3%) had FT3 <4 pmol/L, 3 (4%) had FT4 <9 pmol/L, and 4 (5.3%) had TSH >5 µIU/L [Figure 3].
|Figure 2: Correlation of Glasgow Coma Scale with thyroid profile in patients with ischemic cerebrovascular accidents|
Click here to view
|Figure 3: Correlation of Scandinavian Stroke Scale with thyroid profile in patients with ischemic cerebrovascular accidents|
Click here to view
In the age group of <49, 50–59, 60–69, and 70 years, the number of males and females with Type 2 diabetes mellitus and hypertension were 1 (100%) and nil, nil and nil, 2 (66.6%) and 1 (33.3%), and nil and 4 (100%), respectively.
Among 43 patients of NTIS studied, only 26 (60.4%) survived. Seven (16.2%) patients were lost to follow-up and 10 (23.2%) expired at different time intervals. In 43 patients studied, the range, mean and SD of FT3 and FT4 were 0.33–3.71, 2.22 ± 0.97 and 11.2–19.8, 10.99 ± 5.24, respectively.
Among 13 euthyroid patients studied, only 3 (60.4%) survived. Two (16.2%) patients were lost to follow-up and 8 (23.2%) expired at different time intervals. In 13 patients studied, the range, mean and SD of FT3 and FT4 were 4.01–8.81, 4.94 ± 1.29 and 9.42–16.21, 12.6 ± 2.47, respectively.
Among six hyperthyroid patients studied, only 3 (50%) survived. One (16.6%) patient was lost to follow-up and 2 (33.3%) expired at different time intervals. In six patients studied, the range, mean and SD of FT3 and FT4 were 9–24.56, 16.37 ± 6.28 and 72.06–106, 77.41 ± 28.11, respectively.
Among nine patients of SCH studied, only 4 (44.4%) survived. Three (33.3%) patients were lost to follow-up and 2 (22.2%) expired at different time intervals. In nine patients studied, the range, mean and SD of FT3 and FT4 were 3.13–4.6, 4.16 ± 0.6 and 9.6–19, 13.6 ± 2.95, respectively.
Among four hypothyroid patients studied, only 2 (50%) survived. One (25%) patient was lost to follow-up and 1 (25%) expired at different time intervals. In four patients studied, the range, mean and standard deviation of FT3 and FT4 were 0.43–4.8, 1.66 ± 1.38 and 0.64–4.8, 3.16 ± 1.8, respectively [Table 1].
|Table 1: Range, mean and standard deviation of the thyroid profile of the patients in each subgroup|
Click here to view
| Discussion|| |
Observations similar to the present study were made by Alevizaki et al. An analogous finding has been reported in a previous small study. In agreement, one study recently showed that low T3 was an independent predictor of 1-year death in patients with cardiac disorders. Low T3 was also the strongest predictor of death at 1 year in patients with respiratory failure.
Alevizaki et al., in 2007, found that a high proportion of patients with acute CVA were found to have low T3 levels soon after the event and low T3 syndrome is an independent predictor of early and late survival in these patients. It has, however, been noted that a fall in thyroid hormone levels occurs in most sick patients and there is a continuum from normal to low T3 levels; when the illness becomes worse, T4 levels also fall and the probability of death becomes higher., It has also been reported in studies performed in ICUs that in acute stroke patients, the combination of low T3 with low T4 appeared to be associated with worse prognosis.,,, This clearly shows that low FT3 and low FT4 levels are associated with poor neurological outcome. This fact has been demonstrated in the study by Zhang and Meyer. Results of the present study are in agreement with these studies as lower values of FT4 and FT3 were associated with low SSS scores and low GCS scores, thereby indicating a poor prognosis associated with these values. This might indicate the participation of central functional hypothyroidism in the most severely ill. Interestingly, the occurrence of both low T3 and T4 was not related to the brain region affected by stroke. This supports the view that our findings are related to a disturbance of thyroid hormone metabolism and not to structural/functional disturbance of the hypothalamic–pituitary–thyroid axis, resulting from blood supply abnormalities. Alevizaki et al. have reported that patients with preexisting hypothyroidism may have better survival after acute stroke, possibly because of the increased prevalence of transient ischemic attacks found in this subgroup of patients, which may be offering the advantage of brain “preconditioning.”
A reduction of serum T3 without elevation of TSH appears to be associated with the severity of stroke and worse clinical outcome., So far, there were two studies that have been published to address the importance of monitoring for NTIS after acute stroke. Hama et al. from Japan reported malnutrition and NTIS after stroke; another one was by Alevizaki et al. who described that low T3 level is associated with outcome in acute stroke patients from Greece. The probable correlation between the decrease of thyroid hormones and severity of stroke as well as the poststroke recovery needs further investigation.
In the present study, we found that low FT3 and FT4 levels were associated with poor prognosis in hemorrhagic and ischemic CVA as observed by the association between low values of FT3, FT4 and low scores on SSS and GCS. However, there was no statistically significant difference between low FT3 levels and patients with high GCS and SSS score. A retrospective study by Zhang and Meyer  showed the association of T3 levels with short-term outcome after the event of acute ischemic stroke. Low T3 has been reported in intracerebral hemorrhage from either trauma or hemorrhagic infarct.,
It has been generally accepted that low T3 accompanying severe illness is considered as an adoptive response to stress to spare energy.,,,, As seen in other systemic severe illness, a reduction of serum T3 without elevation of TSH appears to be associated with the severity of stroke and worse clinical outcome.,, Possible mechanisms include the following: (1) peripheral thyroid hormone metabolism changes due to alterations in activity of the enzymes responsible for peripheral conversion of T4 to T3,, (2) pro-inflammatory cytokine action involvement, (3) a disturbed shift in the distribution of thyroid hormones or an alteration in binding proteins,, (4) excessive glucocorticoids release in severe illness which produce inhibition of activities from hypothalamic–pituitary–thyroid axis and the conversion of T4 to T3.
In the present study cohort, a weak negative correlation was found between age and FT3 (−0.125) and a weak positive correlation was found between age and FT4 (0.101). A negative correlation was found between age and TSH values (−0.26). Zhang and Meyer  in their study showed that patients with low T3 were slightly but not significantly older than those with normal T3; Alevizaki et al. in their study showed significant older age in low T3 group. This may be due to the fact that elderly patients usually had a low baseline of thyroid function and tended not to fully compensate when such event occurs.
Low T3 appeared to be associated with stroke severity and short-term outcome; furthermore, there was a negative correlation detected between FT3 levels and SSS scores and GCS scores on admission among all patients. This finding indicates that a worse neurological impairment is related to the degree of a decrease in FT3 level; thus, FT3 levels monitoring could potentially serve as an easy, quick, and feasible prognostic parameter for clinicians in the future if confirmed by further studies. Similar findings were reported by Rothwell and Lawler. Our finding is consistent with Alevizaki et al. who stated that low T3 is a possible independent predictor for stroke outcome. As in several studies performed in ICUs, acute stroke patients with low T3 or the combination of T3 and T4 appeared to be associated with worse prognosis.,,,,,,, Also, interestingly, the alterations of T3 levels do not appear to be related to the region (anterior vs. posterior circulation) affected by stroke. This suggests that the alteration is related to a disturbance of thyroid hormone metabolism rather than a blood supply abnormality induced structural disturbance of the hypothalamic–pituitary–thyroid axis.
The issue of correcting the low T3 syndrome has indeed been discussed but not conclusively answered., Interestingly, experimental data have recently shown that in animals undergoing focal cerebral ischemia, the administration of T3 was associated with reduction of the infarct volume and improvement of the neurological deficit through a rapid, nongenomic effect. Low T3 levels constitute an independent prognostic risk factor for death in acute stroke patients. As there is still no conclusive answer to treatment of low FT3 in the patients of acute stroke, it would also be desirable to design a study on the effects observed by providing proper thyroid hormone replacement.
| Conclusion|| |
NTIS is commonly seen after acute ischemic stroke and low T3 is associated with worse neurological outcome. This fact was observed in the present study by the association between low values of FT3, FT4 and low scores on SSS and GCS. The severity of low T3 syndrome may be a useful predictor of functional improvement in patients with acute ischemic stroke; however, new studies with follow-up on the functional status and including a larger cohort are required to further establish the facts highlighted in the present study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Smith JW, Evans AT, Costall B, Smythe JW. Thyroid hormones, brain function and cognition: A brief review. Neurosci Biobehav Rev 2002;26:45-60.
Alevizaki M, Synetou M, Xynos K, Alevizaki CC, Vemmos KN. Hypothyroidism as a protective factor in acute stroke patients. Clin Endocrinol (Oxf) 2006;65:369-72.
Baek JH, Chung PW, Kim YB, Moon HS, Suh BC, Jin DK, et al.
Favorable influence of subclinical hypothyroidism on the functional outcomes in stroke patients. Endocr J 2010;57:23-9.
Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol Metab 2003;88:2438-44.
Perk M, O'Neill BJ. The effect of thyroid hormone therapy on angiographic coronary artery disease progression. Can J Cardiol 1997;13:273-6.
Alevizaki M, Synetou M, Xynos K, Pappa T, Vemmos KN. Low triiodothyronine: A strong predictor of outcome in acute stroke patients. Eur J Clin Invest 2007;37:651-7.
Wang F, Pan W, Wang H, Wang S, Pan S, Ge J. Relationship between thyroid function and ICU mortality: A prospective observation study. Crit Care 2012;16:R11.
Liang DS. Stroke and thyroid hormones. Zhonghua Shen Jing Jing Shen Ke Za Zhi 1991;24:352-4.
Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, et al.
Low-T3 syndrome: A strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708-13.
Bello G, Pennisi MA, Montini L, Silva S, Maviglia R, Cavallaro F, et al.
Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted to the ICU. Chest 2009;135:1448-54.
De Groot LJ. Dangerous dogmas in medicine: The nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151-64.
Chopra IJ. Clinical review 86: Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82:329-34.
McIver B, Gorman CA. Euthyroid sick syndrome: An overview. Thyroid 1997;7:125-32.
Van den Berghe G, de Zegher F, Bouillon R. Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827-34.
Wartofsky L, Burman KD. Alterations in thyroid function in patients with systemic illness: The “euthyroid sick syndrome”. Endocr Rev 1982;3:164-217.
Zhang Y, Meyer MA. Clinical analysis on alteration of thyroid hormones in the serum of patients with acute ischemic stroke. Stroke Res Treat 2010;2010. pii: 290678.
Hama S, Kitaoka T, Shigenobu M, Watanabe A, Imura I, Seno H, et al.
Malnutrition and nonthyroidal illness syndrome after stroke. Metabolism 2005;54:699-704.
Zhang Z, Cui Z, Zhang Y. Clinical analysis on alteration of thyroid hormones in the serum of patients with acute head injury. Acta Acad Med Nantong1996;16:70-1.
Liang DS. Stroke and thyroid hormones. Chin J Neurol Psychiatry 1991;24:352-84.
Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, et al.
Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin Endocrinol (Oxf) 1977;7:495-508.
Diekman T, Demacker PN, Kastelein JJ, Stalenhoef AF, Wiersinga WM. Increased oxidizability of low-density lipoproteins in hypothyroidism. J Clin Endocrinol Metab 1998;83:1752-5.
Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90:4559-65.
Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:3202-11.
Carter JN, Eastman CJ, Corcoran JM, Lazarus L. Effect of severe, chronic illness on thyroid function. Lancet 1974;2:971-4.
Squizzato A, Gerdes VE, Brandjes DP, Büller HR, Stam J. Thyroid diseases and cerebrovascular disease. Stroke 2005;36:2302-10.
Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002;23:38-89.
Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3'-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1695-9.
Nagaya T, Fujieda M, Otsuka G, Yang JP, Okamoto T, Seo H. A potential role of activated NF-kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106:393-402.
Faber J, Kirkegaard C, Rasmussen B, Westh H, Busch-Sørensen M, Jensen IW. Pituitary-thyroid axis in critical illness. J Clin Endocrinol Metab 1987;65:315-20.
Zhang Y, Meyer MA. Clinical analysis on alteration of thyroid hormones in the serum of patients with acute ischemic stroke. Stroke Res Treat 2010;2010. pii: 290678.
Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med 1995;23:78-83.
Stathatos N, Levetan C, Burman KD, Wartofsky L. The controversy of the treatment of critically ill patients with thyroid hormone. Best Pract Res Clin Endocrinol Metab 2001;15:465-78.
Klemperer JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, et al.
Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:1522-7.
Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, et al.
Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci U S A 2006;103:14104-9.
[Figure 1], [Figure 2], [Figure 3]