Thyroid Research and Practice

ORIGINAL ARTICLE
Year
: 2016  |  Volume : 13  |  Issue : 1  |  Page : 19--24

Thyroid dysfunction in patients of hemorrhagic stroke


Apurva Pande, Vijay Kumar Goel, Amit Rastogi, Abhinav Gupta 
 Department of Medicine, Subharti Medical College, Meerut, Uttar Pradesh, India

Correspondence Address:
Apurva Pande
Department of Medicine, Subharti Medical College, Meerut - 250 005, Uttar Pradesh
India

Abstract

Introduction: Alteration in the thyroid profile has been associated with occurrence of stroke. A lot of work is being done all over the world in order to establish a link between the two events. Materials and Methods: In the present study the variation in the thyroid profile of the patients presenting within 48 hrs of an acute hemorrhagic stroke were studied. Results: Of the 185 patients included in the study, 124 had nonthyroidal illness syndrome (NTIS), 35 were euthyroid, 15 were hyperthyroid, eight had subclinical hypothyroidism (SCH), and three had hypothyroidism. A low free triiodothyronine (FT3) level was associated with unfavorable outcome as accessed by the Glasgow Coma Scale (GCS) and the Scandinavian Stroke Scale (SSS) scoring. Conclusion: In the present study involving patients of acute hemorrhagic stroke, high mortality rates were observed in patients with a low FT3 and free thyroxine (FT4).



How to cite this article:
Pande A, Goel VK, Rastogi A, Gupta A. Thyroid dysfunction in patients of hemorrhagic stroke.Thyroid Res Pract 2016;13:19-24


How to cite this URL:
Pande A, Goel VK, Rastogi A, Gupta A. Thyroid dysfunction in patients of hemorrhagic stroke. Thyroid Res Pract [serial online] 2016 [cited 2019 Jul 23 ];13:19-24
Available from: http://www.thetrp.net/text.asp?2016/13/1/19/159531


Full Text

 Introduction



Cerebrovascular accident (CVA) represents an acute stress state with a complex pathophysiological mechanism. It usually affects the elderly and is associated with varying degrees of central nervous system (CNS) involvement and hormonal alteration. Acute hemorrhagic stroke is a leading cause of mortality and morbidity in adults. Several conditions like hypertension, atherosclerosis, diabetes mellitus, thyroid dysfunction, etc., are identified as risk factors in the etiology of stroke. To what extent these factors contribute to the aggravation of stroke-induced injury and neurological deficits is not clearly known.

Thyroid hormones, in addition to their role in cellular metabolic activity also regulate neural development. The CNS is particularly dependent on thyroid hormone for normal maturation and function. In addition circulating thyroid hormone levels seem to modulate the outcome of ischemic reperfusion injury (Smith et al).[1] Several comorbidities have been associated with increased mortality in acute stroke patients. Hypothyroidism is considered as a possible risk factor for stroke although there are few studies to prove this. It is not known whether hypothyroidism (either clinical or subclinical) affects outcome in patients with acute cerebrovascular disease.

Hypothyroidism has been shown to be neuroprotective in stroke patients (Alevizaki et al).[2] In a detailed study on 744 acute stroke patients having a median age of 70 years, it was observed that hypothyroid patients had a better survival at follow-up. Similarly Baek et al.,[3] 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 which suggest 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 (LDL) cholesterol particles, induction of diastolic hypertension, altered coagulability, and direct effects on vascular smooth muscle. Furthermore, some evidences suggest that hypothyroidism may exacerbate the cardiovascular risks associated with cigarette smoking and insulin resistance. Elevated levels of total cholesterol, LDL cholesterol, and apolipoprotein B are well-documented features of overt hypothyroidism. Significant progress has been made in clarifying the mechanisms leading to these adverse changes in circulating lipid concentrations. Early studies in humans with hypothyroidism, using isotopically labeled LDL, demonstrated a prolonged half-life of LDL cholesterol because of decreased catabolism, an effect that was reversible with T4 therapy.

Cappola and Ladenson [4] showed a link between hypothyroidism and atherosclerosis. They observed that coronary artery atherosclerosis was twice as common in patients with hypothyroidism. Atherosclerosis, in turn, may lead to strokes. In such patients adequate thyroid hormone replacement therapy protects disease progression (Perk and O'Neill).[5] Thus, SCH could also be a risk factor itself.

The nonthyroidal illness syndrome (NTIS or 'euthyroid sick syndrome' or low-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 triiodothyronine (T3) levels. In the presence of more severe illness, a fall in the level of thyroxine (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.,[6] 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 the 20th century, researchers found that thyroid dysfunction is associated with the mortality of patients admitted to the ICU. Whether thyroid hormone indicators can predict ICU mortality independently is unclear till now. In a recent study by Wang et al.,[7] it was found that free T3 (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 unanimity regarding the precise role of thyroid hormone in CVA patients. Most of the studies done till now focused on patients on ischemic stroke. The present study aims to establish a link between hemorrhagic CVA and thyroid dysfunctions.

 Materials and Methods



Patients of hemorrhagic stroke who were admitted to Subharti Medical College and associated Chhatrapati Shivaji Subharti Hospital, Meerut comprise the subjects of study.

A total of 185 patients of hemorrhagic stroke were studied who attended the institution from the period November 2010 to July 2012.

Every patient was subjected to a detailed clinical history and neurological examination. Two neurological scores viz. 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 > 90 mmHg, or both diagnosed at least twice before the stroke or treatment of hypertension has been given.

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 prior to the CVA.

In each patient a thyroid profile was done which included FT3, free T4 (FT4), TSH, and anti-thyroid peroxidase (TPO) antibody.

The thyroid hormones (FT3, FT4, and TSH) were done on VIDAS automated analyzer using dry chemistry by enzyme-linked fluorescent assay (ELFA) 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; 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. Value of FT3, FT4, 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 FT4, and a low or normal TSH Euthyroid was diagnosed as a normal FT3, FT4, and TSH Hyperthyroid was diagnosed as high FT3, a high FT4, and a low TSH Hypothyroid was diagnosed as a low FT3, a low FT4, and a high TSH SCH was diagnosed as a low or normal FT3, a normal FT4, and a high TSH.

All the values were expressed in terms of mean and SD and statistical analysis was carried out by using Z test at 5% and 1% level of significance, respectively. Further Karl Pearson correlation coefficient was calculated between the low profile group and the high profile group. Analysis of Variance (ANOVA) and 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.

Patients excluded from the study were those who presented to the hospital after 48 h of the event, who have head injury, sub arachnoid haemorrhage (SAH), tumors, and CNS infections. Patients with sepsis, renal, hepatic dysfunction, and drugs known to alter thyroid profile and those with known prior thyroid dysfunction.

 Results



On analysis of the age and sex distribution of the study population, it was found that in the age group <49, 50–59, 60–69, and >70 years the males and females were 14 (8%) and 10 (5%), 15 (8%) and nine (5%), 39 (21%) and 32 (17%), and 42 (23%) and 24 (13%), respectively [Figure 1].{Figure 1}

Among 185 patients, 161 (87%) had a GCS score of <8. Amongst these 122 (66%) patients had FT3 < 4 pmol/L, 37 (20%) had FT4 < 9 pmol/L, and eight (4%) had TSH > 5 µIU/L. Twenty-four (12.9%) patients has a GCS score of >8, of these 15 (8%) had FT3 < 4 pmol/L, four (2%) had FT4 < 9 pmol/L, and 5 (3%) had TSH > 5 µIU/L.

Out of 185 patients, 145 (78.3%) had a SSS score < 15, of these 114 (62%) had FT3 < 4 pmol/L, 35 (19%) had FT4 < 9 pmol/L, and 10 (5%) had TSH > 5 µIU/L. Forty (21.6%) patients had a SSS score of >15, among these 23 (12%) had FT3 < 4 pmol/L, six (3%) had FT4 < 9 pmol/L, and five (3%) had TSH > 5 µIU/L [Figure 2].{Figure 2}

The age and gender distribution of the patients in the study population showed that in the age group of <49, 50–59, 60–69, and >70 years the number of males and females with hypertension were five (5%) and five (5%), six (7%) and six (7%), 17 (18%) and 22 (24%), and 14 (15%) and 17 (18%), respectively.

In the age group of <49, 50–59, 60–69, and >70 years the number of males and females with type 2 diabetes mellitus were four (6%) and three (4%), five (7%) and six (8%), 10 (14%) and 13 (18%), and 21 (29%) and 10 (14%), respectively.

Within the study population in the age group of <49, 50–59, 60–69, and >70 years the number of males and females who had smoking as a risk factor were four (5%) and five (7%), two (3%) and 10 (14%), 14 (19%) and 13 (18%), and 15 (21%) and 10 (14%), respectively.

Of the total 185 patients studied, only 123 (66.4%) survived. The range and mean ± SD of FT3 and FT4 were 0.32–15.7 and 3.28 ± 13.05, and 0.87–93.3 and 16.3 ± 15.5, respectively.

Among 124 patients of NTIS studied, only 90 (72.5%) survived. In these patients the range and mean ± SD of FT3 and FT4 were 0.32–3.82 and 2.56 ± 1.61, and 0.87–19.8 and 16.63 ± 19.2, respectively.

Among the 35 euthyroid patients studied, only 22 (72.5%) survived. In these patients the range and mean and SD of FT 3 and FT 4 were 1.82–8.82 and 2.58 ± 1.62, and 7.49–19.77 and 16.18 ± 18.5, respectively.

Fifteen patients turned out to be hyperthyroid. Of these, only seven (46.6%) survived. In these patients the range and mean ± SD of FT 3 and FT 4 were 8.7–15.7 and 10.2 ± 1.8, and 21–93.9 and 76.98 ± 18.5, respectively.

Eight patients turned out to be subclinically hypothyroid. Among these only three (46.6%) survived. In these patients the range and mean ± SD of FT 3 and FT 4 were 0.60–5.2 and 2.13 ± 1.61, and 8.69–13.67 and 11.17 ± 1.86, respectively.

In the study population, three patients were hypothyroid and only one (33.3%) survived. Amongst these patients the range, mean, and SD of FT3 and FT4 were 0.97–3.14 and 2.18 ± 1.1 and 6.2–12 and 8.7 ± 2.9, respectively [Table 1].{Table 1}

 Discussion



Patients in the study group were subdivided into five subgroups on the basis of their thyroid profile, viz. NTIS, euthyroid, hyperthyroid, hypothyroid, and SCH. The variation in thyroid profile in all these groups was further analyzed.

During critical illness, changes in circulating hormonal levels are a common phenomenon.[8] These alterations are correlated with the severity and outcome of patients in ICU.[9],[10] Thyroid hormone plays a key role in the maintenance of the body growth, modulating metabolism, and the immune system. Back in the last century, studies had found that thyroid dysfunction was associated with the mortality of patients admitted to the ICU.[11],[12],[13] These alterations in serum thyroid hormone levels are referred to as the “euthyroid sick syndrome”[14],[15] or “NTIS”[16],[17] and are characterized by low serum levels of free and total T3 and high levels of reverse T3 (rT3), accompanied by normal or low levels of T4 and normal or low levels of TSH. In the present study, 124 patients had NTIS. Subsequent studies confirmed the association between NTIS and adverse outcome in patients with sepsis,[18],[19] multiple trauma,[20] acute respiratory distress syndrome,[21] respiratory failure,[22] and mechanical ventilation,[23] as well as in unselected ICU patients.[11],[24],[25],[26],[27],[28],[29],[30] Some studies [23],[24] demonstrated that FT3 levels in nonsurvivors was significantly lower as compared to survivors, while other studies [25] showed no association between FT3 levels and outcome of ICU patients. In the present study a GCS < 8 was present in 66% patients and an SSS score < 15 was present in 62% patients. Wang et al.,[7] on the basis of their study on 480 patients admitted to the ICU concluded that FT3 was the most powerful and only independent predictor of ICU mortality. A few other studies have also detected the independent predictive ability of thyroid hormones [11],[24],[26],[27],[30] and additive ability of thyroid hormones to scoring system for predicting ICU mortality [11],[26] have also been accessed.

NTIS describes a condition characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. During acute phase of critical illness, the alterations in thyroid hormones appear as decreased T3, increased T4 and rT3, and normal TSH.[31] In the chronic phase of critical illness, central hypothyroidism is developed and NTIS presents as decreased T3, T4, and TSH.[31] During recovery phase of critical illness, the thyroidal axis begins with a rise in serum TSH and is eventually followed by normalization in T4 concentrations.[31] In a study of 480 unselected ICU patients, FT3 was found the most powerful predictors of ICU mortality.[7] The most common abnormality is the decrease in T3 levels. In the presence of more severe illness, a fall in the levels of T4 occurs while the TSH levels do not show the expected pituitary thyroid axis reactivity. These changes are associated with disease severity [32] and have been connected with poor short-term prognosis.[14],[28],[33],[34]

Recent studies have shown that low T3 may be associated with increased mortality in patients with severe heart disease or respiratory failure who were followed-up longitudinally.[23],[35] Various other stress states such as starvation, surgery, and sepsis may also result in low FT3 levels.[15],[33],[36] NTIS results mainly from changes in peripheral thyroid hormone metabolism, due to alterations in the activity of the enzymes responsible for peripheral conversion of T4 to T3, 5'-monodeiodinases I and II (D1 and D2).[34],[37] Recent evidence suggests that proinflammatory cytokine action is possibly associated with the development of NTIS and specifically that interleukin 6 (IL6) and tumor necrosis factor-alpha (TNF-α) secondary to nuclear factor (NF) kappa B activation may be involved in the pathophysiology of this syndrome,[38],[39] although this has not been a universal finding.[40] Further suggested mechanisms include disturbed nuclear binding and a shift in the distribution of thyroid hormones or an alteration in binding proteins.[16],[36],[41] It has also been opined that the low-T3 syndrome may represent some form of central hypothyroidism.[36],[42]

In the present study, the increased mortality in patients of SCH can be explained on the basis of a low level of FT3. The mortality was higher in patients with SCH which was defined as a low or a normal FT3, a normal FT4, and a high TSH. However, the patients with overt hypothyroidism also had a low FT3, but the proportion of patients having a low FT4 and a low FT3 along with a high TSH was lower than the patients having the thyroid profile consistent with SCH. The patients with low FT3 had a poor neurological outcome as evidenced by a SSS score of <15 and a GCS <8.

No data exists on possible association between thyroid function tests and severity of acute stroke. Furthermore, it is not known if thyroid hormone metabolism has any prognostic value for the outcome in patients with acute stroke.

In the present study we assessed thyroid hormone status in patients admitted to hospital for first ever acute hemorrhagic stroke. True hypothyroidism is a totally different entity, characterized by low T4 and elevated TSH levels and it has been reported that preexisting hypothyroidism may even be protective in acute stroke.[2] Both central as well as peripheral changes have been suggested to be involved in the pathophysiology of the low-T3 syndrome.[15],[16],[36]

Most of the patients in the present study were above the age of 60 years. It has been proved that subclinical thyroid disease and nonthyroidal illness are common in the elderly.[43] Studies have also shown that after excluding subjects with nonthyroidal illness; TSH decreased, FT4 remained steady, FT3 decreased, and rT3 increased with aging.[44] These changes in the elderly can be attributed to the presence of a partial central hypothyroidism due to an impaired activity of type 1 deiodinase (5'D-I). Similarly a reduction in the levels of TSH has been reported in selected healthy old subjects [45] and in a few unselected patients unrelated to subclinical hyperthyroidism.[46] On accessing the patients with the NTIS or euthyroid sick syndrome in hemorrhagic (n = 124), it was observed that out of 124 patients only 90 (72.5%) survived. In this cohort the range and mean ± SD of FT3 and FT4 were 0.32–3.82 and 2.56 ± 1.61, and 0.87–19.8 and 16.63 ± 19.2, respectively.

 Conclusion



In the present study involving patients of acute hemorrhagic stroke, high mortality rates were observed in patients with a low FT3 and FT4. Consequently, low FT3 and low FT4 predict a poor outcome in patients of hemorrhagic stroke.

Ethical committee clearance taken.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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