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Abstract
Vasopressin is not measured routinely clinically, although the recent introduction of its stable precursor copeptin has changed this protocol. Vasopressin is generally estimated on the basis of the circulating levels of copeptin, an inactive peptide that is secreted in equimolar amounts together with the active stress hormone vasopressin.
Brain natriuretic peptide (BNP) has been recommended as a novel biomarker for diagnosis and management of heart faliure and can reflect left ventricular dysfunction.
The function of the thyroid gland is one of the most important in the human body as it regulates majority of the body’s physiological actions. The thyroid gland controls rate of metabolic processes throughout the body via the production of two hormones triiodothyronine and thyroxine (T4). These hormones have key roles in metabolism, development, protein synthesis, and the regulation of many other important hormones. Any dysfunction in the thyroid can affect the production of thyroid hormones (T3 and T4) which can be linked to various pathologies throughout the body. Of the most important conditions is the effect of thyroid hormone levels on cardiovascular and endothelial function.
The aim of this study is to assess the alteration of serum copeptin (as a surrogate marker for AVP) and brain natriuretic peptide (BNP) in patients with thyroid dysfunction. Also to assess the relation of this alteration to cardiovascular performance (left ventricular function) and endothelial function (flow mediated dilatation of the brachial artery) observed in patients with thyroid dysfunction.
The study included 60 patients and 20 healthy subjects. They were divided into 3 groups, group I included 30 hyperthyroid patients, group II included 30 hypothyroid patients, and group III included 20 euthyroid healthy subjects as a control group.
Serum copeptin and thyroid dysfunction
In the present study, in whole groups, there was a significant positive correlation between copeptin and TSH (p=0.0001) and a significant negative correlation between copeptin and T3 (p=0.0001) & copeptin and T4 (p=0.0001) denoting that copeptin is significantly increased in hypothyroid patients.
Serum copeptin and hyperthyroidism:
In the current study, mean serum copeptin in patients with hyperthyroidism was significantly lower than in controls (mean 2.24 ± 1.68 pmol/L Vs 3.34 ± 2.93 pmol/L, p=0.03) and in hypothyroid patients (mean 2.24 ± 1.68 pmol/L Vs 18.78 ± 11.29 pmol/L, p=0.0001).
Serum copeptin and hypothyroidism:
On the basis of the present study, mean serum copeptin level was significantly higher in hypothyroid patients who have increased TSH levels in comparison to controls (mean 18.78±11.29 pmol/L Vs 3.34±2.93 pmol/L, p=0.0001), and to hyperthyroid patients (mean 18.78 ± 11.29 pmol/L Vs 2.24 ± 1.68 pmol/L, p=0.0001). About 70% of hypothyroid patients had elevation of copeptin level above the upper limit of normal. There was a significant negative correlation between copeptin and T4 (p=0.007) and a positive correlation between copeptin and TSH, however this did not reach statistical significance.
Serum BNP and thyroid dysfunction
Serum BNP and hyperthyroidism:
In the present study serum BNP in hyperthyroid group was within the reference range in all patients and was lower than in control group (mean=3.35±0.7 ng/L Vs 3.60±1.38 ng/L, p=0.120), yet this didn’t reach statistical significance.
Serum BNP and hypothyroidism:
In the present study, mean serum BNP in hypothyroid group was significantly higher than in control group (mean=15.02 ± 6.9 Vs 3.60 ± 1.38, p=0.028), although only one patient had elevated serum BNP above reference range. Mean serum BNP was also higher in hypothyroid group than in hyperthyroid group (mean=15.02 ± 6.9 Vs 3.35 ± 0.7, p=0.068), yet this didn’t reach statistical significance.
Serum copeptin and BNP
In the present study, there was a significant positive correlation between serum copeptin and serum BNP in whole groups (p=0.004), and in hyperthyroid group (p=0.01). Also, in hypothyroid group serum copeptin correlated positively with serum BNP, yet this did not reach statistical significance.
Serum copeptin and BNP: relation to electrolytes
In the present study, in whole groups, serum copeptin showed a significant negative correlation with serum Na+ (p=0.0001) and with plasma osmolarity (p=0.0001). Also, there was a significant positive correlation between serum copeptin and urine Na+ (p=0.001). Copeptin correlated positively with urine osmolarity, yet this did not reach statistical significance. Serum BNP showed a significant negative correlation with serum Na+ (p=0.0001) and with serum osmolarity (p=0.002), whereas serum BNP showed a significant positive correlation with urine Na+ (p=0.0001), urine S.G (p=0.007) and urine osmolarity (p=0.007).
Although in the present study, in whole groups, serum TSH levels per se did not correlate with serum Na+, serum T4 showed a significant positive correlation with serum Na+ (P=0.004) and with plasma osmolarity (p=0.006), also did T3 (p=0.02) and (p=0.03) respectively.
Regarding serum K+ in the present study, in whole groups, it showed a significant negative correlation with T4 (p=0.04), while urine K+ showed a significant positive correlation with T3 (p=0.028) & with T4 (p=0.016) and a significant negative correlation with TSH (p=0.036).
In hyperthyroid group:
In the present study, there was no significant difference between serum Na+ and plasma osmolarity between hyperthyroid and control groups. Mean serum K+ was lower in hyperthyroid group than in control, yet this did not reach statistical significance. There was a significant positive correlation between urine K+ and T4 (p=0.01), whereas there was a significant negative correlation between urine Na+ and TSH (p=0.03).
In hypothyroid group:
In the current study, serum copeptin showed a significant negative correlation with serum Na+ (p=0.001) and with plasma osmolarity (p=0.001). Serum copeptin showed a significant positive correlation with urine Na+ (p=0.017).
In the present study, serum BNP showed a significant positive correlation with urine Na+ (p=0.0001), urine S.G (p=0.006) and urine osmolarity (p=0.006), while BNP showed a significant negative correlation with serum Na+ (p=0.007) and plasma osmolarity (p=0.023).
In the present study, serum Na+ showed a significant positive correlation with T4 (p=0.0001). Plasma osmolarity showed a significant positive correlation with T4 (p=0.001). Urine K+ showed a significant negative correlation with T4 (p=0.033).
Serum copeptin and BNP: relation to echocardiographic findings
In the present study, in whole groups, serum copeptin showed a significant negative correlation with EF (p=0.016), while it showed a significant positive correlation with E/A (p=0.017).
In hyperthyroid group:
In the present study, M mode echocardiography in the studied groups revealed that mean EDD in hyperthyroid patients was significantly lower than in control group (mean 49.68±3.94 mm vs 51.70±3.20 mm, p=0.026). Mean ESD in hyperthyroid patients was significantly lower than in control group (mean 30.80 ± 4.30 mm vs 34.55±3.65 mm, p=0.001). Mean EF was higher in hyperthyroid group than in control group, yet this did not reach statistical significance. Mean FS in hyperthyroid patients was significantly higher than in control group (mean 38.19 ± 5.14 % vs 33.18 ± 5.50 %, p=0.003).
Left ventricular diastolic filling as assessed by transmitral pulsed Doppler flow in the currently studied groups revealed that there was no significant difference in mean E/A (a parameter of diastolic function) between hyperthyroid group and control group, suggesting the absence of LV diastolic dysfunction in our patients with hyperthyroidism.
In the present study, assessment of LV function using mitral annular pulsed tissue Doppler revealed that mean early left ventricular filling (E’) was significantly lower in hyperthyroid group than in control group (0.14±0.05 vs 0.23±0.23, p=0.054), also mean E’/A’ was also lower in hyperthyroid group than in control group, yet it did not reach statistical significance. Concerning the global systolic function, the mean velocity of S wave was higher in hyperthyroid group than in control group, however, there was no statistical significance.
In hypothyroid group:
In the present study, M mode echocardiography in the studied groups revealed that mean EDD in hypothyroid patients was lower than in control group, yet it didn’t reach statistical significance. There was a significant decrease in mean ESD in hypothyroid group in comparison to control group (mean 31.63±5.47 mm vs 34.55±3.65 mm, p= 0.014) and there was a significant positive correlation between copeptin and ESD (p=0.01). There was no significant difference in mean EF between hypothyroid group and control group, and there was a significant negative correlation between copeptin and EF (p=0.002). In spite of being within normal range, mean FS in hypothyroid patients was significantly higher than in control group (mean 38.25±6.76 % vs 33.18±5.50 %, p=0.001) and there was a significant negative correlation between copeptin and FS (p=0.01).
Left ventricular diastolic filling as assessed by transmitral pulsed Doppler flow revealed that mean E/A showed no significant difference between the currently studied groups and control group.
In the present study, assessment of LV function using mitral annular pulsed tissue Doppler revealed that mean E’/A’ was significantly lower in hypothyroid patients in comparison to control group (mean 1.15±0.72 vs 1.48±0.48, p=0.03). More than half of the patients (53%) had E’/A’˂1, suggesting the presence of diastolic dysfunction in hypothyroid patients. Concerning the global systolic function, the velocity of S wave was lower in hypothyroid group than in control group, however, there was no statistical significance.
Correlation of serum copeptin and BNP to echocardiographic parameters of systolic & diastolic functions:
Concerning serum copeptin and BNP levels in correlation to LV function in hyperthyroid patients in the present study; there was no significant correlation between serum copeptin or serum BNP levels and both LV systolic & diastolic functions. Whereas in the studied hypothyroid patients, there was a significant positive correlation between ESD and copeptin (p=0.01), also between E/A and copeptin (p=0.001). There was a significant negative correlation between EF (p=0.002) & FS (p=0.01) and copeptin. There was no significant correlation between serum BNP levels and LV systolic & diastolic functions.
In the present study, 13 out of 16 patients with diastolic dysfunction, as evidenced by E’/A’˂1, had increased serum copeptin level, a fact which may suggest the relation between copeptin and diastolic dysfunction in hypothyroid patients.
Serum copeptin and BNP: relation to endothelial function
In the present study, there was a significant positive correlation between FMD and E’/A’ (p=0.005). Such finding suggests a possible common mechanism for the association of endothelial dysfunction with LV dysfunction in patients with thyroid disorders.
Hyperthyroid group:
The present study revealed that FMD in patients with hyperthyroidism was significantly lower than in controls (mean 7.60±5.54 % vs 12.61±5.49 %, p=0.002), suggesting the presence of arterial stiffness and endothelial dysfunction in hyperthyroid patients. There was a significant positive correlation between copeptin and FMD (p=0.01).
Hypothyroid group:
In the present study, FMD in patients with hypothyroidism was significantly lower than in controls (mean 8.88±7.21% vs 12.61±5.49 %, p=0.022). There was a significant positive correlation between FMD and E’/A’ in patients with hypothyroidism (p=0.014) suggesting a common underlying etiology for LV dysfunction and endothelial dysfunction in hypothyroid patients, a condition which may be related to high copeptin serum levels in those patients.