Clinical Proceedings. 2016;12(1):13-19 Original Article Left Ventricular Function In Subclinical Hypothyroidism NK Thulaseedharan, P Geetha, TM Padmaraj Department of Internal Medicine, Govt. Medical College Kozhikode, Kerala, India Address for Correspondence: Dr. NK Thulaseedharan, MD, Department of Internal Medicine, Govt. Medical College Kozhikode, Kerala, India. E- mail: dr.thulaseedharan@gmail.com Abstract Aims: To assess the left ventricular function in subclinical hypothyroidism and to assess the correlation between TSH level and the severity of left ventricular dysfunction and it's reversibility after thyroxine replacement. Materials and methods: Fourty one patients with subclinical hypothyroidism were included in the study. All of them had normal free T3 and T4 with TSH >5microIU/ml. All patients were compared with age and sex matched controls. The patients and the control were subjected to echocardiographic assessment of left ventricular systolic and diastolic function before and after thyroxine replacement. Results: Left ventricular systolic function was normal, but 17% of the patients showed grade 1 diastolic dysfunction as evidenced by prolonged deceleration time, isovolumic relaxation time and reduced E/A ratio, and there was significant improvement in the diastolic parameters after thyroxine replacement. Significant correlation is found between TSH level and diastolic dysfunction. Conclusion: subclinical hypothyroidism causes grade 1 diastolic dysfunction and it is reversible after thyroxine replacement. Keywords: subclinical hypothyroidism, deceleration time, isovolumic relaxation time, E/A ratio, E wave, A wave Introduction Subclinical hypothyroidism is defined as an elevated serum TSH level associated with normal free T4 and T3 values. The prevalence of overt hypothyroidism varies according to different surveys between 0.1 and 2%. Subclinical hypothyroidism is more prevalent and can be seen as many as 20% in women older than 60 years and 4-10% in general population. Cardiovascular system is one of the principal targets of thyroid hormone. Overt hypothyroidism is accompanied by intrinsic myocardial changes reflected by alterations in contractility and relaxation, causing decreased cardiac contraction, cardiac output, heart rate, and left ventricular compliance as well as an increase in total peripheral resistance. Although there is no clear evidence that Subclinical hypothyroidism causes clinical heart disease, changes in thyroid status in Subclinical hypothyroidism are associated with changes in several cardiac parameters manifested by left ventricular diastolic dysfunction at rest and systolic dysfunction on effort, an enhanced risk for atherosclerosis, and myocardial infarction. These
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 14 cardiovascular abnormalities have been shown to regress with L-thyroxine therapy. This study aimed to assess the left ventricular (LV) function in subclinical hypothyroidism and the reversibility of LV dysfunction after thyroxine replacement as well as the correlation between TSH level and severity of LV dysfunction. Materials and Methods This was a hospital based observational study conducted in Government Medical College, Kozhikode. All adult patients who satisfied the biochemical criteria for subclinical hypothyroidism were included in the study. The total duration of the study was 12 months. Patients with age twelve or less, Diabetes mellitus, systemic hypertension, coronary and valvular heart disease, chronic renal failure severe, nonthyroidal illness, pregnancy and patients on Amiodarone were excluded from the study. Patients attended medicine/endocrinology OPD with non specific compliants and patients undergoing routine pre anaesthetic investigations, with normal free T3, and freet4 and TSH above 5mIU were selected. 41 patients were interviewed for possible participation in the study. The arterial blood pressure measured in the sitting position on >2 separate occasions were to be consistently <130/80 mm of Hg. All patients had FBS <100mg/dL and normal resting ECG. In addition 41 asymptomatic and apparently healthy (after history and clinical examination), age and gender matched individuals were seleted for comparison. Lab test consisted estimation of serum free T3, T4 and TSH. TFT was measured by electrochemiluminescence immunoassay "ECLIA". Anti TPO antibody estimation was done in patients using Haem Agglutination Assay "H.A.A". Echocardiography was done in patients with subclinical hypothyroidism and compared with age and sex matched controls. The echocardiographer was blinded as to whether the person undergoing the procedure was hypothyroid or a control subject. Images were obtained in the parasternal short axis and apical views using standard 2D, M mode colour flow Doppler echocardiography (Philips HD11XE). Each patient underwent LV function assessment by M mode quantitative analysis and Doppler echocardiography and conventional Tissue Doppler imaging as per the guidelines laid down by the American Society of Echocardiography. Patients detected to have LV dysfunction was put on thyroxine 50microgram/day and reassessed after 6 months. The parameters obtained were septal wall thickness (mm), posterior wall thickness (mm), LV internal systolic diameter, left atrial dimension (mm) and ejection fraction (%). The LV mass was calculated by Devereux formula which states that LVmass=1.04{(IVST+LVID+PWT) 3 -(LVID) 3 } - 13.64 where IVST, LVID and PWT stand for IVS thickness, LV internal dimension and posterior wall thickness at enddiastole respectively. In Doppler echocardiography, the LV inflow pattern was obtained by keeping the sample volume at the tip of mitral leaflets. The parameters that we studied reflecting diastolic function of the LV were, early (E) and atrial (A) peak velocity (meters per second) and their ratio, E wave deceleration time (milliseconds) and isovolumic relaxation time (time interval between the end of systolic output flow and the transmitral E wave onset. All recordings and measurements were obtained according to the current standards of the practice of echocardiography. LV systolic dysfunction was considered if EF <55, and diastolic dysfunction was considered to be present if any of the following were present. (1) E/A ratio <1 or >2 (2) DT <150 or >220ms (3)IVRT <60 or >100ms. 4)E'/A' <1. Comparisons among control subjects and subclinical hypothyroid patients were performed by Chi-square test, whereas comparisons among the subgroup of 7 subclinical hypothyroid patients, before and 6 months after L-thyroxine treatment, were performed using the two-tailed Student's t test for paired data. A P value less than 0.05 was considered as significant. Observation and Results Patients age ranged from 20 to 65 years and mean age was 41.15. There were 40 (98%) women and 1(2%) man. The female in reproductive age group constituted 72. 37 (90%) 90% of patients in our study used to take iodised salt. 39 patients took mixed diet (95%) with predominantly nonvegetarian
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 15 items. Commonest symptom complained by our patients was muskuloskeletal (muscle weakness and cramps). Goitre was the commonest sign present in our study and was found in 15 patients (36.5%). 16 patients had a TSH value <10(39%), 19 patients had TSH between 10 and 20(46%) and 6 patients had a TSH >20(15%). 23 (51.9%) patients had total cholesterol >200 and 21 (55.8%) patients had LDL more than 100, out of which 5 had LDL >130. 23 patients had positive anti TPO antibodies (56%). L-thyroxine replacement started in 36 patients (88%). The free T3 and T4 values were comaparable in both patients and controls. There was signifiant difference between the TSH values (Table 1). The mean TSH in the patient group was 11.39+/- 2.081 and the mean TSH in the control group was 1.24+/-0.61. The heart rate, systolic blood pressure and diastolic blood pressure were comparable in the two groups. The mean systolic blood pressure was 118.1+/-11.8 mm of Hg in patients and 116.8+/- 12.6 mm of Hg in controls the mean diastolic blood pressure was 76+/-7.1 mm of Hg in patients and 75+/-7.3 mm of Hg in controls.anti TPO was positive in 23 out of the 41 patients. Thyroxine replacement was given 36 patients after Echoardiography. 5 patients were asymptomatic and TSH was below 10. Both groups had similar systolic parameters of ejection fraction, fractional shortening (Table 2). Posterior wall thickness of left ventricle, septal wall thickness, left ventricular end systolic diameters, and left ventricular end diastolic diameters, were comparable in both groups and all values were within normal limits. Table 1: Clinical parameters and thyroid function tests Table 2: M-Mode echocardiographic parameters Of the 41 patients with subclinical hypothyroidism 7 patients had grade 1 diastolic dysfunction and no individuals in the control group had diastolic dysfuntion and it was statistically significant with a p value of 0.006. Significant differences were noted in diastolic parameters like deceleration
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 16 time, isvolumic relaxation time, and E/A ratio as assessed by tissue Doppler imaging E/A ratio was less in patient group but deceleration time and isvolumic relaxation time were higher in the patient group compared to the control subjects (Table 3). Table 3: Doppler echocardiographic parameters Out of 6 patients, who had TSH more than 20, 4 patients had grade 1 diastolic dysfuntion. 18 patients who had TSH between 10 and 20, 3 of them had grade 1 diastolic dysfunction. No individual with TSH less than 10 had diastolic dysfunction. So there is statistically significant association between TSH level and diastolic dysfunction with a p value of 0.001. Only 2 patients had dyspnea during exertion and on evaluation both of them had grade 1 diastolic dysfunction. Out of 12 patients with fatigue only 2 patients had diastolic dysfunction.out of 29 patients who didn't have any fatigue, 5 of them had diastolic dysfunction. There is no significant association found between fatigue and diastolic dysfunction. In our study anti TPO was positive in 23 patients, and 5 of them had diastolic dysfunction and anti TPO was negative in 18 patients and 2 of them had diastolic dysfunction.on statistial analysis the p value was 0.37, so there is no significant association is found between anti TPO positivity and diastolic dysfunction. The patients with diastolic dysfunction were put on thyroxine 50 micrograms/day and reassessed after 6months. All diastolic parameters showed significant improvement after thyroxine replacement. E/A ratio increased whereas the deceleration time and isovlumic relaxation time were decreased. Table 4: Change in Doppler echocardiographic parameters with treatment Discussion Studies have shown that subclinical hypothyroidism is often asymptomatic (70%); however, nearly 30% of patients with this condition may have symptoms that are suggestive of thyroid hormone deficiency. Only 12% of patients in present study were asymptomatic. Studies from Western literature indicate that prevalence of subclinical hypothyroidism increases in the elderly. We had only 10 patients above 50yr (24%). Antithyroid peroxidase (TPO) antibodies were found in 56%. Anti TPO positivity was also comparable. Previous studies have shown that 75% of patients
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 17 have only mildly elevated TSH (<10). In our series 61 % of the patients had TSH >10. Since present study was a hospital based observational study asymptomatic patients with mild TSH elevations are likely to be missed. Another important observation was significant incidence goitre and subclinical hypothyroidism in a population where majority were on diet rich with sea fish (74% of nonvegetarians) and iodised salts (90% of total study group). Iodine is essential for thyroid function. Thyroid disorders related to iodine deficiency decreased progressively with the continuous iodine prophylaxis and the increased iodine intake. Our study clearly revealed that patients with subclinical hypothyroidism had increased incidence of goitre. A cross-sectional survey of 102 Peace Corps volunteers in Niger, West Africa, in 1998 had previously demonstrated a high rate of thyroid dysfunction and goiter attributable to excess iodine from their water filters [1]. Our study was mainly aimed to evaluate the left ventricular function. The heart rate,systolic blood pressure and diastolic blood pressure were normal in study population and is comparable with healthy control group. In previous studies resting heart rate was normal in all patients in whom it was evaluated. Studies done by Bello et al [2] and Forfar et al [3] in patients with subclinial hypothyroidism showed normal ejetion fraction at rest and decreased ejection fraction on exercise. Systolic function at rest was found to be normal in our study as evidenced by the normal ejection fraction and normal fractional shortening. The left ventriular endsystolic and enddiastolic dimensions were normal. All of these systolic parameters are comparable with the normal subjects. Cardiac function, evaluated from systolic time intervals, was also normal in patients with subclinical hypothyroidism. In contrast, the pre ejection period and the interval from Q wave to pulse arrival at the brachial artery were prolonged, and the pre ejection period - left ventricular ejection time ratio was higher in 20 patients with subclinical hypothyroidism than in the same patients after L-thyroxine replacement therapy. Forfar JC et al [3] evaluated 10 patients before and after TSH concentrations were normalized with L-thyroxine, the treatment did not affect left ventricular ejection fraction at rest but did enhance the increase in ejection fraction during exercise. In our study no abnormality detected in the Left ventricular structure. There was no pericardial effusion or any regional wall motion abnormality. Left ventricular structure and function at rest were evaluated by using Doppler echocardiography by Biondi B et al [4] in 26 selected patients with stable subclinical hypothyroidism due to Hashimoto thyroiditis and in 30 normal controls. In 10 randomly selected patients, the evaluation was repeated after 6 months of L-thyroxine therapy (daily dose, 68 micrograms). No significant abnormality in left ventricular structure was seen, whereas Doppler-derived mean aortic acceleration, a reliable index of left ventricular systolic function, was significantly lower in patients than in controls. This acceleration normalized after L-thyroxine therapy. Some studies showed that systolic function at rest was normal as in our study and in other studies there is abnormality in the systolic parameters like preejection period and aortic acceleration during exercise in subclinical hypothyroidism and these abnormality found to be reversible with thyroxine replacement.
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 18 The key finding in our study is that 17% of the patient had grade 1 diastolic dysfunction. E/A ratio was decreased, deceleration time is prolonged and isovolumic relaxation time is prolonged and all the changes in these parameters were statistically significant. E'/A' ratio also was decreased. Diastolic parameters were normal in the healthy control group. Similar result had been obtained in the previous studies. In the Study by Biondi et al, isovolumic relaxation time was prolonged, and the early-late ratio of Doppler-derived transmitral peak flow velocities was lower in patients than in controls. The 7 patients with subclinical hypothyroidism having grade 1 diastolic dysfunction showed significant improvement after thyroxine replacement, on reassessment after 6months. There was significant improvement in all the diastolic parameters the finding is consistent with other studies. In the study by Biondi et al [4], isovolumic relaxation time was prolonged, and the early-late ratio of Doppler-derived transmitral peak flow velocities was lower in patients than in controls. Both measures of diastolic function returned to normal after L-thyroxine replacement. In our study it is observed that there is strong association between TSH level and diastolic dysfunction. The incidence of diastolic dysfunction increases when the TSH is increasing especially when above 20. Out of the 6 patients with TSH above 20, 4 of them showed grade 1 diastolic dysfunction. On correlating with symptoms in patients with diastolic dysfunction 2 of them complained dyspnea and none of the patients with normal LV function had dyspnea and it showed significant association. 2 patients with diastolic dysfunction also complained fatigue, but 10 patients with normal LV function also had fatigue and the association was insignificant on analysis. No significant association is observed between diastolic dysfunction and the Anti TPO positivity. Conclusions Incidence of subclinical hypothyroidism is more in females. Asymptomatic patients constitute only 12% in present study unlike Western study where 70% patients are asymptomatic. Symptoms and signs showed similar trends while comparing with Western data on sub clinical hypothyroidism but only differs in prevalence. Most common symptom reported was muskuloskeletal and most common sign was goitre. Significant incidence of goitre and sub clinical hypothyroidism noted in a population likely to be on excess iodine since majority were consuming sea foods and were getting iodised salt. Only 24% of patients in our study were above 50 yrs. Studies from Western literature indicate that prevalence of subclinical hypothyroidism increases in the elderly. The heart rate, systolic blood pressure and diastolic blood pressure were normal in study population as observed in other studies. Systolic function at rest was found to be normal in our study as evidenced by the normal ejection fraction and normal fractional shortening (%). The left ventriular endsystolic diameter, enddiastolic diameters and left ventricular mass index were normal. Left ventricular mass index was comparable in patients with diastolic dysfunction and without diastolic dysfunction. No abnormality was detected in the Left ventricular structure. There was no pericardial effusion or regional wall motion abnormality. 17% of the patients had grade 1 diastolic dysfunction as evidenced by decreased E/A ratio, prolonged deceleration time, prolonged isovolumic relaxation time and decreased E'/A' ratio Significant association is found between TSH level and diastolic dysfunction, there is increased incidence of diastolic dysfunction when the TSH is above 20. Diastolic dysfunction was reversible after thyroxine replacement, on reassessment after 6 months. There was significant improvement in all the diastolic parameters and the finding is consistent with other studies. There is no significant association between symptoms like fatigue, and diastolic dysfunction but dyspnea showed association. No significant association is found between Anti TPO positivity and diastolic dysfunction.
Thulaseedharan NK et al, Left Ventricular Function In Subclinical Hypothyroidism 19 References 1. Khan LK, Li R, Gootnick D. Thyroid abnormalities related to iodine excess from water purification units. Peace Corps Thyroid Investigation Group. Lancet. 1998;352(9139):1519. 2. Di Bello V, Monzani F, Giorgi D, Bertini A, Caraccio N, Valenti G, et al. Ultrasonic myocardial textural analysis in subclinical hypothyroidism. J Am Soc Echocardiogr. 2000; 13:832-40. 3. Forfar JC, Wathen CG, Todd WT, Bell GM, Hannan WJ, Muir AL, et al. Left ventricular performance in subclinical hypothyroidism. Q J Med. 1985; 57:857-65. 4. Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, et al. Left ventricular diastolic dysfunction in patients with subclinical Hypothyroidism J Clin Endocrinol Metab. 1999; 84: 2064-7.