European Journal of Cardiovascular Medicine

Though incidence of cardiovascular events remain higher among the elderly, a potential epidemic of cardiovascular disease for young adults is also being forecasted in view of their physical inactivity, poor diet, obesity and high prevalence of smoking and substance abuse.^{[1,2 ]}  However, in young adults the cardiovascular risk contributed by thyroid diseases remains relatively less explored, despite high worldwide prevalence of thyroid dysfunction and its association with cardiovascular diseases (CVD).^[3]

Expectedly, hypothyroidism is associated with higher incidence of CVD by causing hyperlipidemia and consequent hypercoaguable state as well as endothelial dysfunction^[3-5]  TSH >10 MIU/L dictates higher cardiovascular risk and is associated with a need for initiation of therapy.^[6] For hyperthyroids also total mortality due to heart disease (mainly due to atrial fibrillation) increases markedly when TSH levels are <0.01 MIU/L.^[7,8] Even subclinical hyperthyroidism as well as subclinical hypothyroidism are associated with several biological effects on cardiovascular system.^[9,10]

Carotid intima media thickness (CIMT) is considered as a fair marker of early atherosclerosis and it is considered as a strong predictor of future cardiovascular events as MI and stroke.^[11] CIMT is known to increase in hypothyroidism (due to dyslipidemia and increased arterial stiffness) ; even in those who achieve post treatment euthyroid status.^[3,12] Hyperthyroidism also causes increase in CIMT by stimulating renin angiotensin system secondary to peripheral vasodilation and by leading to angiotensin 2 mediated smooth muscle cell growth and matrix synthesis.^[8,13] It has also been observed that endothelial dysfunction, an earliest indicator of cardiac disease has been noted to be possibly reversed by L-thyroxine supplementation in patients with hypothyroidism.^[14] However, this finding was not uniformly observed by all authors.^[15] Differences in study designs may be the cause of this discrepancy and the fact that most studies targeted only one type of thyroid disorders in a particular study.

CIMT can be non-invasively measured and has been accepted as an indirect indicator of  future cardiovascular risk of an individual. It is influenced by multiple co-morbidities including thyroid dysfunction.

We aimed to study  CIMT in young adults with thyroid dysfunction and minimal or no co morbidities, using stringent inclusion criteria. This way it was expected that CIMT would be influenced maximally/exclusively by thyroid functional status and thus the study would help to evaluate relationship between the risk of cardiovascular events purely/mainly due to thyroid dysfunction. The correlation of  biochemical profile of these subjects can help understand  the pathogenesis of cardiovascular disease in context of thyroid dysfunction

Fifty adults younger than 40 years, receiving treatment for thyroid dysfunction at our centre were enrolled into the study over a two month period. Since study aimed to explore the effect of underlying thyroid functional status on CIMT, application of strict inclusion criteria excluded the subjects with co-morbidities as congenital hyperlipidemia, connective tissue disorder, diabetes, smokers, substance abuse, history of any coronary event in the past or with coronary artery disease, obesity, malignancy and chronic diseases like Chronic Obstructive Pulmonary Disease/liver or kidney disease Complete history included demographic and treatment details and  Clinical examination including height, weight, BMI and neck examination

Investigations including haemogram, lipid profile, glycosylated haemoglobin, renal function test and thyroid function test. Further measurement of CIMT were done as per the procedure described below.

Measurement of CIMT

CIMT was measured with an ultrasound machine using the linear transducer of 7 MHz frequency. The subject was placed in supine position with his/her neck in extension and rolled contra- laterally by about 45 degrees. The intima-media thickness was taken on the far wall, 10 mm proximal to the common carotid bulb. CIMT was evaluated as the distance between the lumen intima and the media-adventitia interface. A single radiologist manually measured the CIMT.

Statistical Analysis: The data was entered in MS Excel sheet and was analysed using SPSS version 25. P value <0.05 was considered significant. The correlation between quantitative variables was done by Spearman’s formula and Mann- Whitney U Test for association between different groups.

The mean age of our study subjects was 27.6 +/- 7.1 years while  majority of our subjects (70%, n=35) aged between 21-35 years. None of our study subject was obese or had comorbidities.  Majority of subjects (n=37) had overt hypothyroidism while remaining were overt hyperthyroid (n=13)  and were receiving treatment at endocrinology clinic of our tertiary referral hospital. There were no subjects with subclinical hypothyroidism or hyperthyroidism.  All study subjects underwent sonological examination for estimation of CIMT (Right and left separately), haematological, biochemical investigations. The results of findings of these are shown in the tables 1 and 2 as given below.

Table 1: Distribution of anthropometric variables among study participants (n=50)

Table 2: Biochemical and clinical profile study participants (n=50)

HbA1c ranged within normal limit in all subjects. A few patients had higher than normal lab values of lipids .Cholesterol (>230 mg% , n=3), LDL ( > 180mg%, n= 3 ) and serum TGs> 160 mg%, n=7 ). The mean ± standard deviation of LDL/ HDL ratio in our sample was 3.2 ± 1.8 (within normal limits) which could be computed in 28 subjects only.

Next all our study variables were correlated separately with right and left CIMT values as few workers had observed only right CIMT to be more affected ^[16]. It was worth noting that while a significant positive correlations of age was found both with right as well as left CIMT, a significant positive correlation between HbA1C was found only for right CIMT. No other parameters (including BMI) was found to be significantly correlated with CIMT (Table 3 and 4)

Table 3: Correlation of age and anthropometric factors with CIMT

* Correlation is significant at the 0.01 level (2-tailed).

Table 4: Correlation of biochemical factors with CIMT

* Correlation is significant at the 0.01 level (2-tailed).

Correlation was computed for all above anthropometric as well as biochemical variables with TSH levels for the entire study group irrespective of nature of thyroid dysfunction. No correlation of any parameter was found with TSH levels.

Next data was categorised into two major groups i.e those with hypothyroidism (Group 1; n=37) and those with hyperthyroidism (Group 2 ; n=13) and correlation of TSH with all study variables for each of two groups was studied separately.

TSH among hypothyroids negatively but significantly correlated with age, thereby implying that as age increased TSH tended to decrease in our study group. Also though while both right and left CIMT expectedly had negative correlation with TSH levels the same did not reach significance.

It was observed that hyperthyroid group had significant positive correlation of TSH with Right CIMT (not with left CIMT) and also with Serum Creatinine. Also a significant negative correlation was noted between Serum Cholesterol and TSH levels, thereby implying that with increasing TSH levels a decrease in serum cholesterol occurred. (Table 5)

Table 5: Correlation of clinical and biochemical factors with TSH levels in Hyperthyroids

*Correlation is significant at the 0.01 level (2-tailed).

On studying CIMT and biochemical profile between the two categories of thyroid dysfunction, we found that CIMT  values (right or left) were comparable for both categories of thyroid dysfunctions, though hypothyroids had significantly higher HbA1C (p=0.038) and Serum cholesterol (p=0.028) in comparison to hyperthyroid subjects (Table 6)

Table 6: Mean distribution of Age anthropometry and Biochemical factors among study group:

Our study differed from those quoted in the literature as stringent inclusion criteria allowed enrolling of only those young adults who were non obese and without associated co morbidities. All subjects were being treated at thyroid clinic of our tertiary centre with either type of overt thyroid dysfunction. This stratergy helped us exclude confounding factors for atherosclerosis which can influence CIMT so that effect of thyroid dysfunction on this parameter could be explicitely observed Since the English literature has conflicting reports regarding correlation of CIMT with different categories of thyroid dysfunctions, the results of our study hailing from South East Asia country with healthy young are worthy of attention.

Most of our study subjects were between 21 to 35 years of age. There was expectedly female predominance as noted for thyroid disorders. In a review of thyroid disorders in India by Unnikrishnan and Menon, the prevalence of thyroid disease, especially hypothyroid disease in females was quoted to be 11.4% which was about two to four folds higher in comparison to general population^[17]. Also the prevalence of subclinical hypothyroid disease increases with age. Hence it was surprising to find a negative correlation of TSH with age among hypothyroids in our study group. However, we found a report  from Scotland on  people with no obvious thyroid disease wherein it was noted that in healthy individuals median TSH levels dipped while going across 18-30 year gap(median TSH= 1.67) to 31 to 40 year (median TSH=1.58) gap^[18]. Since all our study group consisted of subjects less than 40 years of age this finding of negative correlation of TSH with age just points that  this trend of TSH with age was followed by our young hypothyroid patients also.

CIMT is an easily measured parameter which is that can be considered as surrogate marker to predict risk of cardiovascular disease in a given population^[13]. Since intimal thickness could be affected by lipid deposits and hyperlipidemia or hypercoaguable states, we included only non obese young adults with no comorbidities so as to gauge mainly the impact of underlying thyroid dysfunction on CIMT ^{[12,16,19,20,21,22,23]}. As per NHM guidelines , BMI >30 kg per sq. metre is taken obese though for Asian population some workers take it as 25 kg/sq metre^[24].

CIMT is conventionally recorded in the right carotid though some authors observed that measurement in left carotid is also as good. However few workers have found that the right CIMT values may differ in some cases with left CIMT^[16]. We agree with this observation as for some parameters in our study, the correlation differed with CIMT in the right and the left side. For example, among hyperthyroid subjects there was significant positive correlation of TSH with right CIMT but not with left. However a significant positive correlation of age was found with both sided CIMT. This finding goes hand in hand with the available literature as arterial thickness does increase with age. The positive correlation just shows that phenomenon of arterial thickening with age is a generalised phenomenon, irrespective of population under study.

It is observed that thyroid sub/hypofunction predisposes to atherosclerosis and hyperlipedemic states and hence causes increased CIMT ^[11,19]. On the other hand, hyperthyroidism can also cause increased CIMT by causing peripheral vascular dilatation and increased smooth muscle cell growth^{[21,25,26,27]}. In our study which included both these thyroid dysfunctions, we did not find TSH levels significantly correlating with CIMT. Hence either type of dysfunction can alter CIMTby different mechanisms

CIMT was found to be significantly and positively correlating with HbA1c and age. Positive correlation of CIMT  with HbA1C has not been  previously quoted in context of thyroid dysfunction.  The association of diabetes with hypothyroidism is well known^[19,28,29] and among diabetics, higher HbA1C levels are related to increased cardiovascular risk. But our study included non diabetic young adults with no comorbidities. Hence a significant positive correlation of HbA1c with CIMT points to the fact that in patients with thyroid dysfunction even HbA1c levels in non- diabetic range dictates higher risk for cardiovascular events and hence requires closer monitoring.  Interestingly HbA1C levels did not correlate significantly  with CIMT among the healthy geriatric population (without endocrine dysfunction)  aged >71 years^[30].  With this background we deduce that underlying thyroid dysfunction could have been responsible for our observations. The other factor could be differences in ethnicity of the studied populations.  Age showed positive correlation with CIMT though all our study subjects were young. Similar findings were quoted by Alizagar et al among community dwellers and non- diabetic individuals though their study subjects were older than 30 years^[31]. Hence, we observed that thyroid dysfunction can cause age related alterations in CIMT even younger subjects with no associated  co-morbidities.

Association with HbA1c and CIMT has been variably stated and variably studied. Lee et al studied HbA1c and carotid atherosclerosis among elderly Koreans with normal fasting glucose and found that HbA1c positively correlated with risk of atherosclerosis. Their assessment did not include  study of thyroid dysfunction but was limited to diabetic and non- diabetics^[32,33]. On the other hand, Alizagar et al studied CIMT and carotid plaque scores among non diabetic community dwellers aged above 30 years. They found that HbA1C had a high prediction value for high carotid plaque score and hence can be taken as a risk for carotid atherosclerosis even among non- diabetic individuals. They concluded that HbA1c, systolic blood pressure, waist circumference and blood urea nitrogen correlated with early and late stage atherosclerosis^[31].      Again thyroid dysfunction was not  evaluated by them. In another study from community dwelling Japanese subjects based on 2702 subjects age 40-79 years who underwent OGTT it was found that in subjects with glucose intolerance increased HbA1c were significantly associated with increased CIMT and both HbA1c and glycated albumins are useful in assessing carotid atherosclerosis. With these community based studies in the background and the fact that variable results of CIMT with thyroid dysfunction are available in the literature it seems that any thyroid dysfunction causes increased CIMT can finally affect CVD risk^[34]. However, how thyroid dysfunction involves or interacts with HbA1C to cause this requires further evaluation.

In continuation with above context, it is worthwhile to quote the results of study by Bhattacharjee et al wherein they found that baseline HbA1c levels were found to be significantly higher in hypothyroid patients compared to control individuals despite similar glucose levels and these levels decreased upon accomplishment of euthyroid state without much change in glucose levels^[37]. No such results were seen in hyperthyroid patients. In our study too when mean levels of all study variables were compared between hypothyroids and hyperthyroids, it was found that the former have significantly higher HbA1c and serum cholesterol levels as compared to hyperthyroid subjects (Fig 2-5).  All above observations not only point to the fact that even young patients with thyroid dysfunction are at a risk for cardiovascular events but it also hints that HbA1C may also be taken as pointer of such risk besides  or alongwith CIMT

Many reports regarding hyperlipidemic state created by hypothyroidism causes increased CIMT and increased risk for CVD^[3-5,36,37]. Also hypothyroidism affects the renal function by causing a decrease in GFR^[37]. In our study a significant positive correlation of TSH with cholesterol and creatinine was found but among hyperthyroid subjects only. TSH increases post treatment among hyperthyroids and this result should alert treating clinician for close monitoring of above parameters as both are associated with higher CVD risk.

Even young otherwise healthy adults with thyroid dysfunction require close follow up for CVD by monitoring of CIMT. This  especially holds true for  hypothyroids as they were found to have significantly higher levels of HbA1c and S.cholesterol in comparison to  hyperthyroids, as both these parameters are risk factor for atherosclerosis development. Since higher HbA1C levels had been found to be positively associated with higher CIMT  in our study and in earlier studies, it can be considered as handy tool alongwith CIMT to predict CVD risk in subjects with thyroid dysfunction. More studies are required from different ethnic groups with higher number of subjects to support the results of our study. 

Limitations: Small sample size ( time bound short term study project by ICMR)

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