A study of the cardiac risk factors emerging out of subclinical hypothyroidism.

INTRODUCTION: Subclinical hypothyroidism is defined as a serum TSH level above the upper limit of normal with normal levels of serum free thyroxine. It is a common thyroid disorder affecting 3-15% of the adult population. AIMS AND
OBJECTIVES: To study the cardiovascular profile of patients with subclinical hypothyroidism, and to establish cardiac risk factors emerging out of subclinical hypothyroidism.
METHODOLOGY: Adult patients attending General Medicine department and diagnosed with subclinical hypothyroidism over a period of 2 months were enrolled. History and general examination was done. Fasting lipid profile, hsCRP, electrocardiography and echocardiography were done.
RESULTS: The mean age was 35.1 (SD = 10.26). Most common age group affected is 20-30 years. There are about 12% of the enrolled patients were overweight (OW), and 24% were obese (OB). 16% had stage 1 hypertension, and 4% had stage 2 hypertension. 92% of the patients had dyslipidemia. 64% patients had raised LDL. 44% of the patients had raised hsCRP levels. 44% patients showed abnormal findings and the most common abnormality was found to be grade 1 left ventricular diastolic dysfunction.
CONCLUSION: Subclinical hypothyroidism is seen to be associated with a rise in hsCRP independent of other cardiac risk factors. A large number of patients have dyslipidemia which is a significant cardiac risk factor. Early Diagnosis and treatment of subclinical hypothyroidism will have possible cardioprotective advantages.

Introduction

Subclinical hypothyroidism is defined as a serum TSH level above the upper limit of normal with normal levels of serum free thyroxine, and it may or may not be associated with signs and symptoms of hypothyroidism.[1] It is a common thyroid disorder affecting 3-15% of the adult population.[2] In as many as 33 to 55% cases, subclinical hypothyroidism can progress to overt hypothyroidism.[3] Diagnosis is difficult due to its asymptomatic nature. But with easy availability of the thyroid function tests, it is possible to detect subclinical hypothyroidism cases early, and the progression to overt hypothyroidism can be checked by early intervention.

Thyroid hormones play a role in lipid metabolism, and consequently lipid abnormalities are well known with primary hypothyroidism.[4] Studies have reported significant increase in total cholesterol, and low density lipoprotein cholesterol in subjects with subclinical hypothyroidism.[56]

The cardiovascular system is an important site for thyroid hormone action.[7] Subclinical hypothyroidism can cause changes in cardiovascular status similar to those observed in overt hypothyroidism therebyindicating that cardiac effects progress from subclinical disease through overt hypothyroidism. Studies have shown that the most frequently encountered cardiac abnormality in subclinical hypothyroidism is left ventricular diastolic dysfunction.[89] This causes impaired diastolic relaxation and has a negative prognostic value since left ventricular dysfunction has been found to increase morbidity and mortality in the general population.[10] We have done echocardiography of our patients diagnosed with subclinical hypothyroidism to look for their cardiac status and particularly for diastolic dysfunction.

Hypothyroidism is a known risk factor for hypertension. Whether subclinical hypothyroidism also has a similar risk is controversial. Our study also evaluates this parameter to establish cardiovascular risk, if any.

It is well established that high body mass index, hypertension, obesity, and dyslipidemia are all independent risk factors for cardiovascular disease. Along with that, hsCRP is known to be a useful predictor of cardiovascular risk. It is often used for prognosis and risk scoring. Researchers have tried to find out whether CRP is elevated in subclinical hypothyroidism. With these background information, we have screened our patients of subclinical hypothyroidism for deranged lipid profile, elevated hsCRP, high BMI, obesity and hypertension to study about the cardiac risk factors emerging from subclinical hypothyroidism.

There are large number of studies showing the clinical significance of subclinical hypothyroidism.[5] The present study aims to evaluate the cardiovascular risk factors emerging from subclinical hypothyroidism. If a significant risk can be established, it provides a ground to start early intervention. The morbidity relating to cardiovascular disease can be prevented by early intervention.

Subclinical hypothyroidism is the earliest stage of hypothyroidism which can be diagnosed by a careful history and vigilant examination followed by relevant tests. A substantial population of such patients attending primary care physicians can be diagnosed at that level if there is proper suspicion. This will help prevent the progression to overt hypothyroidism if treatment is instituted at the right time, and thus prevent complications of same. Primary care physicians should be well versed with the cardiac complications and principles of diagnosis and treatment of subclinical hypothyroidism.

Aims and Objectives

To study the cardiovascular profile of patients with subclinical hypothyroidism

To establish cardiac risk factors emerging out of subclinical hypothyroidism.

Materials and Methods

Study Design: A hospital based cross sectional study.

Study population

Adult patients attending General Medicine department and diagnosed with subclinical hypothyroidism.

Study period: Two months.

Selection Criteria

Inclusion criteria

Age group: 15-50 years

All patients with subclinical hypothyroidism (those who have normal T3 and T4 but raised TSH) except those mentioned in the exclusion criteria.

Exclusion criteria

Known cases of thyroidal illness (hypothyroidism or hyperthyroidism)

Patients taking drugs for thyroid disease

Patients with known cardiac illness

Patients with concomitant severe illnesses

Patients taking drugs known to alter thyroid hormone levels (eg. Amiodarone).

Methodology

After approval by the Institutional Ethics Committee, patients as per the selection criteria were enrolled in the study after due informed consent. A brief history of the demographic details, history of cardiac symptoms and addiction to nicotine and tobacco was taken, and the following parameters were recorded: height, weight, body mass index, waist hip ratio, pulse, blood pressure, and postural drop in blood pressure (if any). The cardiovascular system was examined including presence of any markers of cardiac disease (xanthalesma, xanthoma, and premature hair greying, corneal arcus). Overnight fasting blood samples were collected and fasting lipid profile was done. Serum samples were collected and stored at -20°C. These are later tested for hsCRP levels by ELISA. Electrocardiography and echocardiography were done for all the patients to look for any ischemic changes in ECG and diastolic dysfunction in echocardiography. At the end of two months, the above mentioned parameters were tabulated and analysed statistically.

Chi square test is used for tests of statistical significance wherever appropriate and a P value <0.05 is considered to be statistically significant. Statistical analysis was done using SPSS software (Version 21).

Results

A total of 25 patients were enrolled in this study within the specified 2 months period.

80% of the participants are females and 20% are males. The mean age was 35.1 (SD = 10.26).

The mean age of the female participants was 34.25 (SD = 9.21) and the mean age of male participants was 34.8 (SD = 13.12).

Age distribution

Most common age group affected was 20-30 years [Figure 1].

Figure 1

Age distribution

BMI

The participants were grouped according to the Indian criteria i.e. greater or equal to 23 kg/m2 was taken as overweight and greater than or equal to 25 kg/m2 was taken as obese.

Average BMI was found to be 21.9 kg/m2.

According to Indian criteria, 12% of the enrolled patients were overweight (OW), and 24% were obese (OB) [Figure 2].

Figure 2

BMI in the subjects (N = Normal; OW = Overweight; OB = Obese)

Waist hip ratio

44% patients had high waist hip ratio (males >0.9, females >0.85), indicating central obesity [Figure 3].

Figure 3

Waist hip ratio in the subjects

BMI vs WHR

20% of the patients had both high BMI and high waist hip ratio. 12% patients had normal BMI and high waist hip ratio. 16% patients had high BMI and normal waist hip ratio [Table 1].

Table 1

Relationship of Body mass index (BMI) and waist hip ratio (WHR)

BMI	WHR
	Normal (%)	High (%)
Normal	48	12
High	16	20

Smoking history

None of the patients were chronic smokers.

Cutaneous markers

None of the patients had any cutaneous markers of cardiovascular disease i.e. xanthelesma, xanthoma, corneal arcus and premature hair greying.

Blood pressure

80% of the patients had normal blood pressure, 16% had stage 1 hypertension and 4% had stage 2 hypertension. Postural drop in blood pressure was not observed in any of them [Figure 4].

Figure 4

Blood pressure in the subjects

General examination

Only 20% patients showed symptoms of hypothyroidism like puffiness of limbs, thyroid swelling.

Cardiovascular system examination

None of the patients showed any abnormality on clinical examination.

Lipid profile

92% of the patients had dyslipidemia (defined as any one or more of the parameters above the upper limit of normal i.e. triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol).

36% patients had raised triglycerides. Cut off value was taken to be 150 mg/dl [Table 2].

Table 2

Prevalence of dyslipidemia in the subjects

Dyslipidemia	Frequency (n)	Percent (%)
Triglycerides (>150 mg/dl)	9	36
LDL (>100 mg/dl)	16	64
HDL (<40 mg/dl)	17	68
Total cholesterol (>200 mg/dl)	9	36

36% patients had raised total cholesterol values. Cut off value was taken to be 200 mg/dl.

32% patients had raised VLDL. Cut off value was taken to be 30 mg/dl.

64% patients had raised LDL. Cut off value was taken to be 100 mg/dl.

68% patients had lowered HDL. Cut off value was taken to be 40 mg/dl.

LDL vs HDL

40% patients had both LDL and HDL raised while 24% have raised LDL and normal HDL.

High sensitivity C reactive protein (hsCRP)

44% of the patients had raised hsCRP levels. The cut off was taken as 5 mg/l.

45% females and 40% males in the study had raised hsCRP. However, raised hsCRP was not significantly associated with female gender (P value = 0.854) [Table 3].

Table 3

Relationships of hsCRP

Parameter	% of	High hsCRP (>5 mg/l) (%)	P
Gender	Males	40	0.854
	Females	45
BMI	Normal BMI	31.3	0.087
	High BMI	66.7
BP	Normal BP	45	0.84
	Hypertensives	40
Echo	Normal Echo	40	0.237
	Diastolic Dysfunction	75

45% non hypertensives and 40% hypertensives had raised hsCRP. Association between hypertension and raised hsCRP was not statistically significant (P value = 0.84).

31.3% participants with normal BMI had raised hsCRP while 66.7% patients with high BMI have raised hsCRP. Raised hsCRP was not significantly associated with high BMI (P value = 0.087).

75% patients with left ventricular diastolic dysfunction in echocardiography had raised hsCRP while 40% with normal echo had raised hsCRP. There was no statistically significant association between raised hsCRP and echocardiography. (P value = 0.237) Hence, subclinical hypothyroidism patients with normal echo study can also have raised hsCRP which is cardiac risk marker.

2D Echocardiography

44% patients showed abnormal findings and the most common abnormality was found to be grade 1 left ventricular diastolic dysfunction affecting an average age group of 40-50 years [Table 4].

Table 4

Prevalence and relationships of echocardiographic diastolic dysfunction

Parameter	% of	Diastolic Dysfunction (%)	P
Gender	Males	20	0.597
	Females	33.3
BMI	Normal	22.2	0.48
	High	40
BP	Normal	18.2	0.099
	Hypertensives	66.7
hsCRP	Normal	14.3	0.237
	Raised	42.9

33.3% females and 20% males had diastolic dysfunction. But diastolic dysfunction was not significantly associated with female gender (P value = 0.597).

22.2% patients with normal BMI had diastolic dysfunction while 40% patients with high BMI had diastolic dysfunction. Diastolic dysfunction was not significantly associated with high BMI (P value = 0.48).

18.2% non hypertensives had diastolic dysfunction while 66.7% hypertensives had diastolic dysfunction. But, the association between diastolic dysfunction and hypertension was not statistically significant (P value = 0.099).

14.3% patients with normal hsCRP had diastolic dysfunction while 42.9% patients with raised hsCRP had diastolic dysfunction. There was no statistically significant association between diastolic dysfunction and raised hsCRP (P value = 0.237).

Discussion

Cardiovascular diseases (CVD) are a major cause of death worldwide involving high treatment expenditure. Efforts should be made to modify CVD risk factors thereby decreasing the CVD risk. Subclinical hypothyroidism holds clinical importance because of its high prevalence, future risk of progression to clinical hypothyroidism, and its association with direct and indirect CVD risk factors. Studies have also reported that subclinical hypothyroidism is associated with an increased risk of coronary heart disease and hence prevention of the same would be of paramount importance.

The mean age of patients in our study was 35.1 (SD = 10.26), which is close to the mean age in other studies.[11] V Deshmukh et al. found that 74% subjects with subclinical hypothyroidism belonged to the age group 35–54 years, and prevalence showed rising trend with age.[12]

80% of our study population were females. In the study by TK Mishra et al., 90% of the cases were females.[11] V Deshmukh et al. found that the prevalence was more in females (M:F ratio 1:3.7) and increased with age.[12]

20% of our patients had hypertension. We found mean SBP was 121.36 (SD 17.16) and mean DBP was 79.76 (SD 8.84). Diaz-Olmos et al. found 33.3% prevalence of hypertension in subclinical hypothyroid patients and mean SBP 120.6 (SD 13.5) and DBP 81.0 (SD 8.1).[13] Our finding closely relates to available literature.

Average BMI of our patients was found to be 21.9 kg/m2. Diaz-Olmos et al. found average BMI in their patients to be 28.0 kg/m2.[13] B A Laway in their study from Kashmir reported BMI as 23.67 (SD 2.39) kg/m2.[14] Our data resembles the North Indian data.

We found mean total cholesterol (mg/dl) 184.48 (SD 39.45), LDL 118.9 (SD 30.22), HDL 39.64 (SD 13.93), TG 141.04 (SD 80.2) and VLDL 27.54 (SD 16.05). P Sharma et al. in their study at Eastern India found the corresponding values as 172.06 (± 27.5), 99.10 (± 27.43), 38.56 (± 4.14), 169.67 (± 31.2), and 34.40 (± 7.17).[15] R Shekhar et al. in their study from coastal Andhra Pradesh found the values as 203.41 (± 29.12), 118.10 (± 29.76), 40.81 (± 8.22), 170.94 (± 111.01) and 32.26 (± 18.06) respectively.[16] Hence, our study shows similar findings as that of the previous studies.

44% of our patients had raised hsCRP levels. High-sensitivity C-reactive protein (hsCRP) is one of the inflammatory markers related to cardiovascular disease. Sharma R et al. in their study had found that patients with subclinical hypothyroidism had significantly higher levels of serum hs-CRP.[17] Rajendra KC et al. had found that a higher number of subclinical hypothyroid cases had hs-CRP > 1 mg/L compared to euthyroid controls.[18] We did not find any significant difference in hs CRP levels with respect to gender, BMI, or blood pressure levels. Rajendra KC et al. found that males had significantly higher hsCRP compared to females.[18] Yu YT et al. reported that adult Taiwanese with subclinical hypothyroidism were associated with elevated hsCRP.[19]

We studied echocardiography in all 25 patients and found that 44% patients showed abnormal findings and the most common abnormality was found to be grade 1 left ventricular diastolic dysfunction. P Karki et al. in their study from Nepal found that diastolic dysfunction was detected in 37.5%, and pericardial effusion was observed in 12.5% cases of subclinical hypothyroidism. They also suggested that thyroid hormone replacement therapy may reverse diastolic dysfunction in subclinical hypothyroidism.[20] The echo abnormalities were independent of gender, BMI, blood pressure or hsCRP levels as indicated by the insignificant P values.

Conclusion

This study was done with the aim to study the cardiac risk factors emerging out of subclinical hypothyroidism. It was a small study, yet we were able to show the association of few risk factors, most notably hs CRP. From our data it is clear that females are more commonly affected with subclinical hypothyroidism as compared to that of males and the most vulnerable age group is 20-30 years. Subclinical hypothyroidism is seen to be associated with a rise in hsCRP independent of other cardiac risk factors like BMI, dyslipidemia, hypertension, and diastolic dysfunction (by echo). A large number of patients have dyslipidemia which is a significant cardiac risk factor. Subclinical hypothyroidism is associated with obesity (almost one fourth of our patients were obese), which is a well proven cardiovascular disease risk factor. High-sensitivity C-reactive protein (hsCRP) is one of the inflammatory markers related to cardiovascular disease. Hs CRP levels can be elevated in subclinical hypothyroid patients (44% of the patients in our study).

Echocardiography is of value in these patients and most commonly grade 1 left ventricular diastolic dysfunction is found. This itself gives evidence of the future cardiac disease that such patients are at risk of. Research has shown that the diastolic dysfunction of subclinical hypothyroidism can be reversed with l-thyroxine therapy.[17]

Our study has shown that various risk factors of cardio vascular disease are prevalent in patients of subclinical hypothyroidism. Being subclinical in nature it is quite obvious that a large section of the population remains undetected. This population is at risk for cardiovascular disease. Public health measures need to be undertaken to detect these patients early. It may be possible to reduce the cardiovascular risk in such patients by screening of the vulnerable population (i.e. females above 20 years). Early Diagnosis and treatment of subclinical hypothyroidism may have possible advantages firstly by preventing the progression to clinical hypothyroidism and secondly by detecting and mitigating the various associated cardiac risk factors. Early replacement with thyroxine in the at-risk population is a bigger question that needs to be looked into.

Financial support and sponsorship

Indian Council of Medical Research (ICMR) STS was received by Vineetha Kanneganti.

Conflicts of interest

There are no conflicts of interest.