Association between different degrees of hypothyroidism and serum lipids.
The association between overt hypothyroidism (OH) and altered lipid
profile is well known, however the significance of dyslipidemia in
subclinical hypothyroidism (SCH) remain controversial. Therefore, this
study was conducted to determine any association between lipid profile
and different degrees of thyroid dysfunction. Thyroid and lipid profile
parameters were analysed in 58 patients with overt (TSH [greater than or
equal to] 10.0 [micro]IU/L and/or abnormally low fT4 and fT3 levels) and
87 patients with subclinical hypothyroidism (TSH 6.0-9.9 [micro]IU/L
with normal fT4 and fT3 levels) in this case-control study. These were
compared with 100 age- and sex-matched euthyroid controls. It was found
that only mean serum level of total cholesterol in patients with SCH was
significantly high from that in controls (p=0.045). Other lipid
parameters did not show any statistical significance. Whereas patients
with OH had statistically significant higher levels of total cholesterol
(p<0.001), triglyceride (p<0.05), LDL-C (p<0.001) and VLDL-C
(p<0.05). There was also an increase in HDL-C in both SCH and OH
group though not significant statistically. In conclusion, lipid profile
is not much deranged in SCH whereas OH is a major cause of secondary
dyslipidemia which may lead to increased risk of coronary artery
disease. Therefore, thyroid hormone replacement would be most beneficial
in patients with OH instead of SCH. However, patients with SCH should be
monitored for deterioration of thyroid function and dyslipidemia at
KEY WORDS: Cholesterol; Dyslipidemia; HDL cholesterol; Hypothyroidism; Subclinical
(Complications and side effects)
Dyslipidemias (Risk factors)
Dyslipidemias (Causes of)
|Publication:||Name: Internet Journal of Medical Update Publisher: Dr. Arun Kumar Agnihotri Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2012 Dr. Arun Kumar Agnihotri ISSN: 1694-0423|
|Issue:||Date: July, 2012 Source Volume: 7 Source Issue: 2|
|Topic:||Event Code: 310 Science & research|
Primary hypothyroidism is a graded phenomenon with different levels of severity, showing a wide inter-individual range of clinical and biochemical presentation. Hypothyroidism results from reduced secretion of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland (1). Biochemically decrease in T4 and T3 concentrations lead to hyper secretion of pituitary TSH and an amplified increase in serum TSH levels. This is a key laboratory finding, particularly in the early detection of thyroid failure.
Subclinical hypothyroidism (SCH), also called mild hypothyroidism, is a term used for a condition in which there are small elevations in TSH, yet normal circulating levels of thyroid hormones. This condition is more common in the elderly and is found twice as often in women as in men (2,3). While it is uncommon in younger persons, by the age of 65 years, the overall prevalence of the disorder is about 17% in women and 7% in men (4). SCH has been detected with increasing frequency in recent years and is causing major controversies concerning management and treatment. SCH is usually detected during biochemical screening for nonspecific symptoms by TSH measurements (5), especially in tertiary care hospitals.
Overt hypothyroidism (OH) is associated with abnormalities of lipid metabolism, which may predispose to the development of atherosclerotic coronary artery disease (CAD) (6,7). Whether SCH also has any demonstrable effect on serum lipid concentrations has been controversial (8-15). Some studies of patients with subclinical hypothyroidism have shown that patients have elevations in their cholesterol levels (16,17). However, a precise relationship between different degrees of hypothyroidism and CAD has not been confirmed. This study was, therefore, planned to evaluate the changes in biochemical lipid profile parameters in subclinical and overt hypothyroid subjects, and to correlate these values with thyroid profile (TSH, fT3 and fT4) of the patient.
The study was conducted on 245 ambulatory subjects of age group 20 to 50 years referred to thyroid clinic in a tertiary care hospital of northern India after being approved by institutional review board. After informed consent, brief clinical history and examination was done to rule out renal disorders, liver disorder, or any other inflammatory condition which would have influenced the parameters under study.
For these analyses, we excluded subjects who were receiving concurrent treatment with drugs that could contribute to hypothyroidism (lithium, amiodarone, or iodine), those receiving antithyroid medication (methimazole or propylthiouracil) for hyperthyroidism and treatment with lipid lowering drugs for dyslipidemia.
After overnight fasting, 6ml venous blood sample was collected. After centrifugation (10 min at 3000 x g), serum was divided into aliquots for lipid profile parameters and thyroid function tests (TSH, fT3 and fT4). Both the aliquots were independently analyzed, such that the person analysing lipid profile was unaware of patient's thyroid function test results and vice versa. Sample for lipid profile was analyzed immediately. Samples for thyroid function tests were stored at -40[degrees]C until batch analysed.
Lipid Profile tests
Serum total cholesterol (TC) was analyzed by enzymatic CHOD-PAP method and triglyceride (TG) was estimated by GPO-PAP method using diagnostic kits by Randox Laboratories (Crumlin, United Kingdom) on Synchron CX4 and CX9 autoanalyzer (Beckman Coulter, USA). Highdensity lipoprotein cholesterol (HDL-C) was determined directly using system pack kits from Beckman Coulter. Low density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula (18).
Thyroid function tests
Serum TSH, fT4 and fT3 were assayed using fully automated chemiluminescent immunoassay Access 2 by Beckman and Coulter (USA). Reference intervals provided by the manufacturer were TSH 0.34-5.6[micro]IU/L, fT3 2.5-3.9pg/mL and serum fT4 0.6-1.12ng/dL. The sensitivities of the TSH, fT3, and fT4 were 0.0025[micro]IU/L, 1 pg/mL, and 0.4ng/dL respectively. The intraassay coefficients of variation for TSH, fT3 and fT4 were 1.7%, 2.7%, and 3.2% respectively.
After conducting thyroid function tests, subjects having euthyroid state (n=100, TSH[less than or equal to] 6.0uIU/ml, normal fT3 and fT4 levels) were taken as controls. Patients with TSH levels >6.0[micro]IU/ml were considered as hypothyroid (n=145). These patients were further divided into sub-clinical hypothyroid (n=87; TSH- 6.1 to 9.9uIU/ml with normal fT4 and fT3 levels) and overt hypothyroid (n=58 with TSH [greater than or equal to]10[micro]IU/ml and/or abnormally low fT4 and fT3 levels).
Statistical analysis was carried out using SPSS for windows 15.0 software (SPSS Inc, Chicago, IL, USA). Continuous variables were expressed as mean [+ or -] standard error of mean (S.E.M.). One way analysis of variance (ANOVA) and student's t test was applied to the data. The Pearson correlation was used to test whether TSH, fT4 and fT3 was correlated with TC, LDL-C, HDL-C, TG, VLDLC, TC/HDL-C and LDL/HDL-C. P value <0.05 was considered statistically significant.
In our study population, both the hypothyroid and control groups were age and sex-matched. Majority of the patients and the controls were women, since the hospital is popular mainly for its gynecology and obstetrics services. Mean age of the hypothyroid patients was 31.55 [+ or -] 2.1 years and that of euthyroid group was 30.76 [+ or -] 1.9 years. Hypothyroid group consisted of 80.22% women whereas the euthyroid group had 78% women. Mean serum TSH level in the control group was 2.428 [+ or -] 0.11[micro]IU/ml (table 1). The subclinical hypothyroid (7.615 [+ or -] 0.1[micro]IU/ml) patients showed significant increase in TSH levels and it was much more significant in overt hypothyroid cases (39.758 [+ or -] 4.46[micro]IU/ml) when compared with controls. The levels of fT4 (0.84 [+ or -] 0.03ng/dL) and fT3 (3.08 [+ or -] 0.07pg/dL) decreased slightly in subclinical hypothyroid patients as compared to the corresponding values in controls (0.94 [+ or -] 0.03ng/dL and 3.20[+ or -] 0.04pg/dL respectively) but this was significant statistically. In overt hypothyroid cases, fT3 and fT4 (2.60 [+ or -] 0.07pg/dL and 0.43 [+ or -] 0.1532ng/dL respectively) levels showed a highly significant decrease as compared to the control group.
Mean serum level of TC in patients with SCH (236.724 [+ or -] 9.47mg/dl) was significantly high from that of value in controls (179.133 [+ or -] 6.69mg/dl) (p=0.045) (table 2). All other parameters were not statistically significant as compared to the controls. Patients with OH had statistically significant higher levels of TC (260.04 [+ or -] 11.07mg/dl, p<0.001), TG (171.76 [+ or -] 1.8mg/dl, p<0.05), LDL-C (151.635 [+ or -] 8.44mg/dl, p<0.001) and VLDL-C (34.35 [+ or -] 4.06mg/dl, p<0.05) when compared with controls. There was an increase in HDL-C in both SCH and OH group though not significant statistically. LDL C/HDL-C and TC/HDL-C ratios were also not significant statistically in either group. When subclinical and overt hypothyroid cases were compared, TSH, fT3 and fT4 values showed a statistical significance. The mean levels of atherogenic lipid variables were greater in OH than in SCH, although the differences did not reach statistical significance.
Correlation coefficients (r) between TSH, fT3 and fT4 levels, and lipid parameters were also calculated to find if any association exists between them. No correlation was found in any of the parameters in SCH except HDL which showed a negative correlation with fT4 (table 3). Other parameters did not show any statistically significant correlation.
In OH group, TSH showed a positive correlation (p<0.05) and fT4 levels showed a negative correlation with TC (table 4). There was also negative correlation of serum HDL-C and fT4. Moreover, fT3 also showed significant negative correlation with TC/HDL-C and LDL/HDL-C ratios in OH cases (p<0.05).
The data in our study shows that the mean age of the hypothyroid subjects was 31.55 [+ or -] 2.1 years, majority were women, and prevalence of hypothyroidism (overt and subclinical) was high in this group. The hypothyroidism in young adult women could be iodine deficiency- related as at this age, Hashimoto's disease is most unlikely. In our study, it was found that patients with OH had significantly higher levels of TC, LDL-C, TG and VLDL-C as compared to control group. Moreover, there was positive correlation of TC with TSH level (p=0.035) and negative correlation with fT4 (p=0.023) in overt hypothyroid group. However, in SCH patients, only TC was slightly high (p=0.045) as compared to the controls. The explanation for these observed findings lie in the fact that thyroid hormones regulate the activity of some key enzymes in lipoprotein transport and therefore alter the lipoprotein levels in hypothyroidism. The primary mechanism for hypercholesterolemia in hypothyroidism is accumulation of LDL cholesterol due to a reduction in the number of cell surface receptors for LDL (19), resulting in decreased catabolism of LDL. The promoter of the LDL receptor gene contains a thyroid hormone responsive element (TRE) which allows the triiodothyronine (T3) to upregulate the gene expression of the LDL receptor (20). Furthermore, decreased thyroid function not only increases the number of LDL particles but also promotes LDL oxidability (21,22). Hypertriglyceridemia associated with increased levels of VLDL is attributable to the decreased activity of lipoprotein lipase, which results in a decreased clearance of triglyceride-rich lipoproteins (23). Thus, hypothyroidism is a major cause of secondary dyslipidemia, and may represent an increased risk for coronary heart disease.
It is interesting to note that in the levels of HDL were progressively increased from euthyroid to SCH to OH, though not statistically significant. Further, there was increase in TC/HDL-C and LDL-C/HDL-C ratios in both the hypothyroid groups as compared to the controls which emphasizes the fact that the increased HDL alone does not protect against coronary heart disease (24). Plasma HDL concentrations have been reported to be elevated in severe hypothyroidism (25-27). These conflicting results are partly because of the recently reported regulation of cholesterol ester transfer protein (CETP) and hepatic lipase (HL) activity by thyroid hormone (24). CETP transports cholesteryl esters from HDL2 to VLDL, IDL and remnants, and replaces it with triglycerides (28). HDL2 is consequently hydrolyzed and converted to HDL3 by HL. The activity of CETP and HL are low in hypothyroidism thereby leading to increased HDL2 levels (29).
An increasing number of patients with SCH are being detected by the widespread use of TSH screening. However, until now, no direct association between SCH and atherosclerosis has been proven (6,30,31) and whether SCH should be treated for the risk of cardiovascular disease is controversial (32). A few studies (33,34) have suggested that the majority of patients with SCH did not differ from controls in risk factors for coronary heart disease. In this respect, in our study, patients with SCH had only moderate increase in TC (p<0.05), whereas other lipid profile parameters did not differ significantly when compared with control individuals.
Our study concludes that overt hypothyroidism is a major cause of secondary dyslipidemia as it is associated with increase in the levels of total cholesterol, LDL-C, VLDL-C and triglycerides which may lead to increased cardiac risk. Our study also shows high prevalence of hypothyroidism in women of reproductive age group which is a cause of serious concern due to its effects during pregnancy and its association with dyslipidemia. Subclinical hypothyroidism has only a moderate increase in total cholesterol. Further, as SCH progresses to OH, there is gradual derangement of lipid profile. Thus, patients with dyslipidemia should be screened for hypothyroidism before being given specific lipid-lowering drug therapy. It seems that thyroid hormone replacement, if used, would be most beneficial in patients with OH instead of SCH.
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(Received 28 July 2011 and accepted 01 October 2011)
Vandana Saini * ([PSI]) MD, Amita Yadav ** MD, Sarika Arora ** MD, Ritu Singh *** MD and Jayashree Bhattacharjee *** MD
* Senior Resident, ** Assistant Professor, *** Professor, Department of Biochemistry, Lady Hardinge Medical College and associated hospitals, New Delhi, India
([PSI]) Correspondence at: Department of Biochemistry, Lady Hardinge Medical College and associated hospitals, New Delhi, India; Mobile: +919911087969; Email: email@example.com
Table 1: Comparison between the TSH, fT4 and fT3 values obtained in hypothyroid and euthyroid subjects Euthyroid SCH OH TSH 2.428 [+ or -] 7.615 [+ or -] 39.758 [+ or -] ([micro]IU/ml) 0.11 0.11 ** 4.46 ** fT4 0.943 [+ or -] 0.84 [+ or -] 0.43 [+ or -] (pg/dl) 0.03 0.03 * 0.02 ** fT3 3.205 [+ or -] 3.08 [+ or -] 2.60 [+ or -] (ng/ml) 0.04 0.07 * 0.07 ** * p value vs controls <0.05; ** p value vs controls <0.001 Table 2: Lipid parameters in patients with hypothyroidism vs controls Parameters Control SCH TC 179.133 [+ or -] 6.697 236.724 [+ or -] 9.472 LDL-C 113.840 [+ or -] 8.467 154.193 [+ or -] 17.042 HDL-C 41.500 [+ or -] 3.126 45.296 [+ or -] 3.783 VLDL-C 23.133 [+ or -] 2.483 33.296 [+ or -] 1.995 TG 115.667 [+ or -] 8.022 166.48 [+ or -] 7.481 TC/HDL-C 4.643 [+ or -] 0.404 5.798 [+ or -] 0.757 LDL/HDL 3.035 [+ or -] 0.344 3.843 [+ or -] 0.669 Parameters p value * OH p value ** TC 0.045 260.043 [+ or -] 11.073 0.000 LDL-C 0.212 151.635 [+ or -] 8.446 0.001 HDL-C 0.476 49.059 [+ or -] 3.494 0.125 VLDL-C 0.115 34.35 [+ or -] 4.068 0.041 TG 0.115 171.761 [+ or -] 1.800 0.041 TC/HDL-C 0.278 5.132 [+ or -] 0.514 0.281 LDL/HDL 0.624 3.439 [+ or -] 0.38 0.232 * SCH vs control; ** OH vs controls Table 3: Correlation of lipid profile parameters with thyroid function in subclinical hypothyroid cases TSH ft4 r values p value r values p value TC 0.033 0.830 -0.004 0.978 LDL-C -0.278 0.236 -0.089 0.736 HDL-C -0.144 0.544 -0.519 0.005 VLDL-C 0.156 0.312 0.057 0.630 TG 0.156 0.312 0.057 0.630 TC/HDL-C 0.359 0.120 0.337 0.086 LDL-C/HDL-C 0.158 0.518 0.203 0.321 ft3 r values p value TC -0.007 0.952 LDL-C 0.212 0.278 HDL-C 0.108 0.591 VLDL-C -0.151 0.208 TG -0.151 0.208 TC/HDL-C 0.005 0.979 LDL-C/HDL-C 0.052 0.801 Table 4: Correlation of lipid profile parameters with thyroid function in overt hypothyroid cases TSH fT4 r values p value r values p value TC 0.315 0.035 -0.264 0.023 LDL-C 0.127 0.628 -0.282 0.512 HDL-C -0.010 0.969 -0.447 0.017 VLDL-C 0.139 0.362 0.078 0.512 TG 0.139 0.362 0.078 0.146 TC/HDL-C 0.013 0.959 0.343 0.074 LDL-C/HDL-C 0.031 0.906 0.214 0.275 fT3 r values p value TC -0.098 0.952 LDL-C -0.237 0.278 HDL-C 0.398 0.114 VLDL-C -0.115 0.452 TG -0.115 0.452 TC/HDL-C -0.541 0.025 LDL-C/HDL-C -0.526 0.030
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