Levothyroxine therapy and its impact on serum lipids: Addressing dyslipidemia in hypothyroidism

ABSTRACT

Background and Objective:

The major goal of this study was to analyse the influence of levothyroxine medication on serum lipid levels in individuals with hypothyroidism, as well as its efficacy in controlling dyslipidemia caused by thyroid hormone deficiencies. This method provides a complete assessment of therapy efficacy and aids in identifying factors that may influence treatment results.

Methodology:

This prospective observational study, conducted from September 2019 to October 2020 at Shri Shiv Prasad Gupt Divisional District Hospital in Varanasi, India, included 150 patients with newly diagnosed hypothyroidism. A predesigned proforma was used in the study to collect demographic and medical history information. The data were analysed using SPSS version 23.

Results:

The study of 150 newly diagnosed hypothyroidism patients, predominantly aged 31–40 years and with a significant female predominance (95.4%), found a notable age and gender distribution in subclinical versus overt hypothyroidism. Subclinical cases were all female and concentrated in the 31–40 age group, while overt hypothyroidism was more evenly distributed, with a higher prevalence in the same age group and extending to older ages. TSH levels were significantly higher in overt hypothyroidism (45.1 ± 30.4 μU/mL) compared to subclinical hypothyroidism (8.6 ± 0.82 μU/mL, P < 0.01), reflecting more severe thyroid dysfunction in overt cases. Levothyroxine therapy improved lipid profiles in both conditions: In subclinical hypothyroidism, total cholesterol and triglycerides decreased and HDL increased; in overt hypothyroidism, total cholesterol, triglycerides, and LDL decreased, while HDL increased significantly. Levothyroxine also effectively normalized TSH levels in both subclinical (8.6 ± 0.8 μU/mL to 2.9 ± 1.33 μU/mL) and overt hypothyroidism (45.1 ± 30.4 μU/mL to 3.5 ± 1.1 μU/mL), demonstrating its efficacy in managing thyroid function and associated dyslipidemia.

Conclusion:

The study found that levothyroxine therapy significantly improved lipid profiles and reduced TSH levels in both subclinical and overt hypothyroidism. Despite these positive outcomes, the small sample size and short duration suggest the need for further research with a larger cohort and longer follow-up to validate and expand on these findings.

Introduction

Hypothyroidism, a prevalent thyroid hormone disorder, affects many people globally, especially women in older age groups. The World Health Organization reports that approximately two billion people are iodine deficient,[1] a leading cause of hypothyroidism worldwide. In areas with adequate iodine, autoimmune diseases like Hashimoto’s Thyroiditis and iatrogenic causes, such as treatment for hyperthyroidism, are the most common causes of hypothyroidism.[2] In a Colorado study, 9.5% of participants had elevated levels of thyroid-stimulating hormone (TSH), indicating the condition’s prevalence.[3]

In a study across eight major Indian cities, the prevalence of hypothyroidism was found to be 10.95%.[4] A separate study in Meerut and nearby areas reported high rates of abnormal thyroid hormone levels, with overt hypothyroidism (OH) at 8.2% and subclinical hypothyroidism (SH) at 8.4%, showing a female predominance.[5] Hypothyroidism is a significant cause of secondary hyperlipidemia, accounting for about 2% of such cases, ranking just behind diabetes mellitus.[6]

Hypothyroidism often causes secondary dyslipidemia by elevating total and LDL cholesterol (LDL-C) levels as thyroid function declines. This thyroid disorder alters lipoprotein composition and transport. Typically, hypothyroidism is linked to hypercholesterolemia primarily due to increased LDL-C levels, while high-density lipoprotein cholesterol (HDL-C) levels are usually normal or even elevated.[7]

Decreased thyroid secretion significantly raises plasma triglyceride levels,[8] largely due to reduced lipoprotein lipase (LPL) activity,[9] which impairs the clearance of triglyceride-rich lipoproteins. Dyslipidemia is a recognized risk factor for cardiovascular diseases, with an increased risk of coronary heart disease and other atherosclerotic conditions associated with higher plasma cholesterol levels, especially when the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol rises. In addition, there is a weak positive correlation between plasma triglyceride levels and coronary heart disease risk.[10]

Correction of hypothyroidism typically resolves associated lipid abnormalities. Levothyroxine sodium, the preferred thyroid hormone replacement therapy, is chosen for its consistent potency and prolonged duration of action. The standard daily dose is 1.5 μg/kg (approximately 100–150 μg), with adjustments made based on TSH levels to achieve and maintain normal TSH concentrations.[11] Evidence suggests that thyroxine therapy is beneficial for patients with subclinical hypothyroidism to prevent progression to overt hypothyroidism. In addition, thyroid hormone replacement may attenuate the progression of coronary heart disease due to its favorable effects on lipid profiles.[12]

Hypothyroidism is a significant yet often overlooked cause of secondary hypertension, particularly diastolic hypertension, due to increased peripheral resistance. Restoration of euthyroidism through thyroxine therapy has been shown to substantially reduce both systolic and diastolic blood pressure.[13]

Extensive research has explored lipid profiles in hypothyroid patients, yet debates persist regarding the influence of thyroid hormone disorders on cardiovascular events and lipid levels. Data on this topic is scarce in India, particularly in Uttar Pradesh. To address this gap, a study was conducted at SSPG Divisional District Hospital in Varanasi, Uttar Pradesh, focusing on dyslipidemia in newly diagnosed hypothyroid patients and evaluating the impact of levothyroxine therapy on their lipid profiles.

Materials and Methods

Study population

This prospective observational study was conducted from September 2019 to October 2020 at Shri Shiv Prasad Gupt Divisional District Hospital, Varanasi, India. The study included 150 patients with newly diagnosed hypothyroidism who had not yet started treatment and were over 14 years old, all of whom provided informed consent to participate. Exclusions included individuals with chronic kidney disease, those on lipid-lowering medications, diabetics, people with familial dyslipidemia, pregnant women, and those with excessive alcohol consumption.

Data collection

Relevant clinical data, including demographic information (age, sex, place, occupation) and medical history, were collected from the patients.

Diagnostic criteria

A thorough clinical examination was conducted for each patient, followed by thyroid function tests (T3, T4, TSH) and a fasting lipid profile (total cholesterol, triglycerides, LDL, HDL). Patients were classified as either having overt hypothyroidism (high TSH with low T3 and T4) or subclinical hypothyroidism (high TSH with normal T3 and T4). Patients with abnormal T3, T4, and TSH levels were further evaluated. Blood samples were collected aseptically after 12 hours of overnight fasting to assess their lipid profile, including total cholesterol, triglycerides, HDL-C, LDL-C, and VLDL.

Laboratory methods

Serum T3 and T4 levels were measured using an immunochemiluminescence microparticle assay, while serum TSH was measured with an ultrasensitive sandwich chemiluminescent immunoassay. Total cholesterol was assessed using the CHOD/PAP method, triglycerides with the G PO/PAP method, and HDL cholesterol with the PEG/CHODPAP method. LDL cholesterol was calculated using Friedewald’s formula for triglyceride levels ≤4.5 mmol/L; otherwise, it was measured directly in ultracentrifuged plasma. VLDL cholesterol was estimated as one-fifth of the plasma triglyceride level.

Patient categorization

Patients with hypothyroidism were categorized into overt hypothyroidism (OH) and subclinical hypothyroidism (SCH). Those with borderline or abnormal levels of total cholesterol and/or triglycerides were classified as dyslipidemic and further subgrouped into hypercholesterolemia only, hypertriglyceridemia only, or both hypercholesterolemia and hypertriglyceridemia.

Treatment protocol

Patients with overt hypothyroidism (OH) were prescribed 50 to 100 μg of levothyroxine daily, adjusted to normalize TSH levels, while those with subclinical hypothyroidism (SCH) received 25–50 μg/day with the same goal.

Additional assessment

Body mass index was calculated as weight in kg divided by height in meters squared, and blood pressure was measured twice after a 30-minute rest, with the average used. Patients were reassessed at 3–4 months, 6–7 months, and 9–10 months for T3, T4, TSH, lipid profile, and blood pressure, with additional observation of dyslipidemic patients for partial reversal if multiple lipid parameters were abnormal.

Reference ranges for lipid and thyroid profiles

The normal ranges for lipid profile parameters are serum cholesterol 130–200 mg/dl, serum triglycerides 30–200 mg/dl, HDL cholesterol 40–59 mg/dl, and LDL cholesterol up to 150 mg/dl. For thyroid profile, the normal ranges are serum T3 0.58–1.59 ng/dl, serum T4 4.87–11.72 μg/dl, and serum TSH 0.35–4.94 μIU/ml. TSH values between 4.94 and 10 μIU/ml indicate subclinical hypothyroidism, while values above 10 μIU/ml denote overt hypothyroidism.

Statistical analysis

Data were recorded using a predesigned study proforma and analyzed with SPSS version 23. Continuous variables were reported as mean ± standard deviation, while categorical variables were presented as number (percentage). Paired t-tests were used to compare quantitative data between groups, with a significance level set at a P value < 0.05.

Results

The study comprised 150 newly diagnosed cases of hypothyroidism. The predominant age group was 31–40 years, accounting for 36.0% of the cases, followed by individuals aged ≤30 years at 26.7% and those aged 41–50 years at 21.3%. The mean age of the participants was 38.1 ± 10.7 years. The study revealed a significant female predominance, with females constituting 95.4% of the hypothyroidism cases. However, the P value of 0.352 suggests that the age distribution of males and females with hypothyroidism is not significantly different. Most males with hypothyroidism are concentrated in the 31–40 age group, while females are more evenly distributed across various age ranges [Table 1].

Table 1.

Distribution of patients on the basis of their age and gender

Age in years	Gender		P
	Male (n=7)	Female (n=143)
≤30	1 (14.3)	39 (27.3)	0.352
31-40	4 (57.1)	50 (34.9)
41-50	0 (0.0)	32 (22.4)
51-60	1 (14.3)	16 (11.2)
>60	1 (14.3)	6 (4.2)

The distribution of subclinical and overt hypothyroidism cases by age and gender reveals notable trends. Among the 21 cases of subclinical hypothyroidism, all females were concentrated in the 31–40 age group (42.9%), with no cases observed in males across the age ranges studied. In contrast, the 129 cases of overt hypothyroidism were more evenly distributed across different age groups, with the highest prevalence in the 31–40 age group for both genders, showing 3.3% of males and 31.8% of females affected. Overt hypothyroidism cases were also observed in older age brackets, including 12.4% of females aged 51–60 years and 3.9% of females aged over 60 years. The mean age of patients with subclinical hypothyroidism was 36.6 ± 9.3 years, slightly younger than those with overt hypothyroidism, whose mean age was 38.3 ± 10.9 years. This distribution highlights a clear female predominance in both forms of hypothyroidism, with a significant concentration of cases in the 31–40 age group, and suggests that overt hypothyroidism tends to occur later in life compared to subclinical forms [Table 2].

Table 2.

Distribution of hypothyroid patients by age and gender

Age in years	Subclinical Hypothyroidism (n=21)		Overt Hypothyroidism (n=129)
	Male	Female	Male	Female
≤30	0 (0.0)	6 (28.6)	1 (0.8)	33 (25.6)
31-40	0 (0.0)	9 (42.9)	4 (3.3)	41 (31.8)
41-50	0 (0.0)	5 (23.8)	0 (0.0)	24 (18.6)
51-60	0 (0.0)	0 (0.0)	1 (0.8)	16 (12.4)
>60	0 (.0)	1 (4.8)	1 (0.8)	5 (3.9)
Mean Age	36.6±9.3 years		38.3±10.9 years

The mean TSH levels for patients with subclinical hypothyroidism (8.6 ± 0.82 μU/mL) are significantly lower compared to those with overt hypothyroidism (45.1 ± 30.4 μU/mL), with a P value of less than 0.01 indicating statistical significance [Table 3]. This substantial difference in TSH levels reflects the more severe thyroid dysfunction in overt hypothyroidism compared to subclinical hypothyroidism. The elevated TSH levels in overt hypothyroidism are consistent with a greater degree of thyroid hormone deficiency, leading to a stronger compensatory increase in TSH production.

Table 3.

Mean values and standard deviations of thyroid parameters for Subclinical Hypothyroidism (SCH) and Overt Hypothyroidism (OH)

TSH (μU/mL)	Subclinical Hypothyroidism (n=21)	Overt Hypothyroidism (n=129)	P
TSH	8.6±0.82	45.1±30.4	<0.01

Levothyroxine therapy significantly improved lipid profiles in patients with dyslipidemia, regardless of hypothyroidism severity. In subclinical hypothyroid patients, total cholesterol and triglycerides decreased significantly (P < 0.001 and P = 0.016, respectively), while HDL-cholesterol increased significantly (P = 0.002). Although LDL-cholesterol also decreased, this change was not statistically significant (P = 0.218) [Table 4]. For overt hypothyroid patients, levothyroxine therapy led to significant reductions in total cholesterol (from 245.0 ± 31.1 mg/dL to 201.2 ± 30.4 mg/dL, P < 0.001), triglycerides (from 250.8 ± 60.1 mg/dL to 198.4 ± 44.0 mg/dL, P < 0.001), and LDL-cholesterol (from 135.3 ± 36.6 mg/dL to 116.1 ± 36.0 mg/dL, P < 0.001), while HDL-cholesterol increased significantly (from 46.9 ± 7.3 mg/dL to 51.2 ± 7.2 mg/dL, P < 0.001) [Table 4]. These results highlight the overall beneficial impact of levothyroxine on lipid abnormalities associated with both subclinical and overt hypothyroidism.

Table 4.

Lipid parameters before and after levothyroxine therapy in patients with subclinical and overt hypothyroidism with dyslipidemia

Lipid Parameters (mg/dL)	Condition	Before Therapy	After Therapy	P
Total Cholesterol	Subclinical Hypothyroidism (n=21)	218.7±29.9	180.1±20.9	<0.001
	Overt Hypothyroidism (n=129)	245.0±31.1	201.2±30.4	<0.001
Triglycerides	Subclinical Hypothyroidism (n=21)	186.1±35.6	154.9±44.1	0.016
	Overt Hypothyroidism (n=129)	250.8±60.1	198.4±44.0	<0.001
HDL-Cholesterol	Subclinical Hypothyroidism (n=21)	47.8±6.1	54.7±7.6	0.002
	Overt Hypothyroidism (n=129)	46.9±7.3	51.2±7.2	<0.001
LDL-Cholesterol	Subclinical Hypothyroidism (n=21)	81.4±18.4	73.6±21.9	0.218
	Overt Hypothyroidism (n=129)	135.3±36.6	116.1±36.0	<0.001

Levothyroxine replacement therapy effectively normalized thyroid function in both subclinical and overt hypothyroid patients with dyslipidemia. In subclinical hypothyroidism, TSH levels decreased significantly from 8.6 ± 0.8 μU/mL to 2.9 ± 1.33 μU/mL (P < 0.001) [Table 5], while in overt hypothyroidism, TSH levels dropped from 45.1 ± 30.4 μU/mL to 3.5 ± 1.1 μU/mL (P < 0.001) [Table 5]. These reductions confirm the efficacy of levothyroxine in managing thyroid function across both conditions.

Table 5.

TSH levels before and after levothyroxine replacement therapy in subclinical and overt hypothyroid patients with dyslipidemia

Condition	TSH Before Therapy (µU/mL)	TSH After Therapy (µU/mL)	P
Subclinical Hypothyroidism (SCH)	8.6±0.8	2.9±1.33	<0.001
Overt Hypothyroidism (OH)	45.1±30.4	3.5±1.1	<0.001

Discussion

Hypothyroidism, caused by a deficiency in thyroid hormones, slows metabolic processes and can lead to growth and mental development issues in infants and children. The study included 150 patients with newly diagnosed hypothyroidism, predominantly aged 31–40 years and with a significant female predominance (95.4%). Thyroid hormones are essential for hemoglobin synthesis and maturation, and their deficiency can impair oxygen metabolism, resulting in anemia. The prevalence of anemia in hypothyroid patients ranges from 20.0% to 65.0%, highlighting a strong link between the two conditions.[14]

Hypothyroidism can be induced by medications such as amiodarone, cytokines, and lithium, and presents with a range of nonspecific symptoms affecting various body systems, including endocrine, cardiovascular, central nervous, musculoskeletal, hematological, reproductive, gastrointestinal, and dermatological. Common symptoms include lethargy, weight gain, hair loss, dry skin, forgetfulness, constipation, and depression, though they may vary in severity and not all symptoms are present in every patient, especially in cases of mild hypothyroidism.[5]

In the present study, most patients were aged 31–40 years (36.0%), with a mean age of 38.1 ± 10.7 years. The cohort was predominantly female (95.4%), with only 4.6% male patients. In addition, 14.0% of the patients had subclinical hypothyroidism, while 86.0% had overt hypothyroidism. Similar to our study, Saxena et al.[6] found a predominance of females in hypothyroidism cases, with a male-to-female ratio of 1:6.5. They reported that the highest proportion of hypothyroid females were in the 21–30 years age group (33.89%), followed by the 31–40 years group (31.67%). For males, the highest incidence was in the 41–50 years age group (6.11%). This suggests that hypothyroidism more commonly affects younger females and middle-aged males. In another study, Deshpande et al.[15] reported a mean age of 36.25 years for hypothyroid patients, with the majority (37 cases) in the 21–30 years age group (4 males and 33 females) and the fewest in the 61–70 years age group (2 females). The present study findings are consistent with those of Shekhar et al.[11] In addition, Das et al.[7] conducted a study on dyslipidemia and hypothyroidism in East Medinipur, West Bengal, involving 260 patients. This study included 83 with subclinical hypothyroidism and 177 with overt hypothyroidism, with 151 females and 105 males, the majority of whom were in the 20–40 years age group.

In the present study, TSH levels were significantly lower in subclinical hypothyroidism (8.6 ± 0.82 μU/mL) compared to overt hypothyroidism (45.1 ± 30.4 μU/mL). These findings align with Arem et al.,[16] who reported mean TSH values of 9.1 ± 1 μU/mL for subclinical hypothyroidism and 42 ± 6.5 μU/mL for overt hypothyroidism. Similarly, Saxena et al.[6] reported mean TSH levels of 14.2 ± 6.1 μU/mL for subclinical hypothyroidism and 79.2 ± 56.6 μU/mL for overt hypothyroidism.

In this study, levothyroxine replacement therapy significantly improved lipid parameters in both subclinical and overt hypothyroid patients with dyslipidemia. Total cholesterol, triglycerides, and LDL-cholesterol decreased, while HDL-cholesterol increased significantly (P < 0.05). Specifically, HDL-cholesterol levels rose from 46.9 ± 7.3 mg/dL to 51.2 ± 7.2 mg/dL (P < 0.001) in overt hypothyroidism cases. Overall, levothyroxine therapy effectively reduced hypercholesterolemia and hypertriglyceridemia and increased HDL levels. The study findings are in consistent with those of Saxena et al.,[6] who observed a statistically significant decrease in the mean levels of total cholesterol (TC), triglycerides (TG), and LDL-cholesterol, alongside a significant increase in HDL-cholesterol levels following levothyroxine replacement therapy. Similarly, Kumar et al.[14] reported a notable decrease in mean serum cholesterol levels, from 226.19 to 186.71 (P < 0.001). Shekhar et al.[11] also demonstrated a significant reduction in TC values from baseline (231.01 ± 27.84) to the first follow-up (210.36 ± 27.42) and further to the second follow-up (177.33 ± 23.17). In addition, significant reductions in TG and LDL levels were observed between the baseline and follow-up periods. In contrast, HDL levels showed a statistically significant increase from baseline (35.42 ± 6.73) to the first follow-up (46.45 ± 4.64) and maintained an elevated level at the second follow-up (46.86 ± 8.53). The study’s results are in agreement with these findings and further corroborate the positive impact of levothyroxine replacement therapy on lipid profiles, as also supported by the research conducted by Sharma P et al.[17]

Hypothyroidism affects the cardiovascular system, leading to hypertension and dyslipidemia, which contribute to atherosclerosis and coronary heart disease. Levothyroxine replacement therapy helps restore normal thyroid function and improves cardiovascular health by significantly reducing cholesterol and triglyceride levels, and increasing HDL. This therapy enhances LDL receptor activity, which boosts LDL particle breakdown, and stimulates lipid metabolism through cholesterol ester transfer protein and lipases.[18] In addition, it inhibits LDL oxidation, contributing to a lower risk of coronary artery disease, stroke, and peripheral vascular diseases.

In the study, TSH levels significantly decreased after levothyroxine replacement therapy: from 8.6 ± 0.8 to 2.9 ± 1.33 μU/mL in subclinical hypothyroidism (P < 0.001) and from 45.1 ± 30.4 to 3.5 ± 1.1 μU/mL in overt hypothyroidism (P < 0.001) similar to other studies.[14,19] In another study, Shekhar et al.[11] reported a notable reduction in TSH levels from 68.45 ± 42.07 at baseline to 7.42 ± 9.44 in follow-up. This suggests effective thyroid function normalization with levothyroxine. In addition, TSH levels and serum lipid profiles are interconnected with insulin sensitivity, which is influenced by thyroid function.

Conclusion

The study included patients predominantly aged 31–40 years (36.0%), with a mean age of 38.1 ± 10.7 years, and showed a strong female predominance (95.4%). Significant improvements were observed after levothyroxine therapy, including reductions in total cholesterol, triglycerides, and LDL-cholesterol, and an increase in HDL-cholesterol (P < 0.05) in both subclinical and overt hypothyroidism. In addition, TSH levels decreased significantly (P < 0.01) in both conditions. The study highlights that dyslipidemia is prevalent in hypothyroidism, and levothyroxine therapy effectively addresses both thyroid hormone deficiency and lipid abnormalities. Early diagnosis and treatment of hypothyroidism can prevent progression and associated complications.

Owing to the small sample size and limited duration of the study, we recommend conducting further research with a larger sample size and extended timeframe. This would help to validate study findings and provide a more comprehensive understanding of the topic. In addition, the study included only a single follow-up, which restricts our ability to assess long-term outcomes and changes over time.

Ethical approval

Ethical clearance for the study was obtained from the Ethics Committee of IMS BHU, Varanasi (No. Dean/2019/EC/1793).

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.