Effect of Levothyroxine Therapy on the Lipid Profile of Patients With Hypothyroidism: A Systematic Review

Hypothyroidism, also known as underactive thyroid, is a condition where the thyroid gland does not produce enough thyroid hormone. Deficiency or lack of thyroid hormone causes patients to have a slower metabolism, which may lead to secondary medical issues such as weight gain, fatigue, depression, and increased cardiovascular risk. This systematic review aims to explore the effect of levothyroxine therapy on the lipid profile of hypothyroid patients. Through a comprehensive search, 3096 articles were retrieved using keywords such as Hypothyroidism, Levothyroxine, Lipid, Dyslipidemia, and Cholesterol from PubMed, PubMed Central, Google Scholar, and ScienceDirect databases. The Medical Subject Headings (MeSH) strategy was also leveraged to extensively search the PubMed database. Research articles that were published from the year 2020 until May 2024, including randomized control trials, observational studies, meta-analyses, systematic reviews, literature reviews, and case reports, were included in the research. Research papers published before 2020, written in languages other than English, and animal studies were excluded. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were used in the design of the systematic review. Levothyroxine therapy is the treatment of choice in patients suffering from hypothyroidism, and based on our review, the treatment has a positive impact, leading to a significant decrease in total cholesterol, low-density lipoproteins, and triglyceride values in hypothyroid patients. The research highlights the importance of starting timely levothyroxine therapy in hypothyroid patients to maintain normal lipid levels and reduce the associated cardiovascular risk.


Introduction And Background
Hypothyroidism is an endocrine disorder caused by the failure of the thyroid gland to produce adequate thyroid hormone, which affects the body's metabolism and may lead to obesity, fatigue, anorexia, hypertension, and hyperlipidemia [1].It is divided into primary, secondary, and tertiary types.In primary hypothyroidism (PHT), the thyroid gland does not produce enough thyroid hormone, which results in a compensatory increase in thyroid-stimulating hormone (TSH).Secondary hypothyroidism is caused by pituitary disorders and is characterized by decreased levels of TSH and triiodothyronine (T3) or thyroxine (T4).Tertiary hypothyroidism is caused by hypothalamic dysfunction, which results in decreased levels of thyrotropin-releasing hormone (TRH), causing a decrease in TSH and T3/T4 [2][3][4].Overt hypothyroidism is defined as elevated TSH and decreased thyroxine concentrations, whereas subclinical hypothyroidism (SCH) is defined as elevated TSH and a normal serum free thyroxine (FT4) level [5,6].Both overt and SCH are associated with dyslipidemia [7]. Figure 1 illustrates the mechanisms of the different types of hypothyroidism.Hypothyroidism affects up to 5% of the general population worldwide, with a further estimated 5% being undiagnosed.The National Health and Nutrition Examination Survey (NHANESIII) found the prevalence of overt hypothyroidism among individuals aged 12 years and above in the US to be 0.3% and subclinical hypothyroidism 4.3%.Iodine deficiency is the most common cause of hypothyroidism, but in areas of iodine sufficiency, Hashimoto's disease is the most common cause of thyroid failure [2,5].
Thyroid dysfunction may alter the synthesis and degradation of lipids as well as the function of various enzymes in the lipid metabolism pathway.Insufficient production of thyroid hormones causes changes in the lipid profile, including levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), and the levels of apolipoprotein A (apoA) and apolipoprotein B (apoB) [7][8][9].In hypothyroidism, dyslipidemia is mainly caused by an increased synthesis rate compared to the degradation rate, resulting in elevated levels of TC, particularly LDL.These elevated lipid levels serve as substrates for lipid peroxidation by reactive oxygen species (ROS), resulting in oxidative stress [10].The coexistence of dyslipidemia and hypothyroidism has emerged as a significant risk factor for atherosclerosis development.This combination can adversely affect cardiovascular disease risk by altering atherogenic lipid components, increasing arterial hypertension, and promoting inflammation and oxidative stress.These changes lead to endothelial dysfunction, which is the primary cause of death from coronary heart disease [11,12].Levothyroxine (LT4) is the standard replacement therapy for hypothyroidism and is associated, through metabolic correction, with a substantial reduction in body weight and serum lipids [13].The antioxidant and hypolipidemic properties of LT4 are proven, and LT4 therapy has a favorable effect on cardiovascular function and lipid profile [14].The purpose of our study was to gather, evaluate, and present recent research and findings regarding the effect of LT4 treatment on the lipid profile of hypothyroidism patients.

Review Methodology
The 2020 updated Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines have been followed for the design and reporting of this systematic review [15].

Eligibility Criteria
The review question was formulated based on the population, intervention, and outcome (PIO) elements: the population includes patients diagnosed with hypothyroidism, the intervention is treatment with LT4, and the outcome includes any variation in the lipid profile of the patient.Besides these PIO elements, additional inclusion and exclusion criteria were used to narrow down the articles under consideration.The inclusion criteria included research articles with free full text in English published between 2020 and 2024, and human studies were included.The exclusion criteria were articles published before the year 2020, written in languages other than English, and animal studies.[16][17][18].

Data Collection Process
Based on the results of the quality assessment tools, the research papers were shortlisted, and a comprehensive review of the shortlisted papers was conducted.Variation in the lipid profile values, which was the core outcome of the study, was evaluated.Most of the results showed how the lipid profile values changed after LT4 administration.

Results
Using PubMed, PubMed Central, Google Scholar, and ScienceDirect databases, a total of 3096 research papers were retrieved, and 121 duplicates were removed through EndNote.From the remaining, 420 articles were discarded as they were ineligible according to the inclusion criteria.After this initial filtering, 2555 research articles remained, which were screened manually by going through the titles.Finally, 23 research articles were sought for retrieval.The 23 articles were screened by going through the abstract, full free-text, and considering the inclusion-exclusion criteria.Out of these, eight articles were not retrieved due to no free or open access, or non-English or only abstract availability.Quality assessment was performed on the final 15 papers by standardized assessment tools, and two papers were removed due to the low quality or risk of bias.Finally, 13 papers, which included case-control studies, cohort studies, systematic review and metaanalysis, and pre-post interventional studies, were considered for our study.Figure 2 shows the PRISMA 2020 flow diagram [15].The NOS assessment tool for case-control studies was employed to evaluate seven case-control studies that met the standards, and the results are presented in Table 2.The NOS assessment tool for cohort study was used to evaluate one cohort research that met the standards, and the assessment results are presented in Table 3.

TABLE 2: Results of the Newcastle-Ottawa Scale (NOS) assessment tool for case-control studies
The passing score is 7/9 Reference: [16] Checklist Items

Maiti et al. [14]
Selection Representativeness of the exposed cohort 1 Selection of the non-exposed cohort 1 Ascertainment of exposure 1 Demonstration that outcome of interest was not present at the start of the study 1

Comparability of cohorts
Study controls for the most important factor (age) 1 Study controls for any additional factor(s) 1

Assessment of outcome 1
Was follow-up long enough for outcomes to occur? 1 Adequacy of follow-up of cohorts 1 Total 9/9 Quality Pass

TABLE 3: Results of the Newcastle-Ottawa Scale (NOS) assessment tool for cohort studies
The passing score is 7/9 Reference: [16] Two systematic reviews included in our study were evaluated using the AMSTAR 2 checklist, as illustrated in Table 4 [17].Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group by the NIH was used for pre-post interventional studies in our studies, as illustrated in Table 5 [18].

[27]
Did the research questions and inclusion criteria for the review include the components of Population, Intervention, Control, Outcome (PICO) framework?Yes Yes Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?

Yes Yes
Did the review authors explain their selection of the study designs for inclusion in the review?A total of 15 articles underwent quality appraisal, and two articles were removed following the risk-of-bias assessment.Finally, 13 papers were included in the review, and Table 6 below provides details of those included articles along with their key findings.

Discussion
A few research projects have explored the effects of LT4 therapy on hypothyroid patients.A significant study by Raut et al. was conducted on 122 patients diagnosed with SCH and had positive thyro-peroxidase antibodies [30].The patients recruited in the study were administered LT4 based on their TSH levels and were followed up after six to nine weeks.Significant reductions were observed in their mean TSH, TC, and LDL levels.Further supporting these findings, an observational prospective cohort study by Maiti et al. involved the recruitment of 60 hypothyroid patients to assess changes in cardiovascular risk markers, thyroid function, and other metabolic parameters [14].The study observed significantly improved results of thyroid function tests, with reductions in TSH levels and apoA.Additionally, LT4 therapy led to notable decreases in serum lipid levels, including TC, LDL, and TG [14,30].These findings suggest that LT4 therapy is effective in improving the lipid profiles in hypothyroid patients, and potentially reducing cardiovascular risks associated with dyslipidemia.
Beysel et al. conducted a retrospective observational study to evaluate the impact of thyroxine treatment on cardiovascular risk factors in patients with SCH [20].The study included 30 SCH patients and 40 age-and sex-matched healthy controls.The SCH patients were treated with thyroxine 50 μg/day for three months.Before treatment, the patients had higher body mass index (BMI), serum glucose, TC, LDL, and highsensitivity C-reactive protein (hs-CRP) levels compared to controls.After treatment, there was a significant decrease in BMI, LDL, and hs-CRP levels in the patients, while TC, TG, and HDL levels remained unchanged.
The study found that TSH levels were positively correlated with BMI, glucose, LDL, and hs-CRP levels [20].
The logistic regression analysis indicated that TSH was independently associated with LDL levels.
A comprehensive systematic review and meta-analysis by Kotwal et al. reviewed 166 studies with a total of 12,855 patients, including both hyperthyroidism and hypothyroidism cases [26].The analysis identified a statistically significant change in TC, LDL cholesterol, HDL cholesterol, and TG levels due to LT4 therapy in patients with overt hypothyroidism.However, according to the analysis, the changes in cholesterol levels were less significant in patients with SCH, and there was no statistically significant change in HDL levels [26].
An innovative study by Benabdelkamel et al. used high-resolution mass spectrometry to analyze plasma samples from 18 hypothyroid patients before and after achieving a euthyroid state with LT4 treatment [28].Significant decreases in ceramide, phosphatidylcholine, TG, acylcarnitine, and peptides were observed posttreatment, indicating changes in fatty acid transportation and enhanced β-oxidation.Additionally, an increase in glycocholic acid suggested thyroid hormone involvement in bile acid production and secretion.Despite these findings, no notable changes in serum concentrations of TC, LDL, and TG were observed after treatment [28].This study underscores the utility of metabolomics in understanding the molecular impact of LT4 therapy on hypothyroidism and its potential role in refining treatment approaches.
Shatla and Faisal investigated the relationship between overt hypothyroidism and non-alcoholic fatty liver disease (NAFLD) and assessed the impact of LT4 therapy on NAFLD [22].Conducted on 325 hypothyroid patients and 325 controls, the study showed a significantly higher prevalence of NAFLD, elevated metabolic variables, and liver enzymes in the hypothyroidism group compared to controls.After 12 months of LT4 therapy, there was a significant reduction in NAFLD prevalence and substantial improvements in BMI, waist circumference, TC, TG, LDL, fasting blood glucose, HbA1c, and liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase) [22].
Roohigilani et al. evaluated the impact of LT4 therapy on metabolic parameters and insulin resistance (IR) in 153 patients with SCH.After six months of LT4 treatment, there were significant improvements in TSH, T3, and T4 levels, and reductions in fasting blood sugar, fasting insulin, two-hour postprandial glucose, homeostasis model assessment estimated insulin resistance (HOMA-IR) score, TC, LDL cholesterol, and Creactive protein (CRP) levels [32].HDL cholesterol levels increased significantly.However, the treatment had no significant effect on TG, BMI, waist circumference, uric acid, and mean systolic and diastolic blood pressure.The number of patients with high blood pressure decreased significantly.The study concluded that LT4 therapy is beneficial for improving IR and lipid profiles in SCH patients, and it is strongly recommended for those with IR, dyslipidemia, obesity, and hypertension [32].
Another study by Ostadrahimi et al. focused on the impact of LT4 on IR, lipid profiles, and BMI in hypothyroid patients [29].Conducted on 105 untreated hypothyroid patients, the study measured insulin, fasting blood glucose, and lipid profiles at diagnosis and three months post-LT4 therapy.The findings revealed significant improvements in BMI, TC, TG, LDL, fasting insulin, and TSH levels following treatment.However, no significant changes were observed in IR as assessed by the HOMA-IR and, the quantitative insulin sensitivity check index (QUICKI) and HDL.The study concluded that while LT4 therapy significantly improves lipid profiles and BMI, it does not improve IR and suggests the need for more sensitive tests to evaluate LT4 therapy's effects on mild IR cases [29].
Another study by Abdulhadi et al. investigated the metabolic effects of hypothyroidism on leptin (LP), adiponectin (ADP), and the leptin-adiponectin ratio (LAR) [19].The study included 62 PHT patients (27 newly diagnosed and 35 on LT4 therapy) and 28 healthy controls, and their anthropometric, lipid, and pressure profiles were evaluated, along with TSH, T3, T4, LP, and ADP serum levels.The study concluded that hypothyroidism is associated with poor cardio-metabolic profiles and high LAR, with LT4 therapy improving all the evaluated parameters [19].

Effect of LT4 Therapy on Pregnant Patients
The effects of LT4 therapy on lipid profiles and overall health outcomes during pregnancy have been a subject of significant interest.Xu et al. conducted a retrospective study involving 164 pregnant patients with isolated hypothyroxinemia and 407 euthyroid controls [24].The study investigated the association between low FT4 levels and lipid metabolism in pregnant women, as well as the impact of LT4 treatment on these parameters and found that hypothyroid patients had significantly higher levels of TC, TG, LDL cholesterol, and apoB when compared to controls.An inverse correlation between FT4 and TG levels was observed, which remained significant after adjusting for pre-pregnancy BMI.Patients receiving LT4 treatment showed a slower progression of hypercholesterolemia during pregnancy compared to those receiving dietary iodine supplementation [24].
Yang et al. conducted a large-scale cohort study involving 20,365 pregnant patients, including 319 in the subclinical hypothyroidism LT4 treatment group, 103 in the SCH non-intervention group, and 9598 controls [25].The research found that serum lipid levels, specifically TC, TG, LDL, and HDL, vary significantly throughout pregnancy and established reference ranges for these lipids in the first and third trimesters.The study concluded that LT4 treatment effectively reduced TC and LDL levels in pregnant women with SCH, with treatment effects influenced by BMI.Notably, the treatment only lowered HDL levels in obese women, exacerbating the negative effects of obesity [25].
The findings underscore the clinical importance of routine thyroid function screening and managing lipid levels in pregnant women with SCH, especially those with high pre-pregnancy BMI or hyperlipidemia, to potentially prevent adverse pregnancy outcomes such as gestational diabetes mellitus (GDM), preeclampsia, and preterm delivery [24,25].

Effect of LT4 Therapy on Older Patients
A systematic review and meta-analysis by Zhao et al. examined the effects of LT4 treatment on older patients with subclinical hypothyroidism [27].Through a comprehensive meta-analysis of 13 studies, including approximately 5000 participants aged 60 and above, the research revealed that LT4 significantly reduced TC, TG, LDL cholesterol, and apoB levels, suggesting a potential benefit in lipid profile improvement.However, LT4 did not considerably affect bone mineral density, fatigue, hypothyroid symptoms, quality of life, BMI, cognitive function, depression, blood pressure, serum creatinine, fasting blood glucose, HDL, or apoA.The study concluded that while LT4 can improve lipid profiles, its use should be cautious in older patients to avoid unnecessary and excessive treatment [27].

Effect of LT4 Therapy on Polycystic Ovary Syndrome (PCOS) Patients
Investigating the relationship between SCH, PCOS, and the effects of LT4 treatment, Kowalczyk et al. studied 190 women with PCOS by dividing them into three groups: PCOS with untreated SCH, PCOS with SCH under LT4 treatment, and PCOS with normal thyroid function [21].There were no significant differences in lipid profile and glucose metabolism among the groups, and BMI was identified as the primary factor affecting serum lipids, fasting glucose, fasting insulin, and insulin resistance.TSH levels were associated with TC and LDL cholesterol levels, while BMI significantly influenced HDL cholesterol, TG, glucose, and IR.The study concluded that SCH causes mild lipid serum alterations in women with PCOS, but BMI has a more dominant impact on glucose and insulin metabolism.Treatment of SCH in PCOS does not significantly alter lipid and glucose metabolism; therefore, it is important to manage the BMI of these patients [21].

FIGURE 2 :
FIGURE 2: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart NOS: Newcastle-Ottawa Scale; NIH: National Institute of Health

TABLE 4 : Details of the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) checklist for articles retained in the study
[17]heck yes, no, can't answer, and not applicable.The passing score is High quality (>70% Yes)Reference:[17]Published

via California Institute of Checklist Items Benabdelkamel et al. [28] Ostadrahimi et al. [29] Raut et al. [30] Rivera-Hernandez et al. [31] Roohigilani et al. [32]
Was the study question or objective clearly stated?Yes Yes Yes Yes YesWere eligibility/selection criteria for the study population prespecified and clearly described?NR Yes No Yes YesWere the participants in the study representative of those who would be eligible for the test/service/intervention in the general or clinical

TABLE 5 : Results of the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group by the National Institute of Health (NIH)
[18]heck yes, no, cannot determine, not reported, and not applicable.The passing score is High quality (>70% Yes) NA: not applicable; NR: not reported; CD: cannot determine Reference:[18]

Table 7
presents the compiled findings from the reviewed research papers, illustrating the changes in lipid profiles of hypothyroid patients before and after LT4 treatment.