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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">BR</journal-id>
<journal-title-group>
<journal-title>Biomedical Reports</journal-title>
</journal-title-group>
<issn pub-type="ppub">2049-9434</issn>
<issn pub-type="epub">2049-9442</issn>
<publisher>
<publisher-name>D.A. Spandidos</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">BR-21-4-01826</article-id>
<article-id pub-id-type="doi">10.3892/br.2024.1826</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Articles</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Study of the association between thyroid dysfunction and serum lipid abnormalities</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Al-Odat</surname><given-names>Ibrahim</given-names></name>
<xref rid="af1-BR-21-4-01826" ref-type="aff">1</xref>
<xref rid="c1-BR-21-4-01826" ref-type="corresp"/>
</contrib>
<contrib contrib-type="author">
<name><surname>Al-Fawaeir</surname><given-names>Saad</given-names></name>
<xref rid="af1-BR-21-4-01826" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Al-Mahmoud</surname><given-names>Malik H.</given-names></name>
<xref rid="af2-BR-21-4-01826" ref-type="aff">2</xref>
</contrib>
</contrib-group>
<aff id="af1-BR-21-4-01826"><label>1</label>Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Jadara University, Irbid 21110, Jordan</aff>
<aff id="af2-BR-21-4-01826"><label>2</label>Department of Endocrinology, Saudi German Hospital Dubai, Dubai 391093, UAE</aff>
<author-notes>
<corresp id="c1-BR-21-4-01826"><italic>Correspondence to:</italic> Dr Ibrahim Al-Odat, Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Jadara University, 100 Irbid-Amman Highway, Irbid 21110, Jordan <email>623493416@qq.com </email></corresp>
</author-notes>
<pub-date pub-type="collection">
<month>10</month>
<year>2024</year></pub-date>
<pub-date pub-type="epub">
<day>31</day>
<month>07</month>
<year>2024</year></pub-date>
<volume>21</volume>
<issue>4</issue>
<elocation-id>138</elocation-id>
<history>
<date date-type="received">
<day>05</day>
<month>02</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>15</day>
<month>07</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2024, Spandidos Publications</copyright-statement>
<copyright-year>2024</copyright-year>
</permissions>
<abstract>
<p>The prevalence of thyroid dysfunction is increasing, often leading to unfavorable alterations in lipid profiles. Dyslipidemia is a risk factor for cardiovascular disease. The present study aimed to assess the prevalence of thyroid dysfunction and examine its effects on serum lipid profiles among Jordanians. A total of 228 subjects were recruited and divided into two groups: patients with thyroid dysfunction (n=178, mean age=52.6&#x00B1;9.8 years) and a control group (n=50, mean age=51.7&#x00B1;9.2 years). Serum thyroid-stimulating hormone, free thyroxine 4, free triiodothyronine 3, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein and triglycerides (TG) were measured. Results showed that thyroid dysfunction was diagnosed in 75&#x0025; of participants, with an increased frequency among females. The prevalence of overt hypothyroidism was 17.4&#x0025;, subclinical hypothyroidism was 43.8&#x0025;, overt hyperthyroidism was 18.4&#x0025; and subclinical hyperthyroidism was 20.4&#x0025;. There was a significant association between hypothyroidism and elevated TC (&#x003E;200 mg/dl), LDL (&#x003E;130 mg/dl) and TG (&#x003E;200 mg/dl; P&#x003C;0.05). Among the hypothyroid patients, 48.4&#x0025; had hypercholesterolemia and 32.3&#x0025; had hypertriglyceridemia. In conclusion, public screening and education are necessary to combat thyroid dysfunction. There is a notable link between thyroid dysfunction and lipid abnormalities, necessitating regular monitoring for dyslipidemia and cardiovascular disease in affected patients.</p>
</abstract>
<kwd-group>
<kwd>thyroid dysfunction</kwd>
<kwd>lipids abnormalities</kwd>
<kwd>total cholesterol</kwd>
<kwd>free thyroxine 4</kwd>
<kwd>free triiodothyronine 3</kwd>
</kwd-group>
<funding-group>
<funding-statement><bold>Funding:</bold> No funding was received.</funding-statement>
</funding-group>
</article-meta>
</front>
<body>
<sec sec-type="intro">
<title>Introduction</title>
<p>Disorders of the endocrine system, particularly those affecting the thyroid gland, are widespread globally affecting &#x003E;200 million people around the world (<xref rid="b1-BR-21-4-01826 b2-BR-21-4-01826 b3-BR-21-4-01826 b4-BR-21-4-01826" ref-type="bibr">1-4</xref>). Thyroid gland disorders, including both iodine deficiency-related and non-iodine deficiency-related disorders, are increasing (<xref rid="b5-BR-21-4-01826" ref-type="bibr">5</xref>). Among them, non-iodine deficiency-related thyroid disorders, such as thyroid cancer, have shown the highest increase in occurrence compared with other solid tumors (<xref rid="b6-BR-21-4-01826" ref-type="bibr">6</xref>). Indeed, except for Sweden, most countries recorded an increased rate of thyroid cancer over the period 1972-2002. It has been reported that thyroid cancer incidence around the world is 3.2 million individuals. There are &#x003E;560,000 new cases of thyroid cancer reported every year globally (<xref rid="b7-BR-21-4-01826" ref-type="bibr">7</xref>). Hypothyroidism, a severe iodine deficiency-related thyroid disorder, is also increasing worldwide (<xref rid="b8-BR-21-4-01826" ref-type="bibr">8</xref>) with 5&#x0025; of the world&#x0027;s population suffering from this condition (<xref rid="b7-BR-21-4-01826" ref-type="bibr">7</xref>). Hyperthyroidism is also a common thyroid dysfunction condition with a global prevalence of 0.2-13&#x0025; (<xref rid="b9-BR-21-4-01826" ref-type="bibr">9</xref>).</p>
<p>Thyroid hormones are chemical substances produced by the thyroid gland, which is located in the front of the neck and uses iodine to make thyroxine (T4) and triiodothyronine (T3) hormones (<xref rid="b10-BR-21-4-01826" ref-type="bibr">10</xref>). The thyroid gland is regulated by thyroid-stimulating hormone (TSH), produced by the anterior pituitary gland, which is in turn regulated by thyrotropin-releasing hormone (TRH) synthesized in the hypothalamus (<xref rid="b11-BR-21-4-01826" ref-type="bibr">11</xref>). Thyroid hormones play key roles in various metabolic activities, reproduction, growth and development (<xref rid="b12-BR-21-4-01826" ref-type="bibr">12</xref>,<xref rid="b13-BR-21-4-01826" ref-type="bibr">13</xref>). They are directly and indirectly involved in lipid biosynthesis and degradation (<xref rid="b4-BR-21-4-01826" ref-type="bibr">4</xref>). T4 is converted to the active form, T3, by 5&#x0027;-deiodinase type 2(<xref rid="b14-BR-21-4-01826" ref-type="bibr">14</xref>).</p>
<p>Thyroid dysfunction is a condition that alters the amount of thyroid hormones secreted. Over-secretion of thyroid hormones leads to hyperthyroidism, while reduced production results in hypothyroidism (<xref rid="b15-BR-21-4-01826" ref-type="bibr">15</xref>,<xref rid="b16-BR-21-4-01826" ref-type="bibr">16</xref>). Thyroid dysfunction has diverse effects on other health conditions in humans, such as dyslipidemia (<xref rid="b17-BR-21-4-01826" ref-type="bibr">17</xref>) and cardiovascular diseases (<xref rid="b10-BR-21-4-01826" ref-type="bibr">10</xref>,<xref rid="b18-BR-21-4-01826" ref-type="bibr">18</xref>).</p>
<p>Dyslipidemia is characterized by an imbalance of different circulating lipids, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) (<xref rid="b19-BR-21-4-01826" ref-type="bibr">19</xref>). This pathological condition is a major risk factor for cardiovascular diseases and may result from dietary and genetic factors, as well as lifestyle choices such as smoking and physical inactivity (<xref rid="b20-BR-21-4-01826" ref-type="bibr">20</xref>).</p>
<p>In the Jordanian population, an Arab nation, the prevalence of thyroid disorders is reportedly high compared with global statistics (<xref rid="b16-BR-21-4-01826" ref-type="bibr">16</xref>,<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>). It has been reported that the prevalence of thyroid disorders among Jordanians is 11.9&#x0025; (<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>). Nevertheless, the highest prevalence of thyroid disease among adult Americans was observed in non-Hispanic Caucasians at 8.1&#x0025; (<xref rid="b22-BR-21-4-01826" ref-type="bibr">22</xref>). A meta-analysis study of thyroid dysfunction in Europe showed that the mean prevalence of diagnosed and undiagnosed thyroid dysfunction is 3.82&#x0025; for hypothyroidism and 0.75&#x0025; for hyperthyroidism (<xref rid="b23-BR-21-4-01826" ref-type="bibr">23</xref>). A study from Jordan reported no relationship between the high percentage of hyperlipidemia and levels of serum TSH and free thyroxine 4 (T4) hormone (<xref rid="b24-BR-21-4-01826" ref-type="bibr">24</xref>). However, studies from Jordan focusing on the association between thyroid dysfunction and lipid profile biomarkers are sparse or entirely missing. Hence, there is a need to intensify research on the association and/or causative relationship between thyroid dysfunction and lipids abnormalities among Jordanians.</p>
</sec>
<sec sec-type="Materials|methods">
<title>Materials and methods</title>
<sec>
<title/>
<sec>
<title>Subjects</title>
<p>All subjects in the present study enrolled voluntarily. The present study recruited 178 patients with thyroid dysfunction (27 males and 151 females; mean age=52.6&#x00B1;9.8 years). All patients were attending the endocrinology clinic at Tohamma Medical Center in Amman, Jordan, during the period between 15 September 2020 and 19 January 2021. A control group of 50 healthy individuals was also enrolled (25 males and 25 females; mean age=51.7&#x00B1;9.2 years).</p>
<p>Information such as age, sex and family history of chronic disease was collected and recorded for all patients. Patient privacy and confidentiality were ensured and the information was used solely for this research, with proper disposal procedures to be followed afterwards.</p>
<p>The present study received approval with a reference number MLS_R_01/06/2020 from the Ethics and Scientific Research Board at Jadara University (Irbid, Jordan). Written informed consent was obtained from all participants involved in the present study after providing a comprehensive explanation of the present study&#x0027;s purpose, procedures and significance. The present study was conducted in accordance with the principles outlined in the Declaration of Helsinki.</p>
</sec>
<sec>
<title>Exclusion and inclusion criteria</title>
<p>Patients with thyroid dysfunction, clinically diagnosed by alteration in serum levels of thyroid hormones (subclinical and overt) of both sexes and aged &#x2265;18 years were included in the present study. Subclinical thyroid dysfunction is defined by an abnormal level of serum TSH (the normal level is 0.4-4.2 &#x00B5;IU/ml) and normal levels of serum free triiodothyronine 3 (fT3; 0.4-4.0 &#x00B5;g/ml) and free thyroxine 4 (fT4; 0.5-1.9 ng/ml). Overt thyroid dysfunction is defined by alterations in serum levels of TSH as well as serum levels of fT3 and fT4 simultaneously. None of the participants in the present study was known to have or clinically diagnosed with thyroid cancer. All patients diagnosed with chronic kidney disease, liver diseases, diabetes mellitus, pregnancy, women on oral contraceptives, patients with history of thyroxine and hypolipidemic treatment in the last 90 days or being &#x003C;18 years old were excluded from the present study.</p>
<p>Male and female healthy participants with normal serum thyroid hormone levels, no history of disease or medication that affect thyroid gland function and serum levels of lipid and aged &#x003E;18 years were included in the present study.</p>
</sec>
<sec>
<title>Blood sampling and sample analysis</title>
<p>Venous blood samples (5-10 ml) were drawn from participants between 8:00 and 10:00 a.m. into labeled blood tubes after a minimum of 14 h of fasting. The blood samples were left to clot for 15 min at room temperature, then centrifuged at 5,000 x g at room temperature for 10 min, after which serum samples were collected and analyzed for lipid profile and thyroid function parameters.</p>
<p>Serum samples analysis was performed at Tohamma Medical Center in Zarqa&#x0027;a, Jordan. All tests were performed in Teryaq Alrouh medical laboratory. Serum TG, TC and HDL cholesterol concentrations were measured using the Bio Maxima BM 200 chemistry auto-analyzer (BioMaxima S.A.). Levels of serum LDL-cholesterol were calculated using the Friedewald formula: LDL cholesterol=(total serum cholesterol)-(HDL cholesterol)-(triglyceride concentration/5) (<xref rid="b25-BR-21-4-01826" ref-type="bibr">25</xref>).</p>
<p>Levels of serum TSH, fT4 and fT3 were measured using the Cobas e 411 auto-analyzer (Roche Diagnostics GmbH), with corresponding Roche Diagnostics kits (Roche Diagnostics GmbH) used for the analysis of all parameters.</p>
</sec>
<sec>
<title>Reference range</title>
<p>Normal values for lipid profile parameters are as follows: TC (150-200 mg/dl), TG (50-200 mg/dl), HDL-Cholesterol (10-60 mg/dl), LDL-Cholesterol (60-160 mg/dl) and the TC/HDL-Cholesterol ratio is 4 (Roche Diagnostics GmbH).</p>
<p>The normal reference range for thyroid parameters accor-ding to the kits used were as follows: TSH (0.4-4.2 &#x00B5;IU/ml), fT4 (0.5-1.9 ng/ml) and fT3 (0.4-4.0 &#x00B5;g/ml). Hypothyroidism was clinically defined by TSH &#x2265;4.5 &#x00B5;IU/ml and hyperthyroidism was classified clinically by TSH &#x2265;0.1 &#x00B5;IU/ml (Roche Diagnostics GmbH).</p>
</sec>
<sec>
<title>Statistical analysis</title>
<p>All statistical analyses of data were performed using the Statistical Package for the Social Sciences (SPSS) version 20.0 for windows (IBM Corp.) and Microsoft Excel 2010 (Microsoft Corporation). Results are reported as mean &#x00B1; standard deviation (SD). Differences in mean &#x00B1; SD values were analyzed for statistical significance using one-way ANOVA test followed by Tukey&#x0027;s post hoc test. P&#x003C;0.05 was considered to indicate a statistically significant difference.</p>
</sec>
</sec>
</sec>
<sec sec-type="Results">
<title>Results</title>
<sec>
<title/>
<sec>
<title>Prevalence of thyroid dysfunction</title>
<p>In the present study, 178 patients (49 males and 129 females) with thyroid disorders were recruited, along with a sex- and age-matched healthy control group of 50 subjects (25 males and 25 females). The mean age of the patient group was 52.6&#x00B1;9.8 years and it was 51.7&#x00B1;9.2 years for the control group. Among patients with overt thyroid disorders, the mean age was 51.4&#x00B1;8.2 years, while for those with subclinical thyroid disorders, it was 53.9&#x00B1;6.4 years.</p>
<p>The overt hypothyroid group was 17.4&#x0025; of total patients, overt hyperthyroidism was at 17.5&#x0025; and subclinical hypothyroidism was the most prevalent thyroid disorder at 43.8&#x0025;, with subclinical hyperthyroidism accounting for 21.3&#x0025; of total patients. Overt thyroid patients comprised 34.9&#x0025; of the total, while subclinical thyroid patients comprised 65.1&#x0025;. Additionally, the present study found that thyroid dysfunction was more common among females (72.5&#x0025;) compared with males (27.5&#x0025;) across all forms of thyroid dysfunction (<xref rid="tI-BR-21-4-01826" ref-type="table">Table I</xref>).</p>
</sec>
<sec>
<title>Thyroid function analytes</title>
<p>Results of thyroid function tests (<xref rid="tII-BR-21-4-01826" ref-type="table">Table II</xref>) revealed that mean serum TSH levels were significantly higher in the subclinical thyroid group compared with the control group (6.88&#x00B1;0.7 vs. 2.34&#x00B1;0.4 &#x00B5;IU/ml; P&#x003C;0.05), with even higher levels in the overt thyroid group (35.67&#x00B1;1.3 vs. 2.34&#x00B1;0.4 &#x00B5;IU/ml; P&#x003C;0.05). Serum levels of fT4 and fT3 were significantly lower in subclinical thyroid patients compared with the corresponding control group (0.86&#x00B1;0.06 pg/ml vs. 0.97&#x00B1;0.05 pg/ml; P&#x003C;0.05) and (3.12&#x00B1;0.07 ng/ml vs. 3.54&#x00B1;0.09 ng/ml; P&#x003C;0.05) respectively. In overt thyroid patients, serum levels of fT4 and fT3 were significantly lower compared with the control group (0.46&#x00B1;0.03 pg/ml vs. 0.97&#x00B1;0.05 pg/ml; P&#x003C;0.05) and (2.63&#x00B1;0.07 ng/ml vs. 3.54&#x00B1;0.09 ng/ml; P&#x003C;0.05) respectively.</p>
</sec>
<sec>
<title>Lipids analytes</title>
<p>Results of lipid assays (<xref rid="tIII-BR-21-4-01826" ref-type="table">Table III</xref>) indicated significantly higher mean serum levels of TC, TG and LDL-cholesterol in the patient group. Mean serum TC levels were significantly elevated in the subclinical thyroid group compared with the control group (226.86&#x00B1;48.6.7 vs. 172.74&#x00B1;58.6 mg/dl; P&#x003C;0.05), with greater levels observed in the overt thyroid group (248.78&#x00B1;48.7 vs. 172.74&#x00B1;58.6 mg/dl; P&#x003C;0.05). Similar findings were noted for serum TG levels in both subclinical and overt thyroid groups compared with the healthy control group (165.37&#x00B1;44. 2 vs. 127.74&#x00B1;48.7 mg/dl; P&#x003C;0.05) and (184.87&#x00B1;61.01 vs. 127.74&#x00B1;48.7 mg/dl; P&#x003C;0.05) respectively. Serum LDL levels were also significantly higher in both groups (144.14&#x00B1;60.75 vs. 98.76&#x00B1;39.8 mg/dl; P&#x003C;0.05) and (148.17&#x00B1;49.23 vs. 98.76&#x00B1;39.8 mg/dl; P&#x003C;0.05). Additionally, mean serum HDL-cholesterol levels were significantly lower in the patient group compared with the control group (39.86&#x00B1;9.45 vs. 57.66&#x00B1;28.6 mg/dl; P&#x003C;0.05) and (37.35&#x00B1;7.94 vs. 57.66&#x00B1;28.6 mg/dl; P&#x003C;0.05). There was no significant difference in LDL/HDL ratio between patients and the control group.</p>
</sec>
</sec>
</sec>
<sec sec-type="Discussion">
<title>Discussion</title>
<p>The main finding of the present study was the significant increase in serum TC, TG and LDL-C levels in subjects with thyroid dysfunction, along with a significant decrease in serum HDL. This significant association between thyroid dysfunction and serum dyslipidemia is reported for the first time in a community-based study in Jordan, to the best of the authors&#x0027; knowledge. By contrast, the only previous study that investigated the association between the prevalence of dyslipidemia and levels of TSH and T4 hormones among Jordanian patients reported no correlation between these parameters (<xref rid="b24-BR-21-4-01826" ref-type="bibr">24</xref>). These discrepancies between the two studies may be due to the variations in the geographical districts of the south and middle of Jordan. The genetic factors and environmental conditions of two districts could contribute to the discrepancies as the southern district of the study (<xref rid="b24-BR-21-4-01826" ref-type="bibr">24</xref>) is classified as a desert area with mainly indigenous Bedouin inhabitants. By contrast, the middle district of the present study is more westernized in life style.</p>
<p>Thyroid hormones promote the activities of two enzymes related to lipid metabolism: lipoprotein lipase (LPL) and hepatic lipase (HL). LPL catabolizes TG-rich lipoproteins, while HL hydrolyzes HDL2 to HDL3 and contributes to the conversion of intermediate-density lipoproteins to LDL and subsequently, LDL to small dense LDL (<xref rid="b26-BR-21-4-01826" ref-type="bibr">26</xref>,<xref rid="b27-BR-21-4-01826" ref-type="bibr">27</xref>).</p>
<p>Subclinical hypothyroidism is a pathological condition characterized by normal levels of serum fT3 and fT4, together with an increased level of serum TSH (<xref rid="b28-BR-21-4-01826" ref-type="bibr">28</xref>). When serum fT3 and fT4 levels decrease and serum TSH levels increase, the pathological condition becomes overt hypothyroidism (<xref rid="b29-BR-21-4-01826" ref-type="bibr">29</xref>). Consistent with other studies, the current study also demonstrated a higher prevalence of hypothyroidism compared with hyperthyroidism in the present studied population, with subclinical hypothyroidism being more common than overt hypothyroidism. Hypothyroidism is closely linked to lipid metabolism disorders and dyslipidemia, increasing the risk of cardiovascular diseases (<xref rid="b30-BR-21-4-01826" ref-type="bibr">30</xref>).</p>
<p>There is controversy surrounding lipid levels in subclinical hypothyroidism and its clinical significance (<xref rid="b31-BR-21-4-01826 b32-BR-21-4-01826 b33-BR-21-4-01826" ref-type="bibr">31-33</xref>). Manifestations of overt hypothyroidism include serum hypercholesterolemia and an increase in serum LDL due to reduced fractional clearance of LDL. This reduction is due to a decrease in the number of LDL receptor proteins in the liver (<xref rid="b34-BR-21-4-01826" ref-type="bibr">34</xref>).</p>
<p>The results of the present study indicated a high prevalence of thyroid dysfunction in the Jordanian population, consistent with another Jordanian study by Ajlouni <italic>et al</italic> (<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>). In the present study, the frequency of hypothyroidism was higher (64&#x0025;) compared with hyperthyroidism (36&#x0025;). This agrees with what Ajlouni <italic>et al</italic> (<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>) found; that there is a preponderance of hypothyroidism over hyperthyroidism as well as female thyroid dysfunction preponderance over male thyroid dysfunction in the Jordanian population. Ajlouni <italic>et al</italic> (<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>) also reported that 2.9&#x0025; of the Jordanian population studied were known to have thyroid dysfunction. Markedly, the prevalence of newly discovered primary thyroid dysfunction was 9.0&#x0025; among Jordanian participants in his study.</p>
<p>The findings of the present study showed an association between thyroid dysfunction and hyperlipidemia among Jordanians. In patients with subclinical and overt thyroid dysfunction, serum TC, TG and LDL-cholesterol concentrations were significantly higher compared with the control group. These results agree with findings from previous studies that reported an association and causative correlation between hypothyroidism and disturbance of lipid profile in the patients. For example, O&#x0027;Brien <italic>et al</italic> (<xref rid="b35-BR-21-4-01826" ref-type="bibr">35</xref>) reported an association between hyperlipidemia and both primary and secondary hypothyroidism. Additionally, Ahmed <italic>et al</italic> (<xref rid="b36-BR-21-4-01826" ref-type="bibr">36</xref>) demonstrated that primary hypothyroidism is significantly correlated with high BMI and serum cholesterol, TG and LDL levels. Moreover, subclinical hypothyroidism was associated with increased serum LDL-C concentration (<xref rid="b37-BR-21-4-01826" ref-type="bibr">37</xref>).</p>
<p>The association between overt hypothyroidism and hypercholesterolemia has been firmly established; however, the link between subclinical hypothyroidism and hypercholesterolemia remains controversial (<xref rid="b38-BR-21-4-01826" ref-type="bibr">38</xref>). This controversy may primarily stem from a lack of evidence supporting the association between these two variables. On one hand, subclinical hypothyroidism has not been shown to be associated with abnormalities in serum cholesterol or triglyceride levels (<xref rid="b32-BR-21-4-01826" ref-type="bibr">32</xref>). On the other hand, subclinical hypothyroidism can potentially contribute to a pro-atherogenic lipid profile (<xref rid="b39-BR-21-4-01826" ref-type="bibr">39</xref>). Furthermore, consistent with another study (<xref rid="b40-BR-21-4-01826" ref-type="bibr">40</xref>), the results of the present study showed that serum HDL-cholesterol levels were significantly lower in patients with thyroid dysfunction compared with the control group. The effect of thyroid hormones on serum lipids, a risk factor for cardiovascular disease, is not fully understood and understanding the integration of various thyroid hormone pathways remains a great challenge. Thus, comprehending the mechanisms and interactions of the various thyroid hormones signaling pathways in metabolism will enhance our understanding of the link between dyslipidemia and cardiovascular disease.</p>
<p>Lipid homeostasis in the liver is regulated by the direct actions of thyroid hormones. T3 regulates cholesterol synthesis through several mechanisms. A plausible mechanism for hypercholesterolemia in thyroid dysfunction patients is the increased enzymatic activity of 3-hydrox-3-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis signaling pathway, as well as the decreased hepatic uptake of cholesterol from the circulation, both mechanisms being upregulated by T3(<xref rid="b41-BR-21-4-01826" ref-type="bibr">41</xref>). Additionally, thyroid hormones can increase cholesterol absorption in the intestine by activating the Niemann-Pick C1-like 1 protein in enterocytes (<xref rid="b42-BR-21-4-01826" ref-type="bibr">42</xref>).</p>
<p>The physiological function of thyroid hormones requires interaction with their receptors (TRs) &#x03B1; and &#x00DF; in the signaling pathway (<xref rid="b43-BR-21-4-01826" ref-type="bibr">43</xref>). TR regulates cholesterol metabolism through direct actions on gene expression and cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor, liver X receptor and bile acid signaling pathways (<xref rid="b14-BR-21-4-01826" ref-type="bibr">14</xref>).</p>
<p>Serum TG were significantly increased in the thyroid dysfunction patients in the present study. This might be due to decreased activity of lipoprotein lipase, which is responsible for the clearance of triglyceride-rich lipoproteins.</p>
<p>The elevated levels of serum LDL in thyroid dysfunction conditions observed in the present study might be due to the role of thyroid hormones in the expression of LDL receptors and cytochrome P450 7A1, a rate-limiting enzyme in bile acid synthesis. The T3 hormone, in particular, is involved in regulating the gene expression of LDL receptors (<xref rid="b44-BR-21-4-01826" ref-type="bibr">44</xref>,<xref rid="b45-BR-21-4-01826" ref-type="bibr">45</xref>). LDL receptor-related proteins, such as LDL receptor-related protein 1, are cell surface glycoprotein signaling receptors that bind and internalize diverse ligands including lipoprotein particles (<xref rid="b46-BR-21-4-01826" ref-type="bibr">46</xref>). They are expressed in all cell types and, in particular, in hepatocytes. The underlying mechanisms of T3-mediated hypercholesterolemia in the hypothyroidism dysfunction is that the reduced serum level of T3 inhibit the transcription of the LDL-receptor gene, resulting in decreased cholesterol uptake by hepatocytes and reduction in clearance of circulating lipoproteins, leading to hypercholesterolemia in thyroid dysfunction patients (<xref rid="b46-BR-21-4-01826" ref-type="bibr">46</xref>). In particular, T3 may affect the expression of sterol regulatory element binding protein 2 transcription factor involved in the transcription of the LDL-receptor gene (<xref rid="b47-BR-21-4-01826" ref-type="bibr">47</xref>). Additionally, T3 has a protective role in preventing LDL oxidation (<xref rid="b48-BR-21-4-01826" ref-type="bibr">48</xref>). However, thyroid dysfunction not only increases the number of LDL molecules but also promotes LDL oxidation, thereby increasing the risk of atherosclerosis (<xref rid="b49-BR-21-4-01826" ref-type="bibr">49</xref>).</p>
<p>Thyroid hormones are involved in HDL metabolism by enhancing the activity of cholesteryl ester transfer protein, a molecule responsible for converting cholesteryl esters from HDL to very low-density lipoproteins (<xref rid="b10-BR-21-4-01826" ref-type="bibr">10</xref>). This might explain the decrease in serum HDL observed in the current study.</p>
<p>Hyperthyroidism, characterized by excess thyroid hormone, promotes a hypermetabolic state, which reduces cholesterol levels and increases lipolysis. Subclinical hyperthyroidism is marked by normal serum fT3 and fT4 levels and reduced serum TSH (<xref rid="b21-BR-21-4-01826" ref-type="bibr">21</xref>). Overt hyperthyroidism involves elevated serum fT3 and fT4 levels and reduced serum TSH. The effect of hyperthyroidism did not show a significant impact on dyslipidemia in the present study.</p>
<p>The present study also showed a predominance of thyroid dysfunction in females compared with males. Females in the Jordanian population appear to be more susceptible to thyroid dysfunction, particularly subclinical hypothyroidism. This finding is consistent with reports from different populations around the world (<xref rid="b50-BR-21-4-01826" ref-type="bibr">50</xref>,<xref rid="b51-BR-21-4-01826" ref-type="bibr">51</xref>). Women may be more prone to thyroid dysfunction due to the hormonal changes they experience throughout their life cycle, including puberty, the menstrual cycle, pregnancy, childbirth, lactation and menopause (<xref rid="b52-BR-21-4-01826" ref-type="bibr">52</xref>). The immunological changes during antepartum, pregnancy and the postpartum periods that affect thyroid hormone levels can also increase the frequency of thyroid dysfunction in females (<xref rid="b53-BR-21-4-01826" ref-type="bibr">53</xref>,<xref rid="b54-BR-21-4-01826" ref-type="bibr">54</xref>). While the effect of thyroid hormones on female reproduction has been investigated, the effect of female sex hormones on thyroid function and the differences in the frequency of thyroid dysfunction between sexes require further investigation.</p>
<p>The present study has several strengths and limitations. On the one hand, it has the strength that it may be the first to study the association of thyroid dysfunction and dyslipidemia in the Jordanian population. On the other hand, some limitations of the present study included the disproportionate number of female participants compared with male participants, which could bias the results and conclusions. The higher percentage of female patients in the present study is due to the greater susceptibility of females to thyroid diseases compared with males. Hence, there were difficulties in recruiting male patients due to the limited cases in the designated geographical area. Additionally, the age of the subjects was not adjusted in the present study. Further, the present study was conducted in a small population in the middle district of Jordan. It would be a more comprehensive if it involved a larger population sample from the three main districts of Jordan: north, middle and south.</p>
<p>In conclusion, the present study showed that the prevalence of thyroid dysfunction is high among Jordanians. It also demonstrated that the lipid profile is abnormal in thyroid dysfunction conditions. Dyslipidemia is a major risk factor for cardiovascular disease. Therefore, the present study recommended screening high-risk groups for thyroids dysfunction, such as females. Furthermore, educating the public about thyroid dysfunction can help detect thyroid conditions at an early stage for proper intervention. Finally, the present study emphasized the importance of monitoring lipid levels in patients with thyroid dysfunction to prevent or, at the very least, minimize cardiovascular diseases. Supplementing with a full diet of iodine, such as seafood and dairy products helps the thyroid gland to have enough materials to produce hormones and prevent thyroid disease. Thyroid medication including levothyroxine could also enhance the efficacy of hypolipidemic drugs, such as statins, if was prescribed to the patients.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgements</title>
<p>The authors extend their gratitude to Dr Mohammad Abu Zaid from Tohamma Medical Center in Amman, Jordan, for invaluable assistance in facilitating the technical work and providing necessary information for this research.</p>
</ack>
<sec sec-type="data-availability">
<title>Availability of data and materials</title>
<p>The data generated in the present study may be requested from the corresponding author.</p>
</sec>
<sec>
<title>Authors&#x0027; contributions</title>
<p>SA and MA were involved in designing the present study. SA was involved in collecting and analyzing the data and writing the manuscript. SA and IA confirm the authenticity of all the raw data. IA was involved in analyzing the data and writing the manuscript. The initial draft of the manuscript was prepared by SA. SA and IA contributed to revising and finalizing the manuscript. MA provided feedback on the final draft of the manuscript. All authors reviewed and approved the final manuscript.</p>
</sec>
<sec>
<title>Ethics approval and consent to participate</title>
<p>The present study received approval with a reference number MLS_R_01/06/2020 from the Ethics and Scientific Research Board at Jadara University (Irbid, Jordan). Written informed consent was obtained from all participants involved in the present study after providing a comprehensive explanation of the present study&#x0027;s purpose, procedures and significance. The present study was conducted in accordance with the principles outlined in the Declaration of Helsinki.</p>
</sec>
<sec>
<title>Patient consent for publication</title>
<p>Not applicable.</p>
</sec>
<sec sec-type="COI-statement">
<title>Competing interests</title>
<p>The authors declare that they have no competing interests.</p>
</sec>
<sec>
<title>Authors&#x0027; information</title>
<p>Dr Ibrahim Al-Odat: ORCHID: 0000-0001-5829-6391.</p>
</sec>
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<floats-group>
<table-wrap id="tI-BR-21-4-01826" position="float">
<label>Table I</label>
<caption><p>Age, frequencies and percentages of participants in both sex in controls and each condition of thyroid dysfunction.</p></caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="middle">Parameter</th>
<th align="center" valign="middle">Controls (&#x0025;)</th>
<th align="center" valign="middle">Overt hypothyroid frequency (&#x0025;)</th>
<th align="center" valign="middle">Subclinical hypothyroid frequency (&#x0025;)</th>
<th align="center" valign="middle">Overt hyperthyroid frequency (&#x0025;)</th>
<th align="center" valign="middle">Subclinical hyperthyroid frequency (&#x0025;)</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle">Age, years</td>
<td align="center" valign="middle">51.7</td>
<td align="center" valign="middle">51.1</td>
<td align="center" valign="middle">53.8</td>
<td align="center" valign="middle">51.7</td>
<td align="center" valign="middle">53.9</td>
</tr>
<tr>
<td align="left" valign="middle">Male</td>
<td align="center" valign="middle">25(50)</td>
<td align="center" valign="middle">12 (6.7)</td>
<td align="center" valign="middle">21 (11.8)</td>
<td align="center" valign="middle">9 (5.1)</td>
<td align="center" valign="middle">7 (3.9)</td>
</tr>
<tr>
<td align="left" valign="middle">Female</td>
<td align="center" valign="middle">25(50)</td>
<td align="center" valign="middle">19 (10.7)</td>
<td align="center" valign="middle">57(32)</td>
<td align="center" valign="middle">22 (12. 4)</td>
<td align="center" valign="middle">31 (17.4)</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tII-BR-21-4-01826" position="float">
<label>Table II</label>
<caption><p>TSH, fT4 and fT3 serum levels among subjects.</p></caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="middle">Serum levels</th>
<th align="center" valign="middle">Control (n=50)</th>
<th align="center" valign="middle">Subclinical thyroid dysfunction (n=116)</th>
<th align="center" valign="middle">Overt thyroid dysfunction (n=62)</th>
<th align="center" valign="middle">P-value<sup><xref rid="tfna-BR-21-4-01826" ref-type="table-fn">a</xref></sup></th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle">TSH &#x00B5;IU/ml</td>
<td align="center" valign="middle">2.34&#x00B1;0.4</td>
<td align="center" valign="middle">6.88&#x00B1;0.7</td>
<td align="center" valign="middle">35.67&#x00B1;1.3</td>
<td align="center" valign="middle">0.042</td>
</tr>
<tr>
<td align="left" valign="middle">fT4 pg/ml</td>
<td align="center" valign="middle">0.97&#x00B1;0.05</td>
<td align="center" valign="middle">0.86&#x00B1;0.06</td>
<td align="center" valign="middle">0.46&#x00B1;0.03</td>
<td align="center" valign="middle">0.031</td>
</tr>
<tr>
<td align="left" valign="middle">fT3 ng/ml</td>
<td align="center" valign="middle">3.54&#x00B1;0.09</td>
<td align="center" valign="middle">3.12&#x00B1;0.07</td>
<td align="center" valign="middle">2.63&#x00B1;0.07</td>
<td align="center" valign="middle">0.039</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tfna-BR-21-4-01826"><p><sup>a</sup>vs. the Control group. Data were analyzed using one-way ANOVA test followed by Tukey&#x0027;s post hoc test. Results are expressed as mean &#x00B1; SD. P&#x003C;0.05 was considered to be statistically significant. TSH, thyroid-stimulating hormone; fT4, free thyroxine 4; fT3, serum free triiodothyronine 3.</p></fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tIII-BR-21-4-01826" position="float">
<label>Table III</label>
<caption><p>Comparison of mean lipid profiles between controls and thyroid dysfunction patients.</p></caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="middle">Lipid</th>
<th align="center" valign="middle">Control (n=50)</th>
<th align="center" valign="middle">Subclinical thyroid dysfunction (n=116)</th>
<th align="center" valign="middle">P-value<sup><xref rid="tfn1-a-BR-21-4-01826" ref-type="table-fn">a</xref></sup></th>
<th align="center" valign="middle">Overt thyroid dysfunction (n=62)</th>
<th align="center" valign="middle">P-value<sup><xref rid="tfn1-a-BR-21-4-01826" ref-type="table-fn">a</xref></sup></th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle">TC (mg/dl)</td>
<td align="center" valign="middle">172.74&#x00B1;58.60</td>
<td align="center" valign="middle">226.86&#x00B1;48.60</td>
<td align="center" valign="middle">P=0.039</td>
<td align="center" valign="middle">248.78&#x00B1;48.70</td>
<td align="center" valign="middle">P=0.047</td>
</tr>
<tr>
<td align="left" valign="middle">TG (mg/dl)</td>
<td align="center" valign="middle">127.74&#x00B1;48.70</td>
<td align="center" valign="middle">165.37&#x00B1;44.20</td>
<td align="center" valign="middle">P=0.040</td>
<td align="center" valign="middle">184.87&#x00B1;61.01</td>
<td align="center" valign="middle">P=0.033</td>
</tr>
<tr>
<td align="left" valign="middle">LDL (mg/dl)</td>
<td align="center" valign="middle">98.76&#x00B1;39.80</td>
<td align="center" valign="middle">144.14&#x00B1;60.75</td>
<td align="center" valign="middle">P=0.028</td>
<td align="center" valign="middle">148.17&#x00B1;49.23</td>
<td align="center" valign="middle">P=0.022</td>
</tr>
<tr>
<td align="left" valign="middle">HDL (mg/dl)</td>
<td align="center" valign="middle">57.66&#x00B1;28.60</td>
<td align="center" valign="middle">39.86&#x00B1;9.45</td>
<td align="center" valign="middle">P=0.011</td>
<td align="center" valign="middle">37.35&#x00B1;7.94</td>
<td align="center" valign="middle">P=0.030</td>
</tr>
<tr>
<td align="left" valign="middle">LDL/HDL</td>
<td align="center" valign="middle">2.95&#x00B1;0.16</td>
<td align="center" valign="middle">3.71&#x00B1;0.78</td>
<td align="center" valign="middle">P=0.540</td>
<td align="center" valign="middle">3.91&#x00B1;0.78</td>
<td align="center" valign="middle">P=0.220</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tfn1-a-BR-21-4-01826"><p><sup>a</sup>vs. the Control group. Data were analyzed using one-way ANOVA test followed by Tukey&#x0027;s post hoc test. Results are expressed as mean &#x00B1; SD. P&#x003C;0.05 was considered to be statistically significant.</p></fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</article>
