Abstract
Background:
Thyroid hormones play an important role in cardiac tissue function. Therefore, it is important to understand the relationship between thyroid hormone levels and cardiac disorders.Objectives:
The present study aimed to assess the relationship between normal serum level of thyroid hormones and left ventricular systolic and diastolic dysfunction.Methods:
In this cross sectional descriptive retrospective study, 391 patients were selected. They were referred to the Rajaie Cardiovascular Research Center, Tehran, Iran from 2019 to 2021. After extracting echocardiographic and laboratory data from the clinical records, the parameters affecting the left ventricular systolic and diastolic dysfunction were analyzed using statistical software.Results:
The mean age of patients was 41 ± 12.8 years. Among them 58.1% of all patients were female. Tricuspid regurgitation (TR) severity had a significant relationship with thyroid stimulating hormone (TSH) level (P = 0.02). End diastolic interventricular septum thickness (IVSD) was inversely associated with thyroxin4 (T4) level (P = 0.04). Mitral valve inflow deceleration time (MVDT) was inversely correlated with thyroxin3 (T3) (P = 0.04). Left ventricular ejection fraction (LVEF) was inversely related to TSH level and end diastolic right ventricular internal diameter (RVIDd) was directly related to TSH (P = 0.05).Conclusions:
Thyroid hormone levels in the normal range can be associated with the tricuspid regurgitation severity, end diastolic right ventricular internal diameter (RVIDd), mitral valve inflow deceleration time (MVDT), and. end diastolic interventricular septum thickness (IVSD). Due to the high prevalence of heart disorders, information on thyroid hormone levels can be helpful in the identification and timely treatment of these disorders.Keywords
Left Ventricular Dysfunction Thyroid Function Tests Diastolic Heart Failure Systolic Heart Failure
1. Background
From 2015 to 2018, about 121 million people worldwide have been diagnosed with diseases related to cardiac dysfunction (1). In Iran, the prevalence of heart diseases is estimated at about 10%, which is also increasing (2).
Recently, the relationship between thyroid hormone levels and cardiac complications has been considered (3, 4). The prevalence of thyroid diseases in the adult female population is between 9 and 15 percent, although this rate is lower in men (5, 6).
Thyroid dysfunction increases the risk of cardiovascular disease (3, 5). Thyroid hormone receptors are abundant in the myocardium; thus, the heart is very sensitive to changes in thyroid hormone (7). Disorders of thyroid hormones are associated with myocardial infarction, decreased cardiac output, altered heart rate, increased systemic vascular resistance, cardiomyocyte atrophy, endothelial dysfunction, and increased prevalence of atherosclerosis and heart failure (8). It has been observed that subclinical hypothyroidism is associated with left ventricular systolic and diastolic dysfunction (9, 10). Changes in thyroid hormone levels increase the hemodynamic load of the heart, which increases the heart rate and ultimately the size of the heart (11).
Thyroid hormones affect the action potential time and repolarization currents of cardiac myocytes (12). The findings show that the three hormones of TSH, T4, and T3 affect the heart and peripheral arteries, which leads to a decrease in systemic vascular resistance (SVR), and an increase in resting heart rate, left ventricular muscle contraction, and blood volume. In fact, thyroid hormones reduce resistance in peripheral arteries by directly affecting vascular smooth muscle (VSM) cell and reducing mean arterial pressure, thereby increasing the cardiac output pressure through reducing arterial resistance (13, 14). Endothelial-dependent vasodilation disorder has been reported as a result of nitric oxide reduction in subclinical hypothyroidism (15). The role of these hormones in heart failure has been identified, but limited studies have examined the systolic and diastolic ventricular disorders in detail (6, 9, 10, 12).
Given the roles of thyroid hormones in heart function and metabolism, assessing the levels of these hormones in patients with cardiac risk factors can be important.
2. Objectives
The present study aimed to assess the relationship between normal serum level of thyroid hormones and left ventricular systolic and diastolic dysfunction.
3. Methods
3.1. Study Design
In this retrospective cross sectional descriptive study, 391 patients, were selected. They were referred to the Ragaie cardiovascular research center, Tehran, Iran from 2019 to 2021. After extracting echocardiographic and laboratory data from the clinical records, the parameters affecting the left ventricular systolic and diastolic dysfunction were analyzed using statistical software. Dividing patients into normal, mild, moderate and severe in the measured parameters was based on ASE 2016 guideline for cardiac chamber quantification by echocardiography.
3.2. Inclusion and Exclusion Criteria
Inclusion criteria included complete patient satisfaction, no symptoms of hyperthyroidism or hypothyroidism, and no history of treatment with thyroid drugs. Exclusion criteria included, distortion of clinical records, patients with specific diseases such as cancer, liver disorder, renal impairment, chronic infection, hematuria, heart failure, febrile illness, severe hyperglycemia, severe hypertension, and history of consumption of drugs that affect the thyroid test such as glucocorticoids, oral contraceptives, and nonsteroidal anti-inflammatory drugs.
3.3. Data Collection
Demographic and general information, including age and gender, were extracted from the clinical records of studied cases. Information about cardiac dysfunction was extracted from the clinical records of patients with the help of echocardiographic findings. Laboratory information such as TSH, T4, and T3 levels was also extracted from the patients' files. In case of defects in the file, the defects were eliminated through telephone calls. It should be noted that in this study, for all patients, the information about TSH was firstly recorded, and only in case of disorder of this hormone, information about other hormones and antibodies was recorded. Subclinical hypothyroidism was specified as normal levels of T4 and elevated levels of TSH, and clinical hypothyroidism was considered as reduced levels of T4 and increased levels of TSH. Also, hyperthyroidism was specified as increased T4 and reduced TSH levels, and subclinical hyperthyroidism was considered as normal T4 and reduced TSH levels. Normal serum TSH levels were considered to be between 0.4 and 4.2 mlU/L (16). Also, the normal level of total T4 was considered to be 4.4 to 11 mcg/dL in men and 4.8 to 12 mcg/dL in women (2). The normal range of total T3 was considered as 106 to 129 ng/dL in men and 104.5 to 140 ng/dL in women. In order to measure the laboratory variables, 8 cc blood samples had been taken from the subjects and were kept at -80°C. TSH, T4, and T3 levels were measured using the chemiluminescence method.
3.4. Statistical Analysis
After collecting the data by the checklist, SPSS software version 25 (IBM Corp. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) was used to analyze the data and compare the studied groups. Data are expressed as absolute frequency and percentages for qualitative variables. Quantitative variables are described as mean ± standard deviation (SD), depending on the variable distribution. Group comparisons were analyzed using the student t-test for continuous variables, and chi-square test or Fisher exact test for categorical variables. Because many comparisons were performed, P < 0.05 was considered as a cutoff value for statistical significance.
4. Results
The patients’ mean age was 41 ± 12.8 years. 227 (58.1%) patients were female. Table 1 shows the demographic and clinical findings in the studied patients.
Demographic and Clinical Findings of the Studied Patients a
| Parameters | Values |
|---|---|
| Sex | |
| Male | 163 (41.7) |
| Female | 227 (58.1) |
| Age (years old) | 41 ± 12.8 |
| T3 (ng/dL) | 1.03 ± 0.33 |
| T4 (pmol/L) | 8.41 ± 3.6 |
| TSH (mIU/L) | 3.3 ± 2.4 |
| LVDd (cm) | 4.9 ± 2.9 |
| IVSD (cm) | 1.2 ± 5.1 |
| LVDs (cm) | 3.5 ± 2.3 |
| PWD (cm) | 0.8 ± 0.6 |
| LVEF (%) | 47.6 ± 10.3 |
| LA diameter (cm) | 4.1 ± 3.5 |
| LA area (cm2) | 22.7 ± 9.3 |
| RVIDd (cm) | 3.3 ± 0.7 |
| MVE (cm/sec) | 2.3 ± 9.3 |
| MVA (cm/sec) | 1.6 ± 9.3 |
| MVDT (msec) | 251.0 ± 151.2 |
| RVSP (mmHg) | 40.8 ± 18.5 |
Evaluation for the relationship between cardiac parameters and thyroid hormone levels showed that tricuspid regurgitation (TR) severity was significantly associated with different levels of TSH in the normal range (P-value = 0.02).
According to Table 2, the study of the relationship between the studied parameters using Spearman's rank correlation coefficient showed that the levels of thyroid hormones were significantly related to some parameters. LVEF was inversely correlated with TSH levels (r = -0.10, P = 0.04), and interventricular septum thickness in diastole (IVSD) was inversely associated with T4 levels (r = -0.11, P = 0.04). Also, echocardiographic findings showed that mitral valve inflow deceleration time (MVDT) was inversely related to T3 (r = -0.15, P = 0.04). Also, right ventricular internal dimension in diastole (RVIDd) was directly related to TSH and this relationship was at the borderline of significance (r = 0.10, P = 0.05). Considering the statistical analyses performed, no significant relationship was observed between the other functional parameters and thyroid hormone levels (P > 0.05).
Correlation Between the Normal Range of Thyroid Hormones and Cardiac Parameters
| LVDd | IVSd | LVDs | PWD | LVEF | LA diameter | LA area | RVIDd | MVDT | RVSP | |
|---|---|---|---|---|---|---|---|---|---|---|
| T3 (ng/dL) | ||||||||||
| r | 0.01 | 0.01 | 0.05 | -0.04 | -0.02 | -0.07 | -0.05 | 0.09 | -0.15 | 0.02 |
| P-value | 0.78 | 0.82 | 0.32 | 0.407 | 0.69 | 0.18 | 0.35 | 0.09 | 0.04 | 0.69 |
| T3 (pmol/L) | ||||||||||
| r | -0.05 | -0.11 | 0.03 | -0.06 | -0.09 | -0.01 | -0.05 | -0.02 | -0.13 | 0.04 |
| P-value | 0.30 | 0.04 | 0.46 | 0.24 | 0.06 | 0.74 | 0.38 | 0.68 | 0.08 | 0.46 |
| TSH (mIU/L) | ||||||||||
| r | -0.06 | -0.01 | -0.06 | -0.06 | -0.10 | 0.10 | 0.08 | 0.10 | -0.02 | 0.10 |
| P-value | 0.18 | 0.75 | 0.21 | 0.22 | 0.04 | 0.06 | 0.13 | 0.05 | 0.76 | 0.11 |
5. Discussion
In the present study, it was shown that TR and RVIDd were positively correlated with TSH levels, and LVEF was inversely correlated with TSH levels. These findings are consistent with the results of the previous studies in this field (15, 17, 18). A similar study by Nakova et al. showed that TSH levels were inversely related to LVEF, and demonstrated a negative correlation (17). This finding indicates the importance of TSH levels in ventricular function. Another similar finding showed that TSH affects other thyroid hormones by altering the metabolism-related molecular pathways, and changes in the levels of this hormone are directly related to systolic and diastolic disorders (4, 8, 18). Of course, some studies have not shown this relationship (8, 9), but the effects of TSH levels on cardiac output and the ventricular wall have been proven (4, 15, 17, 18). In a study by Erkan et al., it was observed that the posterior ventricular wall thickness and mean diameter of the left atrium were higher in the group of patients with subclinical hypothyroidism (18).
The present study showed that diastolic interventricular septum thickness (IVSD) was inversely associated with T4, and mitral valve inflow deceleration time (MVDT) was inversely correlated with T3, which was consistent with the results of similar studies (19-21). Recent studies by Favuzzi et al. showed that a decrease in T3 was significantly associated with the right ventricular mid cavity diameter (21). Regarding the reduction of T3 in subclinical hypothyroidism, it has been reported that thyroid hormones affect the end-diastolic volume of the left and right ventricular (22, 23). Mousavi Mehdiabadi et al. stated that low T3 levels were negatively and significantly associated with the left ventricular function (24). Also, Neves et al. reported that heart rate was positively associated with T3, diastolic blood pressure was positively associated with TSH, the end systolic and diastolic volume of the LV was inversely related to TSH, and the ejection fraction was nonlinearly related to T3. In addition, the left posterior ventricular wall thickness was inversely related to T4 (25).
Our results also show that T4 levels are an influential factor in IVSD. Other studies have confirmed the association of T4 with heart disorders (25, 26) but the association between T4 levels and IVSD has not yet been established. In a study by Chaker et al., it was observed that a long-term increase in T4 levels is associated with the risk of coronary heart disease in patients with thyroid disorders (27). In another study, it was reported that T4 is an important factor affecting different types of heart disorders and changes in the level of this hormone are associated with the risk of heart disorders (20).
Some researches have shown that T3 and T4 improve several pathophysiological mechanisms associated with heart failure, including diastolic dysfunction and extra cardiac abnormalities (28). T3, as a biologically active hormone, affects cell signaling pathways and increases blood volume by increasing erythropoietin production and red blood cell mass. In hyperthyroidism, these changes lead to an increase in cardiac output. On the other hand, in hypothyroidism, cardiovascular changes are completely reversed and cardiac output is reduced (7). In general, studies have demonstrated the importance of understanding the mechanisms and roles of thyroid hormones in heart function and metabolism (27, 29). Jonklaas et al. have reported that determining the type of hormone used is one of the challenges in the treatment of heart disorders, and evaluating the effectiveness of different thyroid hormones on the heart can help to better understand this issue (30). The present study also had several strengths: First, the study population was in a good range. Secondly, this is the first study in Iran that specifically addresses the relationship between thyroid hormone levels and heart disorders. Lastly, different methods of analysis were used to assess hormone levels in patients with heart disorders, and this shows that our conclusions can be consistent and reliable.
Certainly, further clinical studies should be conducted regarding the effect of thyroid hormone supplements and the drugs that affect thyroid hormones in patients with heart diseases, and the regulation of these hormones can be an important therapeutic target.
5.1. Limitations
One of the limitations of our research was the incompleteness of some clinical files, which was resolved by following up the patients through telephone calls. Certainly, there are many known and unknown factors that may affect the function of the heart in patients, including the type of nutrition, genetics and stress, but it is certainly not possible to study all of these factors in one study. Thus, more studies should be conducted in wider statistical communities. Another limitation was that in this study, all patients with different types of thyroid disorders were studied, although classification of patients based on specific thyroid diseases can be effective in obtaining better results.
5.2. Conclusions
Tricuspid regurgitation severity and end diastolic right ventricular dimension were positively correlated with TSH, and LVEF was inversely correlated with TSH levels. Also, diastolic interventricular septal thickness (IVSD) was inversely associated with T4, and mitral valve inflow deceleration time (MVDT) was inversely correlated with T3. Due to the high prevalence of cardiac disorders, evaluation for their association with thyroid hormone levels can help long-term planning for the prevention and treatment of these disorders.
References
-
1.
Alonso A, Aparicio FHJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson FAP, et al. Heart disease and stroke statistics—2021 update. Circulation. 2021;2021(143):e00.
-
2.
Mohamadzadeh F, Peyman H, Sayemiri K, Soleiman nezhad K. [Evaluating the Prevalence of Cardiovascular Risk Factors in Relation to Demographical Parameters among Young Adults in Ilam]. Journal of Ilam University of Medical Sciences. 2017;25(3):201-12. Persian. https://doi.org/10.29252/sjimu.25.3.201.
-
3.
Langen VL, Niiranen TJ, Puukka P, Lehtonen AO, Hernesniemi JA, Sundvall J, et al. Thyroid-stimulating hormone and risk of sudden cardiac death, total mortality and cardiovascular morbidity. Clin Endocrinol (Oxf). 2018;88(1):105-13. [PubMed ID: 28862752]. https://doi.org/10.1111/cen.13472.
-
4.
Yamakawa H, Kato TS, Noh JY, Yuasa S, Kawamura A, Fukuda K, et al. Thyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside. Front Physiol. 2021;12:606931. [PubMed ID: 34733168]. [PubMed Central ID: PMC8558494]. https://doi.org/10.3389/fphys.2021.606931.
-
5.
Rashad NM, Ashour WM, Samir GM, Abomandour HG. Serum salusin-β levels as predictors of coronary artery disease in obese Egyptian women. The Egyptian Journal of Internal Medicine. 2019;31(3):360-7. https://doi.org/10.4103/ejim.ejim_123_18.
-
6.
Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14(5):301-16. [PubMed ID: 29569622]. https://doi.org/10.1038/nrendo.2018.18.
-
7.
Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501-9. [PubMed ID: 11172193]. https://doi.org/10.1056/NEJM200102153440707.
-
8.
Udovcic M, Pena RH, Patham B, Tabatabai L, Kansara A. Hypothyroidism and the Heart. Methodist Debakey Cardiovasc J. 2017;13(2):55-9. [PubMed ID: 28740582]. [PubMed Central ID: PMC5512679]. https://doi.org/10.14797/mdcj-13-2-55.
-
9.
Paschou SA, Bletsa E, Stampouloglou PK, Tsigkou V, Valatsou A, Stefanaki K, et al. Thyroid disorders and cardiovascular manifestations: an update. Endocrine. 2022;75(3):672-83. [PubMed ID: 35032315]. https://doi.org/10.1007/s12020-022-02982-4.
-
10.
Akin A, Unal E, Yildirim R, Ture M, Balik H, Haspolat YK. Left and right ventricular functions may be impaired in children diagnosed with subclinical hypothyroidism. Sci Rep. 2020;10(1):19711. [PubMed ID: 33184320]. [PubMed Central ID: PMC7661521]. https://doi.org/10.1038/s41598-020-76327-4.
-
11.
Kerp H, Hones GS, Tolstik E, Hones-Wendland J, Gassen J, Moeller LC, et al. Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure. Front Cardiovasc Med. 2021;8:683522. [PubMed ID: 34395557]. [PubMed Central ID: PMC8363198]. https://doi.org/10.3389/fcvm.2021.683522.
-
12.
Sun ZQ, Ojamaa K, Coetzee WA, Artman M, Klein I. Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes. Am J Physiol Endocrinol Metab. 2000;278(2):E302-7. [PubMed ID: 10662715]. https://doi.org/10.1152/ajpendo.2000.278.2.E302.
-
13.
Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, et al. Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci U S A. 2006;103(38):14104-9. [PubMed ID: 16966610]. [PubMed Central ID: PMC1599919]. https://doi.org/10.1073/pnas.0601600103.
-
14.
Kuzman JA, Gerdes AM, Kobayashi S, Liang Q. Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 2005;39(5):841-4. [PubMed ID: 16171808]. https://doi.org/10.1016/j.yjmcc.2005.07.019.
-
15.
Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88(8):3731-7. [PubMed ID: 12915662]. https://doi.org/10.1210/jc.2003-030039.
-
16.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. [PubMed ID: 18945920]. [PubMed Central ID: PMC2606813]. https://doi.org/10.2337/dc08-9025.
-
17.
Nakova VV, Krstevska B, Kostovska ES, Vaskova O, Ismail LG. The effect of levothyroxine treatment on left ventricular function in subclinical hypothyroidism. Arch Endocrinol Metab. 2018;62(4):392-8. [PubMed ID: 30304103]. https://doi.org/10.20945/2359-3997000000052.
-
18.
Erkan G, Erkan AF, Cemri M, Karaahmetoglu S, Cesur M, Cengel A. The evaluation of diastolic dysfunction with tissue Doppler echocardiography in women with subclinical hypothyroidism and the effect of L-thyroxine treatment on diastolic dysfunction: a pilot study. J Thyroid Res. 2011;2011:654304. [PubMed ID: 21860776]. [PubMed Central ID: PMC3153938]. https://doi.org/10.4061/2011/654304.
-
19.
Pearce EN, Yang Q, Benjamin EJ, Aragam J, Vasan RS. Thyroid function and left ventricular structure and function in the Framingham Heart Study. Thyroid. 2010;20(4):369-73. [PubMed ID: 20210671]. [PubMed Central ID: PMC2867586]. https://doi.org/10.1089/thy.2009.0272.
-
20.
Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, et al. Thyroid Hormones and Cardiovascular Function and Diseases. J Am Coll Cardiol. 2018;71(16):1781-96. [PubMed ID: 29673469]. https://doi.org/10.1016/j.jacc.2018.02.045.
-
21.
Favuzzi AMR, Venuti A, Bruno C, Nicolazzi MA, Fuorlo M, Dajko M, et al. Hormonal deficiencies in heart failure with preserved ejection fraction: prevalence and impact on diastolic dysfunction: a pilot study. Eur Rev Med Pharmacol Sci. 2020;24(1):352-61. [PubMed ID: 31957849]. https://doi.org/10.26355/eurrev_202001_19933.
-
22.
Cappola AR, Desai AS, Medici M, Cooper LS, Egan D, Sopko G, et al. Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment. Thyroid. 2019;29(6):760-77. [PubMed ID: 31081722]. [PubMed Central ID: PMC6913785]. https://doi.org/10.1089/thy.2018.0416.
-
23.
Ilic S, Tadic M, Ivanovic B, Caparevic Z, Trbojevic B, Celic V. Left and right ventricular structure and function in subclinical hypothyroidism: the effects of one-year levothyroxine treatment. Med Sci Monit. 2013;19:960-8. [PubMed ID: 24217559]. [PubMed Central ID: PMC3829699]. https://doi.org/10.12659/MSM.889621.
-
24.
Musavi Mehdiabadi F, Rashidinejad A, Mahdavi A, Dehesh T. Relationship Between Thyroid Hormones and Left Ventricular Mass in Peritoneal Dialysis Patients. Iran J Kidney Dis. 2020;14(5):380-8. [PubMed ID: 32943593].
-
25.
Neves JS, Fontes-Carvalho R, Borges-Canha M, Leite AR, Martins S, Oliveira A, et al. Thyroid Hormones within the Normal Range and Cardiac Function in the General Population: The EPIPorto Study. Eur Thyroid J. 2021;10(2):150-60. [PubMed ID: 33981619]. [PubMed Central ID: PMC8077596]. https://doi.org/10.1159/000508407.
-
26.
Ozen K, Süleyman A, Polat C, Ede H, Ozturk O. Relation between Thyroid Stimulating Hormone and Left Ventricular Strain Parameters in Patients with Subclinical Hypothyroidism. American Journal of Cardiology. 2018;121(8):e5-6.
-
27.
Chaker L, van den Berg ME, Niemeijer MN, Franco OH, Dehghan A, Hofman A, et al. Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study. Circulation. 2016;134(10):713-22. [PubMed ID: 27601558]. https://doi.org/10.1161/CIRCULATIONAHA.115.020789.
-
28.
Neves JS, Vale C, von Hafe M, Borges-Canha M, Leite AR, Almeida-Coelho J, et al. Thyroid hormones and modulation of diastolic function: a promising target for heart failure with preserved ejection fraction. Ther Adv Endocrinol Metab. 2020;11:2042018820958330. [PubMed ID: 33088475]. [PubMed Central ID: PMC7543162]. https://doi.org/10.1177/2042018820958331.
-
29.
Vargas F, Moreno JM, Rodriguez-Gomez I, Wangensteen R, Osuna A, Alvarez-Guerra M, et al. Vascular and renal function in experimental thyroid disorders. Eur J Endocrinol. 2006;154(2):197-212. [PubMed ID: 16452532]. https://doi.org/10.1530/eje.1.02093.
-
30.
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-751. [PubMed ID: 25266247]. [PubMed Central ID: PMC4267409]. https://doi.org/10.1089/thy.2014.0028.