|Year : 2020 | Volume
| Issue : 3 | Page : 118-122
Hypothyroidism and obesity: Is there a bidirectional link? What is the impact on our clinical practice?
Geeta Aurangabadkar1, Sirisha Kusuma Boddu2
1 Department of Endocrinology, Care Hospital and Excell Hospital, Hyderabad, Telangana, India
2 Department of Endocrinology, Rainbow Children's Hospital, Hyderabad, Telangana, India
|Date of Submission||25-Aug-2020|
|Date of Acceptance||20-Oct-2020|
|Date of Web Publication||20-Jan-2021|
Dr. Geeta Aurangabadkar
Excell Hospital, Narayanguda, Hyderabad - 500 029, Telangana
Source of Support: None, Conflict of Interest: None
It is well established that hypothyroidism causes weight gain, but novel emerging data suggest that obesity may actually lead to hypothyroidism. The interplay between leptin, thyroid hormones (THs), and thyroid autoimmunity in obese patients needs special attention. Clinicians need to be more cautious while interpreting elevated thyroid-stimulating hormone levels in obese individuals to avoid inappropriate labeling of hypothyroidism and unjustified use of TH therapy. It would seem reasonable to measure circulating plasma levels of THs and thyroid autoantibodies in these individuals. Stimulation of brown adipose tissue in adults, specifically through TH-mediated pathways, may seem a promising therapeutic target for obesity; however, the evidence has been inconclusive regarding effectiveness of TH therapy in treating obesity. Moreover, the effect of weight loss on thyroid function has been variable as per different studies. We aim to review the available evidence regarding the possible bidirectional link between hypothyroidism and obesity, explore responsible underlying mechanisms, and discuss the impact of this knowledge on our clinical practice.
Keywords: Hypothyroidism, leptin, obesity, thyroid autoimmunity, thyroid peroxidase antibody, thyroid-stimulating hormone
|How to cite this article:|
Aurangabadkar G, Kusuma Boddu S. Hypothyroidism and obesity: Is there a bidirectional link? What is the impact on our clinical practice?. Thyroid Res Pract 2020;17:118-22
|How to cite this URL:|
Aurangabadkar G, Kusuma Boddu S. Hypothyroidism and obesity: Is there a bidirectional link? What is the impact on our clinical practice?. Thyroid Res Pract [serial online] 2020 [cited 2022 Jun 28];17:118-22. Available from: https://www.thetrp.net/text.asp?2020/17/3/118/307558
| Methodology of search|| |
A literature search was performed with Medline (PubMed), Scopus, and Google Scholar electronic databases till October 2020, using relevant keywords including hypothyroidism, obesity, thyroid autoimmunity, and leptin, (brown adipose tissue and thyroid stimulating hormone).
| Introduction|| |
Obesity and hypothyroidism are two of the leading noncommunicable diseases with increasing overall prevalence worldwide. Thyroid dysfunction is often implicated in the weight gain seen in patients with hypothyroidism. Indisputably, thyroid dysfunction is associated with changes in body weight and composition, body temperature, and total energy expenditure and resting energy expenditure (TEE and REE), independent of physical activity. However, emerging evidence in recent years suggests that obesity may actually be responsible for changes in thyroid-stimulating hormone (TSH) levels, rather than simply be the effect of them. High leptin levels and increased thyroid autoimmunity in obese individuals might have a role to play., In this brief review, we examine the available evidence pertaining to the interrelationship between hypothyroidism and obesity and discuss how this knowledge could impact our clinical practice.
| Thyroid Hormones, Energy Expenditure, and Brown Adipose Tissue|| |
Thyroid hormone (TH) is an important determinant of energy expenditure and contributes to appetite regulation. It regulates the basal metabolism rate (BMR) and thermogenesis and plays an important role in lipid and glucose metabolism, food intake, and fat oxidation.
Children and adults have two major types of adipose tissues, white adipose tissue: involved in energy storage and brown adipose tissue (BAT): responsible for thermogenesis and energy expenditure. Although predominantly seen in children, functional BAT was found to play a role in energy balance in adults as well. TH signaling substantially affects energy homeostasis and accelerates energy expenditure. TH increases BMR mostly by direct action on metabolically active tissues such as the liver, heart, and skeletal muscle, promoting energy generation, while decreasing thermodynamic efficiency resulting in heat production and increased body temperature. Effects of TH on BAT are either via activation of BAT by local D2-mediated activation of TH or centrally mediated. It was seen that either hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase, increases the sympathetic nervous system activity, and up-regulates thermogenic markers in BAT. Stimulation of BAT in adults, specifically through TH-mediated pathways, is a promising therapeutic target for obesity. However, data so far are inconclusive regarding the effectiveness of TH therapy in treating obesity, whereas such therapy could potentially induce subclinical hyperthyroidism.
| Hypothyroidism Causing Weight Gain|| |
It has been demonstrated that both subclinical and overt hypothyroidism can lead to changes in body weight, body composition, TEE, and REE, independently of physical activity. In the past, hypothyroidism related weight gain was attributed to an expansion of extracellular water compartment of the body. However, studies looking at the effects of thyroxine treatment in those with hypothyroidism and myxedema have shown that, though there was some loss of fat mass, it was predominantly a decrease in the fat-free lean body mass that accounts for most of the bodyweight reduction. Interestingly, even small changes in serum TSH with minimal changes in TH dosage were noticed to result in significant alterations in REE in hypothyroid patients. Hence, it is possible that in subclinical hypothyroidism, altered thyroid function could be the primary event inciting changes in energy expenditure, paving the way for future increases in body mass index (BMI). However, whether this is a result of alterations in REE alone or if TH has any impact on leptin levels is controversial, as studies have shown that both hypo- and hyperthyroidism can either increase, decrease, or have no effect leptin levels.
Conversely, in a study looking at the effect of levothyroxine treatment in obese children with subclinical hypothyroidism, dietary-behavioral management intervention alone contributed to the reduction of BMI, irrespective of levothyroxine use. Overtime, TSH normalized similarly in treated versus untreated groups (90.5% vs. 80.9%). These findings suggest that moderately elevated levels of TSH are most likely a consequence rather than cause of overweight and pharmacological treatment should be avoided.
| Leptin and Thyroid Function Abnormalities in ObesitY – IS Obesity The Cause Or Effect?|| |
The relationship between leptin and thyroid function is complex, interwoven, and controversial. Adipose tissue as an active endocrine organ produces leptin, which physiologically regulates energy homeostasis by signaling the central nervous system about adipose tissue reserves. Leptin modulates the neuroendocrine and behavioral responses to overfeeding, thereby regulating food intake and energy expenditure.
Increased body fat, especially central body fat, is seen to cause a parallel increase in free T3 and TSH, irrespective of insulin sensitivity or other metabolic parameters. In obese children, increased FT3 is the most common thyroid function abnormality, followed by an increase in TSH. Leptin, adjusted for BMI, was found to correlate with TSH, indicating that the increase in TSH and leptin levels in severe obesity could be the result of an increased amount of fat. At the central level, leptin acts as a regulator of the hypothalamic–pituitary–thyroid axis, activating thyrotropin-releasing hormone gene expression in the paraventricular nucleus, contributing to the increased TSH. At the peripheral level, leptin stimulates thyroid deiodinase, increasing the conversion of T4–T3., Curiously, leptin and THs might share some common downstream action sites and could act additively, though independently, to enhance calorigenic metabolism.
Impaired feedback regulation of TSH by FT3/FT4 due to a state of mild TH resistance seen in obesity also contributes to elevated TSH. These elevations in TSH and FT3 might be compensatory adaptive mechanisms to increase REE and thereby slow down weight gain, analogous to the reduction in TSH and FT3 seen in anorexia nervosa, although to achieve the opposite effect. Nevertheless, some studies have reported a decrease in FT4 with increasing BMI, leading to the speculation that thyroid function abnormalities could be the primary reason for increases in BMI, [Figure 1].
|Figure 1: Interrelationship between obesity and thyroid dysfunction. REE: Resting energy expenditure, AITD: Autoimmune thyroid disease, NIS: Sodium iodide symporter, TRH: Thyrotropin-releasing hormone, TSH: Thyroid-stimulating hormone|
Click here to view
| Obesity and Thyroid Autoimmunity|| |
The pathogenesis of autoimmune diseases is both genetically and immunologically mediated.,,, Obesity is a chronic low-grade inflammatory process resulting in the production of cytokines and other inflammatory markers such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha by the adipose tissue. Increased levels of adipokines such as IL-6 and leptin play a vital role in mediation of immune and inflammatory responses., Leptin, by shifting T helper (Th) balance toward Th1 phenotype and inhibiting the function of regulatory T (Treg) cells, might encourage the autoimmune process., Observational research shows that adipokine dysfunction is associated with thyroid autoimmunity., Inflammatory cytokines may also inhibit the mRNA expression of sodium/iodide symporter, influencing iodide uptake activity of human thyroid cells. A meta-analysis revealed that obesity is associated with a 93% increased risk of developing positive thyroid peroxidase antibody. Thyroid autoantibodies are the hallmarks of Hashimoto thyroiditis which is believed to be the main cause of hypothyroidism in iodine-sufficient regions. A recent study has shown that the prevalence of hypothyroidism as diagnosed by low FT3, FT4, and deranged lipid profile was higher in obese when compared with age and sex-matched controls, especially if median leptin levels were >33.8 ug/l, unrelated to BMI or fat mass. On the contrary, the raised serum TSH seen in most of morbidly obese patients, in the absence of low TH or clinical evidence of hypothyroidism, is not accompanied by circulating thyroid Ab. Hence, raised TSH alone (hyperthyrotropinemia, sometimes labeled as subclinical hypothyroidism) may not indicate true hypothyroidism in patients with morbid obesity.
Thyroid ultrasound is often used as a complementary tool to thyroid biochemistry in diagnosing autoimmune thyroid disease (AITD). However, in morbid obesity, alterations in thyroid morphology could result in a hypoechoic pattern in ultrasonogram, with no clinical signs of thyroid disease and with negative thyroid autoantibodies. Marked weight loss achieved by bariatric surgery is seen to reverse these changes. It is possible that obesity-induced elevations in inflammatory markers like ILs increase the vascular permeability in thyroid gland with fluid extravasation giving rise to a hypoechoic pattern.
| Effect of Weight Loss On Thyroid Function|| |
Moderate-to-major diet-induced weight loss is seen to reverse TH alterations, decreasing FT3 and TSH to normal levels and decreasing REE, in adults as well as children.,,,, This fall in FT3 during the initial phases of weight loss due to calorie restriction can significantly decrease REE/BMR, making it difficult to sustain weight loss on long term. However, this supposition was refuted by another observation where higher baseline FT3 and FT4 were associated with greater weight loss in the first 6 months of calorie restriction, without weight regain even at 24-month follow-up. Other studies have noted that weight reduction leads to a long term decrease in the peripheral THs (T3 and T4) but not in TSH.,
| How Does This Impact Our Clinical Practice?|| |
It is quite possible that obesity can induce hypothyroidism, and subclinical hypothyroidism could be the primary instigator, culminating in later obesity by altering REE. However, physicians need to be extremely cautious in diagnosing hypothyroidism in obese patients with isolated elevations of TSH/subclinical hypothyroidism. It is imperative that hypothyroidism should only be diagnosed in those with supportive clinical findings suggestive of impaired TH activity at the tissue level (e.g., delayed deep tendon reflexes and abnormal lipid profile), decreased FT3/T3 and FT4/T4, and/or positive thyroid antibodies. In obese individuals with high serum TSH and high or high normal FT3, absence of thyroid antibodies and a normal lipid profile (which is usually deranged in hypothyroidism) may help to exclude TH deficiency. Moreover, thyroid ultrasound, which is otherwise a commonly used diagnostic tool for AITD, cannot be reliably used for the diagnosis of autoimmune thyroiditis in obese patients. Future studies might throw a better light on the role of leptin as an architect of thyroid autoimmunity and the overall interlink between obesity, leptin, autoimmunity, and hypothyroidism. This article stimulates the need to review the definition of hypothyroidism in obese individuals and avoid inappropriate use of TH in expectation of weight loss.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Prevalence and incidence of endocrine and metabolic disorders in the United States: A comprehensive review. J Clin Endocrinol Metab 2009;94:1853-78.
Rosenbaum M, Hirsch J, Murphy E, Leibel RL. Effects of changes in body weight on carbohydrate metabolism, catecholamine excretion, and thyroid function. Am J Clin Nutr 2000;71:1421-32.
Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relationship of thyroid function with body mass index, leptin, insulin sensitivity and adiponectin in euthyroid obese women. Clin Endocrinol (Oxf) 2005;62:487-91.
Marzullo P, Minocci A, Tagliaferri MA, Guzzaloni G, Di Blasio A, De Medici C, et al.
Investigations of thyroid hormones and antibodies in obesity: Leptin levels are associated with thyroid autoimmunity independent of bioanthropometric, hormonal and weight-related determinants. J Clin Endocrinol Metab 2010;95:3965-72.
Cypess AM, Kahn CR. The role and importance of brown adipose tissue in energy homeostasis. Curr Opin Pediatr 2010;22:478-84.
López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al
. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16:1001-8.
Bianco AC, McAninch EA. The role of thyroid hormone and brown adipose tissue in energy homoeostasis. Lancet Diabetes Endocrinol 2013;1:250-8.
Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: A systematic review. J Clin Endocrinol Metab 2009;94:3663-75.
Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L, et al
. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab 2005;90:4019-24.
Baron DN. Hypothyroidism; its aetiology and relation to hypometabolism, hypercholesterolaemia, and increase in body-weight. Lancet 1956;271:277-81.
Kyle LH, Ball MF, Doolan PD. Effect of thyroid hormone on body composition in myxedema and obesity. N Engl J Med 1966;275:12-7.
Al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 1997;82:1118-25.
Marras V, Casini MR, Pilia S, Carta D, Civolani P, Porcu M, et al
. Thyroid function in obese children and adolescents. Horm Res Paediatr 2010;73:193-7.
Matusik P, Gawlik A, Januszek-Trzciakowska A, Malecka-Tendera E. Isolated subclinical hyperthyrotropinemia in obese children: Does levothyroxine (LT4) improve weight reduction during combined behavioral therapy? Int J Endocrinol 2015;2015:792509.
Feldt-Rasmussen U. Thyroid and leptin. Thyroid 2007;17:413-41.
De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R. Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf) 2007;67:265-9.
Menendez C, Baldelli R, Camiña JP, Escudero B, Peino R, Dieguez C, et al
. TSH stimulates leptin secretion by a direct effect on adipocytes. J Endocrinol 2003;176:7-12.
Wang JL, Chinookoswong N, Yin S, Shi ZQ. Calorigenic actions of leptin are additive to, but not dependent on, those of thyroid hormones. Am J Physiol Endocrinol Metab 2000;279:E1278-85.
Longhi S, Radetti G. Thyroid function and obesity. J Clin Res Pediatr Endocrinol 2013;5 Suppl 1:40-4.
Zimmermann-Belsing T, Brabant G, Holst JJ, Feldt-Rasmussen U. Circulating leptin and thyroid dysfunction. Eur J Endocrinol 2003;149:257-71.
Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gomez-Reino JJ, et al
. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017;13:100-9.
Verbeeten KC, Elks CE, Daneman D, Ong KK. Association between childhood obesity and subsequent Type 1 diabetes: A systematic review and meta-analysis. Diabet Med 2011;28:10-8.
Hedström AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012;18:1334-6.
Gremese E, Tolusso B, Gigante MR, Ferraccioli G. Obesity as a risk and severity factor in rheumatic diseases (autoimmune chronic inflammatory diseases). Front Immunol 2014;5:576.
Russolillo A, Iervolino S, Peluso R, Lupoli R, Di Minno A, Pappone N, et al
. Obesity and psoriatic arthritis: From pathogenesis to clinical outcome and management. Rheumatology (Oxford) 2013;52:62-7.
Fontenelle LC, Feitosa MM, Severo JS, Freitas TE, Morais JB, Torres-Leal FL, et al
. Thyroid function in human obesity: Underlying mechanisms. Horm Metab Res 2016;48:787-94.
Vieira-Potter VJ. Inflammation and macrophage modulation in adipose tissues. Cell Microbiol 2014;16:1484-92.
Hino J, Nakatani M, Arai Y, Tsuchida K, Shirai M, Miyazato M, et al
. Overexpression of bone morphogenetic protein-3b (BMP-3b) in adipose tissues protects against high-fat diet-induced obesity. Int J Obes 2017;41:483-8.
Procaccini C, Carbone F, Galgani M. Obesity and susceptibility to autoimmune diseases. Expert Rev. Clin Immunol 2011;7:287-94.
Fresno M, Alvarez R, Cuesta N. Toll-like receptors, inflammation, metabolism and obesity. Arch Physiol Biochem 2011;117:151-64.
Teixeira PF, Cabral MD, Silva NA, Soares DV, Braulio VB, Couto AP, et al
. Serum leptin in overt and subclinical hypothyroidism: Effect of levothyroxine treatment and relationship to menopausal status and body composition. Thyroid 2009;19:443-50.
Drobniak A, Kanecki K, Grymowicz M, Radowicki S. Serum leptin concentration in women of reproductive age with euthyroid autoimmune thyroiditis. Gynecol Endocrinol 2016;32:128-31.
Karakosta P, Alegakis D, Georgiou V, Roumeliotaki T, Fthenou E, Vassilaki M, et al
. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab 2012;97:4464-72.
Rotondi M, Leporati P, La Manna A, Pirali B, Mondello T, Fonte R, et al
. Raised serum TSH levels in patients with morbid obesity: Is it enough to diagnose subclinical hypothyroidism? Eur J Endocrinol 2009;160:403-8.
Rotondi M, Cappelli C, Leporati P, Chytiris S, Zerbini F, Fonte R, et al
. A hypoechoic pattern of the thyroid at ultrasound does not indicate autoimmune thyroid diseases in patients with morbid obesity. Eur J Endocrinol 2010;163:105-9.
Kyrou I, Adesanya O, Hedley N, Wayte S, Grammatopoulos D, Thomas CL, et al
. Improved thyroid hypoechogenicity following bariatric-induced weight loss in euthyroid adults with severe obesity-a pilot study. Front Endocrinol (Lausanne) 2018;9:488.
Nannipieri M, Cecchetti F, Anselmino M, Camastra S, Niccolini P, Lamacchia M, et al
. Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: Effects of weight loss. Int J Obes (Lond) 2009;33:1001-6.
Kiortsis DN, Durack I, Turpin G. Effects of a low-calorie diet on resting metabolic rate and serum tri-iodothyronine levels in obese children. Eur J Pediatr 1999;158:446-50.
Kok P, Roelfsema F, Langendonk JG, Frölich M, Burggraaf J, Meinders AE, et al
. High circulating thyrotropin levels in obese women are reduced after body weight loss induced by caloric restriction. J Clin Endocrinol Metab 2005;90:4659-63.
Reinehr T, de Sousa G, Andler W. Hyperthyrotropinemia in obese children is reversible after weight loss and is not related to lipids. J Clin Endocrinol Metab 2006;91:3088-91.
Radetti G, Longhi S, Baiocchi M, Cassar W, Buzi F. Changes in lifestyle improve body composition, thyroid function, and structure in obese children. J Endocrinol Invest 2012;35:281-5.
Liu G, Liang L, Bray GA, Qi L, Hu FB, Rood J, et al
. Thyroid hormones and changes in body weight and metabolic parameters in response to weight loss diets: The POUNDS LOST trial. Int J Obes (Lond) 2017;41:878-86.
Reinehr T, Andler W. Thyroid hormones before and after weight loss in obesity. Arch Dis Child 2002;87:320-3.
Agnihothri RV, Courville AB, Linderman JD, Smith S, Brychta R, Remaley A, et al
. Moderate weight loss is sufficient to affect thyroid hormone homeostasis and inhibit its peripheral conversion. Thyroid 2014;24:19-26.