Thyroid Research and Practice

REVIEW ARTICLE
Year
: 2020  |  Volume : 17  |  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

Correspondence Address:
Dr. Geeta Aurangabadkar
Excell Hospital, Narayanguda, Hyderabad - 500 029, Telangana
India

Abstract

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.



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;17:118-122


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 2021 Jul 28 ];17:118-122
Available from: https://www.thetrp.net/text.asp?2020/17/3/118/307558


Full Text



 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.[1] 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.[2] 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.[3],[4] 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.[2]

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.[5] 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.[6] 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.[6] Stimulation of BAT in adults, specifically through TH-mediated pathways, is a promising therapeutic target for obesity.[7] However, data so far are inconclusive regarding the effectiveness of TH therapy in treating obesity, whereas such therapy could potentially induce subclinical hyperthyroidism.[8]

 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.[9] In the past, hypothyroidism related weight gain was attributed to an expansion of extracellular water compartment of the body.[10] 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.[11] 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.[12] 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).[9] 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.[13]

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.[14]

 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.[15] 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.[16] In obese children, increased FT3 is the most common thyroid function abnormality, followed by an increase in TSH.[13] 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.[3] 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.[15],[17] Curiously, leptin and THs might share some common downstream action sites and could act additively, though independently, to enhance calorigenic metabolism.[18]

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.[19] 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[20],[21] [Figure 1].{Figure 1}

 Obesity and Thyroid Autoimmunity



The pathogenesis of autoimmune diseases is both genetically and immunologically mediated.[22],[23],[24],[25] 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.[26] Increased levels of adipokines such as IL-6 and leptin play a vital role in mediation of immune and inflammatory responses.[27],[28] Leptin, by shifting T helper (Th) balance toward Th1 phenotype and inhibiting the function of regulatory T (Treg) cells, might encourage the autoimmune process.[29],[30] Observational research shows that adipokine dysfunction is associated with thyroid autoimmunity.[31],[32] Inflammatory cytokines may also inhibit the mRNA expression of sodium/iodide symporter, influencing iodide uptake activity of human thyroid cells.[19] 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.[33] 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.[4] 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.[34]

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.[35] 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.[36]

 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.[13],[37],[38],[40],[41] 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.[38] 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.[42] Other studies have noted that weight reduction leads to a long term decrease in the peripheral THs (T3 and T4) but not in TSH.[43],[44]

 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.[34] 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

Nil.

Conflicts of interest

There are no conflicts of interest.

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