Vol 74, No 6 (2023)
Review paper
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Thyroid disease and autoimmunity in obese patients: a narrative review

Francesca Bambini1, Elisa Gatta1, Rossella D'Alessio2, Francesco Dondi3, Giusto Pignata2, Ilenia Pirola1, Francesco Bertagna3, Carlo Cappelli1
Pubmed: 37994585
Endokrynol Pol 2023;74(6).

Abstract

Introduction: The high prevalence of obesity and thyroid diseases worldwide justifies di per se their simultaneous coexistence. In recent decades, there has been a parallel and significant rise in obesity and thyroid diseases in industrialised countries, although the underlying mechanisms are complex and not well known.

Material and methods: The authors accomplished a comprehensive literature search of original articles concerning obesity and thyroid status. Original papers exploring the association between these two morbidities in children and adults were included.

Results: A total of 79 articles were included in the present analysis. A total of 12% of obese children (mean age 10.9 ± 1.4 years) showed a thyroid disease, and they were younger than healthy obese children (10.9 ± 1.2 vs. 11.0 ± 0.4 years, p < 0.001). Isolated hyperthyrotropinaemia was the most frequent finding in children (10.1%). Autoimmune thyroid disease was more frequent in puberal age. Thyroid antibodies and subclinical hypothyroidism were more frequent in obese that in non-obese patients (7% vs. 3%, p < 0.001; 10% vs. 6%, p < 0.001). Among obese adults, 62.2% displayed a thyroid disease; those affected were younger (35.3 ± 6.8 vs. 41.0 ± 1.9 years, p < 0.001), heavier [body mass index (BMI): 39.4 ± 6.3 vs. 36.1 ± 2.3 kg/m2, p < 0.001], and more frequently female (13% vs. 8%, p < 0.001). The most frequent disease was overt hypothyroidism (29.9%). BMI appears to be correlated with TSH levels in obese adults. Overt hypothyroidism was significantly more frequent in obese patients (7% vs. 3%, p < 0.005), but no difference was found in thyroid antibodies (15% vs. 14%, p = 0.178).

Conclusions: An undeniable relationship between obesity and thyroid impairments exists. Isolated hyperthyrotropinaemia is frequently seen in obese children, often followed by spontaneous resolution. Subclinical hypothyroidism should never be treated in children or adults with the aim of reducing body weight.

Review

Endokrynologia Polska

DOI: 10.5603/ep.96255

ISSN 0423–104X, e-ISSN 2299–8306

Volume/Tom 74; Number/Numer 6/2023

Submitted: 28.06.2023

Accepted: 18.08.2023

Early publication date: 09.11.2023

Thyroid disease and autoimmunity in obese patients: a narrative review

Francesca Bambini1Elisa Gatta1Rossella D’Alessio2Francesco Dondi3Giusto Pignata2Ilenia Pirola1Francesco Bertagna3Carlo Cappelli1
1Department of Clinical and Experimental Sciences, SSD Endocrinologia, University of Brescia, Azienda Socio-Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy
2Department of General Surgery 2, ASST Spedali Civili di Brescia, Italy
3Nuclear Medicine, University of Brescia, ASST Spedali Civili di Brescia, Italy

Prof. Carlo Cappelli, Department of Clinical and Experimental Sciences, SSD Endocrinologia, University of Brescia, ASST Spedali Civili di Brescia, Piazzale Spedali Civili n°1, 25100, Brescia, Italy; e-mail: carlo.cappelli@unibs.it

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Introduction: The high prevalence of obesity and thyroid diseases worldwide justifies di per se their simultaneous coexistence. In recent decades, there has been a parallel and significant rise in obesity and thyroid diseases in industrialised countries, although the underlying mechanisms are complex and not well known.
Material and methods: The authors accomplished a comprehensive literature search of original articles concerning obesity and thyroid status. Original papers exploring the association between these two morbidities in children and adults were included.
Results: A total of 79 articles were included in the present analysis. A total of 12% of obese children (mean age 10.9 ± 1.4 years) showed a thyroid disease, and they were younger than healthy obese children (10.9 ± 1.2 vs. 11.0 ± 0.4 years, p < 0.001). Isolated hyperthyrotropinaemia was the most frequent finding in children (10.1%). Autoimmune thyroid disease was more frequent in puberal age. Thyroid antibodies and subclinical hypothyroidism were more frequent in obese that in non-obese patients (7% vs. 3%, p < 0.001; 10% vs. 6%, p < 0.001). Among obese adults, 62.2% displayed a thyroid disease; those affected were younger (35.3 ± 6.8 vs. 41.0 ± 1.9 years, p < 0.001), heavier [body mass index (BMI): 39.4 ± 6.3 vs. 36.1 ± 2.3 kg/m2, p < 0.001], and more frequently female (13% vs. 8%, p < 0.001). The most frequent disease was overt hypothyroidism (29.9%). BMI appears to be correlated with TSH levels in obese adults. Overt hypothyroidism was significantly more frequent in obese patients (7% vs. 3%, p < 0.005), but no difference was found in thyroid antibodies (15% vs. 14%, p = 0.178).
Conclusions: An undeniable relationship between obesity and thyroid impairments exists. Isolated hyperthyrotropinaemia is frequently seen in obese children, often followed by spontaneous resolution. Subclinical hypothyroidism should never be treated in children or adults with the aim of reducing body weight. (Endokrynol Pol 2023; 74 (6): 576–590)
Key words: obesity; thyroid; hypothyroidism; hyperthyroidism; autoimmune thyroid diseases

Introduction

Excess weight and obesity are defined as an abnormal or excessive fat accumulation representing a risk to health [1]. They are classified by calculating body mass index (BMI), with overweight classified as a BMI between 25.0 and 29.9 kg/m2 and obese as a BMI30 kg/m2. The obese category is subdivided into class I (BMI 30.0 to 34.9 kg/m2), class II (BMI 35.0 to 39.9 kg/m2), and class III (BMI 40 kg/m2), the latter also referred to as severe or massive obesity [1].

The issue has grown to epidemic proportions both in adults and in children. In the last 40 years, the prevalence of overweight or obese subjects has increased from 4% to 18% worldwide [1]. Many comorbidities are related to this condition, such as type 2 diabetes mellitus, cardiovascular and immune-mediated diseases, and some malignancies [2]. Moreover, more than 4 million people die from obesity complications every year [3].

Thyroid dysfunctions are quite common in the general population. In community surveys, subclinical and overt hypo- and hyperthyroidism have a prevalence ranging from 0.1% to 12.4% and from 0.2% to 10% in adults, respectively [4–9]. The most frequent cause is autoimmune thyroid diseases (AITDs) that are T cell-mediated, organ-specific disorders [10, 11]. Graves’ disease and Hashimoto thyroiditis are the most frequent, both characterised by lymphocytic infiltration, although clinically different [12]. The former is characterized by the presence of thyroid-stimulating hormone receptor antibodies (TRAb) that activate the follicular cell receptor, thereby stimulating thyroid hormone synthesis and secretion [13]. The latter shows antibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) that are correlated with the active phase of disease leading to hypothyroidism [14–17].

The high prevalence of obesity and thyroid diseases worldwide justifies di per se their simultaneous coexistence. Indeed, in recent decades, there has been a parallel and significant rise in obesity and autoimmune disorders, including thyroid diseases, in industrialised countries, although the underlying mechanisms are complex and not well known [18–20].

For these reasons, we performed a literature review with the aim of assessing the prevalence of thyroid dysfunction, focusing on thyroid autoimmunity with or without hypo- and hyperthyroidism, both in obese children and in adults.

Material and methods

The review was conducted according to the PRISMA statement, and the checklist is reported in Supplementary File.

A PubMed/MEDLINE, Web of Science, and Scopus search was performed for free-text words and terms related to “obesity”, “obese”, “overweight”, “thyroid autoimmunity”, “Hashimoto’s thyroiditis”, “Graves’ disease”, “Graves hyperthyroidism”, “hyperthyroidism”, “hypothyroidism”, “thyroid peroxidase antibody”, “TPOAb”, “thyroglobulin antibody”, “thyroglobulin antibodies”, “TgAb”, “thyroiditis”, and “thyrotoxicosis”. Original studies and reviews in English published online up to 30 April 2023 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review.

Three authors extracted data from all the included studies in the full text, tables, and figures concerning general study information (authors, publication year, country, study design, and funding sources) and patient characteristics (i.e. sample size, age, sex ratio, and clinical setting).

The selected method used for assessing the risk of bias in individual studies and the applicability to the review question was QUADAS-2, a tool for evaluating quality in diagnostic test accuracy studies [21]. Three reviewers assessed the studies’ grades in the systematic review in four domains (patient selection, index test, reference standard, and flow and timing) concerning the risk of bias and in three fields regarding the applicability (patient selection, index test, and reference standard).

Results

In the preliminary search, 9742 articles were identified, and 6901 remained after removing duplicates. A total of 458 full-text publications were retrieved after further careful review of abstracts. A total of 143 studies were eligible for full-text and 79 articles were included in the present analysis. A PRISMA flow diagram of the screening and selection process can be found in Figure 1.

179638.png
Figure 1. PRISMA flowchart

Taking advantage of the data reported in each study, the Authors assessed the risk of bias and concerns about the applicability of the included papers based on the QUADAS-2 instruments. The results of the quality assessment are reported in Figure 2.

179891.png
Figure 2. Quality assessment according to the QUADAS-2 tool

Post hoc, the studies were divided by the age of the subjects. In detail, 24 studies involved children (10 cross-sectional studies, 7 case controls, and 7 cohort studies) and 55 involved adults (42 cross-sectional studies, 4 case controls, and 9 cohort studies) (Tab. 1 and 2).

Table 1. Summary of clinical studies about thyroid dysfunctions and autoimmunity in obese children

Author, date

Study design

Total obese patients

Thyropathy

Patients affected (%), male/female*

Outcome

Stichel et al., 2000 [22]

Retrospective case-control

290

AITD

10 (3.4%)

The prevalence of AITD increased in obese children, mostly in those with elevated TSH

Subclinical hypothyroidism

22 (7.6%), 14/8

Hypothyroidism

1 (0.3%)

Eliakim et al., 2006 [29]

Prospective cohort

196

Subclinical hypothyroidism

41 (20.9%), 20/21

No beneficial effects on body weight, body mass index, linear growth, and body lipids were found in treated obese subjects, suggesting that thyroid substitution is not necessary in most cases

Bhowmick et al., 2007 [23]

Retrospective case-control

308

AITD

5 (1.6%), 1/4

A higher prevalence of TSH elevation was observed in the obese group

Subclinical hypothyroidism

36 (11.7%), 14/22

Dekelbab et al., 2010 [35]

Retrospective case-control

191

AITD

6 (3.1%)

Mild elevation of TSH values in the absence of AITD is not uncommon in obese children, but no special characteristics was found

Subclinical hypothyroidism

20 (10.8%)

Grandone et al., 2010 [28]

Prospective cohort

938

Subclinical hypothyroidism

120 (20.8%), 58/62

A moderate elevation of TSH concentrations is frequent in obese children, it is not associated to metabolic risk factors, it is reversible after weight loss, and it should not be treated

Marras et al., 2010 [27]

Prospective cohort

468

Subclinical hypothyroidism

15 (3.2%), 6/9

An increased fT3 concentration is the most frequent abnormality. Serum fT3 and TSH correlate with BMI. Moderate weight loss frequently restores abnormalities

Ong et al., 2012 [134]

Prospective cohort

264

AITD/

hypothyroidism

NA

Childhood weight gain and childhood overweight conferred an increased susceptibility to later hypothyroidism and AITD, particularly in females

Ittermann et al., 2013 [44]

Retrospective case-control

563

Hypothyroidism

29 (5.1%)

Active and passive smoking may mediate the association between thyroid function and BMI in adolescents

Hyperthyroidism

4 (0.7%)

Marwaha et al., 2013 [24]

Retrospective cross-sectional

488

Subclinical hypothyroidism

48 (9.8%), 26/22

Serum fT3 and TSH were positively while fT4 was negatively associated with BMI in apparently healthy euthyroid children

Bouglè et al., 2014 [34]

Prospective cohort

528

Subclinical hypothyroidism

69 (13.1%)

Increased TSH may be predictive of a decrease in insulin resistance, fT4 was associated with a low metabolic risk. Changes in thyroid function could protect against the occurrence of obesity-associated metabolic diseases

Ghergherehchi et al., 2015 [25]

Retrospective case-control

190

AITD

28 (14.7%), 11/17

TSH and fT4 levels are increased in obese children, but the incidence of AITD is lower

Subclinical hypothyroidism

20 (10.7%)

Krause et al., 2015 [42]

Retrospective case-control

572

Subclinical hypothyroidism

28 (4.9%)

Paediatric obesity is associated with higher TSH and lower FT4 concentrations and with a greater prevalence of abnormally high TSH

Matusik et al., 2015 [41]

Prospective cohort

NA

Subclinical hypothyroidism

51, 20/31

In obese children with sHT dietary-behavioural management intervention contributed to reduction of body mass index, irrespective of levothyroxine use. Moderately elevated levels of TSH are a consequence rather than cause of overweight, and pharmacological treatment should be avoided

Garcia-Garcia et al., 2016 [38]

Retrospective cross-sectional

129

AITD

4 (5.6%)

Obese children and adolescents had higher levels of TSH, and among them the prevalence of AITD is higher

Subclinical hypothyroidism

11 (14.4%)

Dahl et al., 2018 [32]

Retrospective case-control

1796

Subclinical hypothyroidism

186 (10.4%), 121/142

The prevalence of SH was higher among overweight/obese study participants. TSH and fT4 are positively correlated with WHtR

Jin, 2018 [40]

Retrospective cross-sectional

111

Subclinical hypothyroidism

27 (24.3%)

SCH is common in obese children; TSH levels were linked with the lipid profile

Dursun et al., 2019 [31]

Retrospective cross-sectional

218

AITD

16 (7.3%), 13/3

Obese adolescents with non-autoimmune thyroiditis had a higher incidence of insulin resistance

Kumar et al., 2019 [45]

Prospective cohort

162

Hypothyroidism

51 (31.4%), 17/34

The addition of levothyroxine to the weight reduction program did not show beneficial effects on body weight, BMI, and thyroid profiles in obese children with isolated hyperthyrotropinaemia

Ruszała et al., 2019 [33]

Retrospective cross-sectional

100

Subclinical hypothyroidism

20 (20.9%), 7/13

Isolated increased TSH level is common in obese adolescents, there is no correlation between TSH, fT3, and fT4 levels and BMI SDS value. Autoimmune thyroiditis in obese adolescents is more common than in the general population.

Thiagarajan et al., 2019 [39]

Prospective cross-sectional

102

Hypothyroidism

15 (14.7%)

No correlation was found between fT4, TSH, and BMI

Özcabı et al., 2021 [37]

Retrospective cross-sectional

56

AITD, TPOAb

13 (23.2%)

An association between central adiposity and TgAb levels was found

AITD, TgAb

17 (30.4%)

Patel et al., 2021 [36]

Retrospective cross-sectional

404

Subclinical hypothyroidism

122 (30.2%)

Obesity-related subclinical hypothyroidism predisposes to increased non-alcoholic steatohepatitis independently of severity adiposity

Dündar et al., 2022 [26]

Retrospective cross-sectional

1130

Subclinical hypothyroidism

59 (5.2%), 25/34

Subclinical hypothyroidism can negatively affect the lipid and glucose profile in obese children

Di Sessa et al., 2023 [30]

Retrospective cross-sectional

844

Subclinical hypothyroidism

85 (10.1%), 27/58

Children with obesity and NAFLD presented increased risk of SCH, and vice versa

Table 2. Summary of clinical studies about thyroid dysfunctions and autoimmunity in obese adults

Author, date

Study design

Total obese patients

Thyropathy

Patients affected (%), male/female*

Outcome

Rimm et al., 1975 [63]

Retrospective cross-sectional

73532

Hypothyroidism

35950 (48.9%), 0/35950

Obesity is related with a higher risk of hypothyroidism and a decreased risk of Graves’ hyperthyroidism

Hyperthyroidism

35651 (48.5%), 0/35651

Szomstein et al., 2002 [94]

Retrospective cross-sectional

195

Hypothyroidism

14 (7.2%)

Article included for epidemiological data

Raftopoulos [90] et al., 2004

Retrospective cross-sectional

86

Subclinical hypothyroidism

9 (10.5%)

Article included for epidemiological data

Holm et al., 2005 [135]

Retrospective cohort

NA

NA

68, 0/68

Obesity was associated with a decreased risk of Graves’ hyperthyroidism

Knudsen et al., 2005 [136]

Retrospective cross-sectional

NA

NA

NA

Even slightly elevated serum TSH levels were associated with an increase in the occurrence of obesity

Moulin de Moraes et al., 2005 [50]

Retrospective cross-sectional

72

Subclinical hypothyroidism

18 (25.0%), 2/16

Article included for epidemiological data

Chikunguwo et al., 2007 [77]

Retrospective cross-sectional

86

Subclinical hypothyroidism

9 (10.5%)

Article included for epidemiological data

Asvold et al., 2009 [57]

Retrospective cross-sectional

27097

Subclinical hypothyroidism

1804 (6.7%), 451/1353

Hypothyroidism is associated with high BMI, both in current smokers and in never-smokers

Hypothyroidism

158 (0.6%), 21/137

Hyperthyroidism

574 (2.1%), 141/433

Gniuli et al., 2009 [80]

Retrospective cross-sectional

45

Subclinical hypothyroidism

11 (24.4%)

Article included for epidemiological data

Gopinath et al., 2010 [137]

Prospective cohort

NA

Subclinical hypothyroidism

1.9%

Obesity is a risk factor for SCH and overt hypothyroidism

Hypothyroidism

6.2%

Marzullo et al., 2010 [47]

Retrospective cross-sectional

165

AITD

18 (10.9%), 3/15

Obese patients had lower fT3 levels and fT4 levels, greater prevalence of hypothyroidism, and higher prevalence of TPOAb positivity

Hypothyroidism

17 (10.3%), 4/13

Somwaru et al., 2011 [138]

Retrospective cohort

NA

Hypothyroidism

1027

Higher BMI was independently associated with greater risk for overt hypothyroidism

Hemminki et al., 2012 [87]

Prospective cohort

29665

Hypothyroidism

83 (0.3%)

The risk of Hashimoto’s disease/hypothyroidism was significantly increased; a small but significant increase was also noted for the Graves’ disease/hyperthyroidism

Hyperthyroidism

54 (0.2%)

Sundaram et al., 2013 [92]

Retrospective cross-sectional

1221

Hypothyroidism

231 (18.9%)

Article included for epidemiological data

Agbaht et al., 2014 [70]

Retrospective cross-sectional

548

AITD

96 (17.5%)

Article included for epidemiological data

Hypothyroidism

123 (22.4%)

Article included for epidemiological data

Ruiz-Tovar et al., 2014 [81]

Retrospective cross-sectional

60

Subclinical hypothyroidism

10 (16.7%)

Article included for epidemiological data

Han et al., 2015 [58]

Retrospective cross-sectional

90 pregnant women

AITD

21 (23.3%), 0/21

Obesity was associated with increases in the odds of hypothyroidism and TPOAb positivity

Subclinical hypothyroidism

7 (7.8%), 0/7

Hypothyroidism

3 (3.3%), 0/3

Janssen et al., 2015 [52]

Retrospective cross-sectional

503

Subclinical hypothyroidism

61 (12.1%)

Article included for epidemiological data

Amouzegar et al., 2016 [139]

Prospective cohort

NA

NA

NA

Early diagnosis of SCH and hypothyroidism was significantly associated with obesity

Bedaiwy et al., 2017 [61]

Retrospective cross-sectional

105

Subclinical hypothyroidism

25 (23.8%), 0/25

Article included for epidemiological data

Răcătăianu et al., 2017 [72]

Retrospective cross-sectional

82

Hypothyroidism

12 (14.6%)

Article included for epidemiological data

Hyperthyroidism

1 (1.2%)

Article included for epidemiological data

AITD

27 (32.9%)

Article included for epidemiological data

Valdes et al., 2017 [75]

Retrospective cross-sectional

1193

Subclinical hypothyroidism

41 (3.4%)

SCH is more prevalent in obese and morbid obese population

Zendel et al., 2017 [84]

Retrospective cross-sectional

1823

Hypothyroidism

93 (5.1%), 8/85

Article included for epidemiological data

Milla Matute et al., 2018 [89]

Retrospective cross-sectional

1581

Hypothyroidism

35 (2.2%)

Article included for epidemiological data

Mousa et al., 2018 [69]

Retrospective cross-sectional

102

AITD

26 (25.5%)

Article included for epidemiological data

Ornaghi et al., 2018 [88]

Retrospective cohort

98 pregnant women

Hypothyroidism

17 (17.3%), 0/17

Obese patients with chronic hypertension showed a 2.4-fold increased risk of developing hypothyroidism during pregnancy versus normal BMI women

Pedro et al., 2018 [83]

Retrospective cross-sectional

1449

Hypothyroidism

106 (7.3%)

Article included for epidemiological data

Răcătăianu et al., 2018 [72]

Retrospective cohort study

158

Hypothyroidism

28 (17.7%)

Article included for epidemiological data

Hyperthyroidism

1 (0.6%)

Article included for epidemiological data

AITD

39 (24.7%)

Article included for epidemiological data

Rudnicki et al., 2018 [93]

Retrospective cross-sectional

1756

Hypothyroidism

90 (5.1%), 17/73

Article included for epidemiological data

Sami et al., 2018 [56]

Retrospective cross-sectional

1193

Subclinical hypothyroidism

19 (15.0%), 6/13

Subclinical hypothyroidism is highly prevalent in obese patients

Wang et al., 2018 [59]

Retrospective cross-sectional

310

AITD

33 (10.6%), 15/18

Obese females had higher risk of SCH than non-obese females. No association between obesity and hypothyroidism was observed in male participants

Subclinical hypothyroidism

37 (11.9%), 14/23

Hypothyroidism

39 (10.6%), 15/24

Zhang et al., 2018 [46]

Retrospective cross-sectional

534

Subclinical hypothyroidism

108 (20.2%), 0/108

Article included for epidemiological data

Abdelbaki et al., 2019 [53]

Retrospective cross-sectional

554

Subclinical hypothyroidism

72 (13.0%), 9/63

Article included for epidemiological data

Almunif et al., 2019 [79]

Retrospective cross-sectional

1480

Subclinical hypothyroidism

106 (7.2%)

Article included for epidemiological data

Hypothyroidism

160 (10.8%)

Article included for epidemiological data

Dambros Granzotto et al., 2019 [49]

Retrospective cross-sectional

215

Subclinical hypothyroidism

20 (9.3%), 6/14

Article included for epidemiological data

Nayak et al., 2019 [62]

Retrospective cross-sectional

175

Hypothyroidism

37 (21.1%), 0/37

Article included for epidemiological data

Neves et al, 2019 [78]

Retrospective cross-sectional

641

Subclinical hypothyroidism

11 (1.7%)

Article included for epidemiological data

SubHyper

4 (0.6%)

Article included for epidemiological data

Xia et al, 2019 [51]

Retrospective cross-sectional

101

AITD

12 (11.9%), 7/5

Article included for epidemiological data

Zhu et al., 2019 [48]

Retrospective cross-sectional

88

Subclinical hypothyroidism

28 (31.8%), 11/17

Article included for epidemiological data

Khan et al., 2020 [91]

Retrospective cross-sectional

883

Hypothyroidism

93 (10.5%), 12/81

Article included for epidemiological data

Makwane et al., 2020 [86]

Retrospective cross-sectional

31

Hypothyroidism

6 (19.0%)

No significant relationship between thyroid hormones and BMI was found in normal or in obese groups

Hyperthyroidism

1 (3.0%)

Wu et al., 2020 [74]

Retrospective cross-sectional

NA

AITD

1041

Obesity was positively correlated with the prevalence of positive thyroid autoantibodies in euthyroid subjects

Mahdavi et al., 2021 [55]

Retrospective case-control

1144

AITD

198 (17.3%), 33/165

Higher prevalence of hypothyroidism and TPOAb positivity among obese patients

Subclinical hypothyroidism

87 (7.6%), 9/78

Hypothyroidism

46 (4.0%), 5/41

Subclinical hyperthyroidism

31 (2.7%), 11/20

Hyperthyroidism

17 (1.5%), 4/13

Yin et al., 2021 [68]

Retrospective case-control

280

AITD

80 (28.5%)

No significant associations between obesity and TGAb levels. Prevalence of SCH was higher in obese patients, rather than overweight and normal ones, whereas there were no differences in prevalence of hypothyroidism, hyperthyroidism, and subclinical hyperthyroidism between the three groups

Subclinical hypothyroidism

56 (20,0%)

Hypothyroidism

3 (1.0%)

Subclinical hyperthyroidism

1 (0.3%)

Hyperthyroidism

1 (0.3%)

Agbaht et al., 2022 [70]

Retrospective cohort study

285

Hypothyroidism

109 (38.2%)

Article included for epidemiological data

AITD

64 (22.5%)

Article included for epidemiological data

Dewantoro et al., 2022 [82]

Retrospective cross-sectional

887

Hypothyroidism

49 (5.5%)

Article included for epidemiological data

Fierabracci et al., 2022 [64]

Retrospective cross-sectional

749

AITD

135 (18.0%)

Autoimmune thyroiditis is highly prevalent in patients with obesity. TgAb may be associated with hypothyroidism in the absence of TPOAb

Subclinical hypothyroidism

153 (20.4%)

Hypothyroidism

104 (13.8%)

Hyperthyroidism

10 (1.3%)

Walczak et al., 2022 [54]

Retrospective cross-sectional

181

AITD

57 (31.4%), 6/51

BMI is significantly higher in patients with high normal TSH

Zhao et al., 2022 [140]

Prospective cross sectional

764

Subclinical hypothyroidism

66 (8.6%)

Article included for epidemiological data

Yan et al., 2022 [66]

Retrospective cross-sectional

289

AITD

58 (20.7%)

No significant associations between obesity and TPOAb levels. Among patients with positive TgAb and TPOAb, SCH prevalence was significantly higher in obese subjects

Subclinical hypothyroidism

27 (9.3%)

Yang et al., 2022 [67]

Retrospective case-control

3697

AITD

870 (23.0%), 358/512

Obesity was a significant independent risk factor for hypothyroidism in males, whereas in females it was not

Sharma et al., 2022 [60]

Retrospective case-control

15

AITD

7 (46.7%), 0/7

Article included for epidemiological data

Alourfi et al., 2023 [141]

Retrospective cross sectional

292

Subclinical hypothyroidism

13 (4.5%)

Article included for epidemiological data

Kang et al., 2023 [76]

Retrospective cross-sectional

51

Subclinical hypothyroidism

42 (82.4%)

Article included for epidemiological data

Thyroid disease in obese children

A total of 9784 obese children were evaluated and enrolled in this review. Among them, 1174 (12%) children (mean age 10.9 ± 1.4 years) showed thyroid autoantibodies and/or hypo-hyperthyroidism (Tab. 1 and 3). Based on the available data, no difference in sex distribution was observed among obese children with (415/343 F/M) or without thyroid dysfunctions (3452/3288, F/M) (p = 0.065) [22, 23], whereas a significant difference in age was identified (10.9 ± 1.2 vs. 11.0 ± 0.4 years, respectively; p < 0.001) [26, 28, 29, 31, 34–36].

Table 3. Summary of data about obese children and adults diagnosed with thyropathies

Thyropathy

Patients affected (%)

Male/female (OR F/M)*

Children (n = 9784)

Autoimmune thyroiditis

86 (0.9%)

1/4 (2.5)

Subclinical hypothyroidism

988 (10.1%)

64/81 (1.4)

Overt hypothyroidism

96 (1.0%)

17/34

Hyperthyroidism

4 (0.1%)

NA

Adults (n = 125,958)

Autoimmune thyroiditis

1741 (1.4%)

415/794 (1.5)

Subclinical hypothyroidism

2752 (2.2%)

480/1474 (1.5)

Overt hypothyroidism

37600 (29.9%)

45/232 (2.5)

Subclinical hyperthyroidism

36 (0.03%)

11/20 (0.8)

Overt hyperthyroidism

36256 (28.8%)

145/36097 (39.3)

Autoimmune thyroiditis was found in 86/9784 children (0.9%) [22, 23, 25, 31, 35, 37, 38], whereas thyroid disfunction was found in 1088 (11%) [22–44]. In more detail, 988 (10.1%) children showed subclinical hypothyroidism [22–30, 32–36, 38, 39], 96 (1%) overt hypothyroidism [22, 39, 44, 45], and 4 (0.04%) hyperthyroidism [44].

Data on sex distribution within each thyroid disease category were only available for a few articles, mainly regarding subclinical hypothyroidism [22–30, 32, 33, 41, 45], which showed that 439/788 (55.7%) obese children suffering from this condition were female [22–30, 32, 33, 41]. In addition, the onset of this condition was observed during puberty for 179/788 (23%) children: 113 (63%) experienced it in prepubertal age [26, 28].

Conversely, Dursun et al. showed, in a small number of patients, the presence of anti-peroxidase and/or thyroglobulin antibodies mainly post puberty (81%) rather than in prepubertal age [31].

Regarding the possible differences in the prevalence of thyroid antibodies between obese and non-obese patients, four studies evaluated 2317 subjects [22, 23, 37, 38]. The data revealed a significantly higher prevalence among obese compared to non-obese children (7% vs. 3%, respectively, p < 0.001). Nine studies, for a total of 9667 subjects, investigated the prevalence of subclinical hypothyroidism; again, the prevalence was higher in obese as compared to non-obese children (10% vs. 6%, p < 0.001) [22–25, 27, 32, 35, 38, 40, 42]. Only one study, conducted in a large cohort of children (6165 subjects), investigated the prevalence of overt hypothyroidism and hyperthyroidism. An equal distribution was found between obese and non-obese children (5% vs. 7%, respectively, p = 0.101), whereas hyperthyroidism was associated more with non-obese subjects (1% vs. 3%, respectively, p < 0.001) [44].

Thyroid disease in obese adults

A total of 125,953 obese adults were evaluated and included in this review. Among them, 78,385 (62.2%) patients (43.2 ± 9.1 years old) showed AITDs and/or hypo-hyperthyroidism (Tab. 2 and 3). The available data revealed significant differences in age, BMI, and sex distribution between obese patients with and without thyroid diseases. In detail, those with thyroid diseases were younger (35.3 ± 6.8 vs. 41.0 ± 1.9 years, p < 0.001) [46–53], heavier (BMI: 39.4 ± 6.3 vs. 36.1 ± 2.3 kg/m2, p < 0.001) [46–49, 51, 52], and more frequently female (13% vs. 8%, p < 0.001) [46–51, 53–62]. These last data were obtained excluding the study by Rimm et al., which enrolled only female patients [63].

Autoimmune thyroiditis was found in 1741/125,953 (1.4%) patients [47, 51, 55, 58–60, 64–47] whereas thyroid dysfunction was found in 76,644 (60.9%) patients. In detail, 2752 (2.2%) subjects showed subclinical hypothyroidism [46, 48–50, 52, 53, 55–59, 61, 64, 66, 69, 75–81], 37,600 (29.9%) overt hypothyroidism [47, 55, 57–59, 62–64, 68, 70–73, 79, 82–94], 36 (0.03%) subclinical hyperthyroidism [55, 68, 78], and 36,256 (28.8%) overt hyperthyroidism [55, 57, 63, 64, 68, 72, 73, 86, 87]. All these conditions were significantly associated with females (Fig. 3). The BMI values according to the patients’ thyroid status are reported in Figure 4. In detail, patients with AITDs showed a BMI of 34.6 ± 7.0 kg/m2 [47, 51, 55, 60, 64–68], those with subclinical hypothyroidism had a BMI of 39.3 ± 7.0 kg/m2 [46, 48–50, 52, 53, 55, 56, 66, 68, 80], and those with overt hypothyroidism had a BMI of 40.9 ± 8.2 kg/m2 [47, 55, 64, 68, 71, 82, 84, 86, 88, 90, 91, 93]. Patients affected by subclinical hyperthyroidism showed a BMI of 31.1 ± 0.6 kg/m2 [55, 68] and those affected by overt hyperthyroidism a BMI of 34.1 ± 4.2 kg/m2 [55, 64, 68, 86].

179799.png
Figure 3. Sex distribution according to adult patients’ thyroid conditions
179813.png
Figure 4. Body mass index (BMI) values related to adult patients’ thyroid condition

Nine studies, including 74,662 patients, compared the prevalence of thyroid autoantibodies in obese compared to non-obese subjects [47, 55, 58–60, 66, 68, 69, 74]. The prevalence was superimposable: 15% of obese and 14% of non-obese patients showed thyroid autoimmunity (p = 0.178). Eight studies, including a total of 23,032 subjects, investigated the prevalence of subclinical hypothyroidism, again comparing obese and non-obese subjects [55, 58, 59, 61, 66, 66, 68, 75, 76], and again no difference was observed among the two groups (10% vs. 9%, respectively, p = 0.296). By contrast, among 16,605 patients, overt hypothyroidism was significantly more frequent in obese patients (7% vs. 3%, respectively, p < 0.005) [47, 55, 58, 59, 62, 68, 86, 88]. Sub-clinical or overt hyperthyroidism was evaluated in 6162 patients: no difference was observed between obese and non-obese subjects (2% vs. 3%, respectively, p = 0.067) and (1% vs. 2%, respectively, p = 0.150) [55, 68, 86].

Discussion

Thyroid impairment and obesity are among the most frequent conditions in the general population [1, 4–9]. Although available data have uncovered an intriguing relationship between these two conditions, the chicken-egg conundrum has not yet been completely solved. Considering the large set of data published on obese adults and obese children, we performed a systematic review with the aim of improving knowledge in this field.

With reference to obese children, thyroid diseases were found to be equally distributed among female and male patients. The large set of data included subjects with a mean age of 10.9 ± 1.4 years, thus mostly prepubertal, and significantly younger than those without thyroid impairments (11.0 ± 0.4 years, p < 0.001). In addition, the most frequent finding was subclinical hypothyroidism, identified in 988/9784 (10.1%) children. Grandone et al. reported that the mean age is lower for obese children with higher thyroid-stimulating hormone (TSH) levels [28]. Moreover, some authors described a spontaneous reduction in TSH with increasing age both in obese and in non-obese children [95–97]. In addition, cross-sectional and longitudinal studies demonstrated a positive correlation between obesity and weight status [22, 23, 27, 28, 41, 98–102]. Isolated hyperthyrotropinaemia is commonly reported in obese children. In the paediatric population, risk groups for this condition include children with diabetes mellitus and those with Down syndrome [29]. Elevated TSH levels in childhood obesity may be a direct effect of nutrition or an effect of leptin (which is usually elevated in obesity) on the production of hypothalamic thyrotropin-releasing hormone (TRH), which stimulates pituitary TSH secretion [29, 103–105]. In addition, Burman et al. suggest the presence of thyroid hormone resistance at the pituitary level [106], whereas D’Adamo et al. believed it may be caused by an increase in oxidative stress [107]. Even without any certain cause, it is reasonable to assume that during puberty there is a sexually dimorphic effect with subtle alterations in the hypothalamic-pituitary-thyroid axis [96]. To treat or not to treat patients with hyperthyrotropinaemia with levothyroxine is still debated, even though it is common and accepted practice to treat patients who test negative for thyroid antibodies and display clinical signs or symptoms of hypothyroidism. In obese children, many authors suggest that pharmacological treatment should be avoided, showing that changes in diet, lifestyle, and physical activity lead to a spontaneous restoration of normal TSH values and reduction of body mass index [27–29, 41]. In particular, Eliakim et al. concluded that there are no beneficial effects on body weight, body mass index, linear growth, and body lipids in treated subjects [29].

Thyroid antibody tests were carried out in 211 children with subclinical hypothyroidism, with just 13% testing positive [22, 23, 25, 29, 33, 34], which would appear to support the notion of isolated hyperthyrotropinaemia.

Dursun et al. compared the positivity for thyroid autoantibodies between prepubertal and pubertal age, finding a prevalence in pubertal age (81%) [31]. These data were recently confirmed by Calcaterra et al. [108]. These results support the idea that sexual hormonal changes during puberty could play a fundamental role in immune function [109–111]. In obese subjects, this seems to amplify the obesity-related, chronic, low-grade inflammation process, which could initiate the autoimmune cascade and consequently affect the autoimmunological response [112]. It is widely accepted that white adipose tissue is a significant source of cytokines, chemokines, and adipokines, such as interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-a) [113], and leptin, a hormone well-known for its role in inflammatory processes and autoimmunity [112]. Indeed, leptin, a 16-kDa polypeptide hormone, appears to exercise several functions in metabolism [114], but it is also implicated in innate and acquired immunity by stimulating the proliferation of monocytes and the production of pro-inflammatory cytokines, such as IL-6, IL-12, and TNF-a [115]. In addition, it promotes an increase in naive T cells, a decrease in T regulatory cells (Tregs), and the differentiation of memory T cells toward T helper 1 (Th1) suppressing T helper 2 (Th2), resulting in an increase of pro-inflammatory cytokines [115]. Therefore, leptin regulates immune response by promoting a pro-inflammatory profile and facilitating the onset of autoimmune disorders, such as AITDs, in the context of obesity [20].

By contrast, greater attention should be paid to obese children with AITDs, insofar as there is the non-negligible risk of progression from subclinical to overt hypothyroidism, indicating that levothyroxine replacement therapy should be started early [116–118].

In terms of obese adults, thyroid diseases are more frequently associated with women, as in the general population [4, 8]. Thyroid impairments occur five times more frequently in obese adults than in obese children. This could be due, firstly, to sexual hormones, which play an unquestionable role in autoimmune regulation. It is well known that male sex protects against the development of autoimmune disease, and it is likely that this is due to sexual hormones and the Y chromosome [119, 120]. On the other hand, women have a marked preponderance of many autoimmune diseases, and this is likely due, at least in part, to the stronger female system. Oestrogen has numerous effects on the regulation of autoimmune cascade, in particular enhancing Th1 responses [121]. Second, it is believed that longer exposure to obesity triggers thyroid diseases di per se [122–128]. In agreement, we showed that adults affected by thyroid diseases had a higher BMI, with one-third showing overt-hypothyroidism. We cannot, however, state that the obesity is caused by hypothyroidism; we are back to the chicken and the egg. Sami et al. give us a Giano Bifronte (two-sided) explanation: “on one side, lack of thyroid hormone leads to weight gain culminating in overt obesity, which in turn predisposes patients to develop autoimmune hypothyroidism. On the other side, raised TSH in obese patients does not show hypothyroidism but it is the result of weight gain rather than its cause” [56].

However, this review clearly showed a direct correlation between BMI and thyroid function (Fig. 4): AITD patients in spontaneous euthyroidism showed a BMI that was midway between hyperthyroid and hypothyroid, as widely expected. Indeed, as Giano teaches us, among a large series of patients, hypothyroidism was more frequent in obese than in non-obese subjects (p < 0.005), even though the prevalence of autoimmunity was superimposable (p = 0.178). According to the data collected, we can assume that the main cause of the rise in TSH levels in adults is progressive thyroid impairment. This is not surprising. On one side, it is reported that pro-inflammatory cytokines can inhibit sodium/iodide symporter (NIS) mRNA expression and iodide uptake [116, 129, 130], leading to a reduction in thyroid function. On the other side, the long-standing inflammation can lead to organ damage. However, these data are in contrast with a recent review by Gajda et al. The Authors described a two-fold higher prevalence of hyperthyrotropinaemia among obese patients, even if the data were gathered from a small number of articles and patients [131].

Differently from that reported for obese children, in adult patients, treatment with levothyroxine should also always be considered for mild hypothyroidism, in line with current guidelines [132]. The Endocrine Work-up in Obesity recommended in any case that hyperthyrotropinaemia should not be treated with the aim of reducing body weight [133].

The major limitation of the present review is the lack of some data which are, unfortunately, often not provided by the authors when requested. However, the large set of patients, the careful selection procedure, and detailed analysis of data strengthen these results.

In conclusion, we summarized the available studies on the association between obesity and thyroid disorders in children and in adults. There is an undeniable relationship between obesity and thyroid impairments, mainly caused by the state of obesity. Isolated hyperthyrotropinaemia is frequently seen in obese children, often followed by spontaneous resolution. BMI appears to be correlated with TSH levels in obese adults. Hyperthyrotropinaemia should never be treated in children and in adults with the aim of reducing body weight.

Authors’ contributions

F.B.: review of literature, writing original manuscript; E.G.: review of literature, formal analysis, writing original manuscript; R.D.: review of literature, writing review and editing; F.D.: review of literature, formal analysis, writing review and editing; G.P.: conceptualization and methodology, writing review and editing; I.P.: formal analysis, supervision, validation, and visualization; F.B.: conceptualization and methodology, supervision, validation, and visualization; C.C.: project administration, conceptualization and methodology, writing review and editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This review did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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