Investigations of Thyroid Hormones and Antibodies

in Obesity: Leptin Levels Are Associated with Thyroid
Autoimmunity Independent of Bioanthropometric,
Hormonal, and Weight-Related Determinants
Paolo Marzullo, Alessandro Minocci, Maria Antonella Tagliaferri,
Gabriele Guzzaloni, Annamaria Di Blasio, Clotilde De Medici, Gianluca Aimaretti,
and Antonio Liuzzi
Department of Clinical and Molecular Medicine (P.M., G.A.), Universita` del Piemonte Orientale
“A. Avogadro,” 28100 Novara, Italy; and Division of General Medicine (P.M., M.A.T., G.G., A.L.),
Metabolic Rehabilitation (A.M.), Laboratory of Molecular Biology (A.D.), and Diagnostic Laboratory
(C.D.), Instituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano, Ospedale S.
Giuseppe, 28921 Verbania, Italy
Objectives: Obesity can alter the thyroid hormone status as a result of a dysregulated endocrine
loop between the hypothalamo-pituitary unit and adipose tissue. The adipocytokine leptin has
beenshowntopromoteautoimmunity; hence, weaimedtoclarify whether leptinexcess of obesity
could increase the susceptibility to develop autoimmune thyroid disease (AITD).
Study design: This cross-sectional study was performed in a tertiary care center.
Methods: Freethyroidhormones, TSH, thyroglobulin, andantithyroidantibodies levels weretestedin
165 obese and 118 lean subjects. Results were plotted against variables related to body compo-
sition, leptin levels, glucose homeostasis, energy expenditure, and pattern of weight accrual.
Results: Compared with controls, obese patients had lower free T
3
levels and free T
4
levels (P Ͻ
0.01), greater prevalence of hypothyroidism (P Ͻ 0.05), and higher commonness of antithyroid
antibodies (P Ͻ 0.05). As a marker of AITD, thyroid peroxidase antibodies were more frequent in
theobesegroup(PϽ0.01). Correlationanalysis showedthat leptinlevels wereassociatedwithAITD
(P Ͻ 0.01) independent of bioanthropometric variables. Multiple logistic regression analysis in
pooled groups identified female sex and leptin as significant predictors of AITD.
Conclusions: Obesity increases the susceptibility to harbor AITD with an emerging role for leptin
as a peripheral determinant, which needs to be confirmed in future investigations. (J Clin Endo-
crinol Metab 95: 3965–3972, 2010)
A
utoimmune thyroid diseases (AITDs) are polygenic
disorders resulting from a combination of genetic
predisposition in conjunction with environmental factors.
Genetic susceptibility is related to diverse loci expressing
an epistasic interaction and additive effects, one single
gene beingneither sufficient alone nor necessarytoexplain
the disease (1). Like human leukocyte antigen-DR, other
non-human leukocyte antigen loci have been identified as
associated to a higher risk of developing AITD, such as
cytotoxic Tlymphocyte antigen 4, CD40, protein tyrosine
phosphatase N22, thyroglobulin (Tg), and TSH receptor
(TSH-R) genes (2). Experimental and epidemiology stud-
ies demonstratedthe critical role of environmental factors,
such as iodine, drugs, infectious organisms, and stress.
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2010 by The Endocrine Society
doi: 10.1210/jc.2009-2798 Received December 30, 2009. Accepted May 11, 2010.
First Published Online June 9, 2010
For editorial see page 3614
Abbreviations: AITD, Autoimmune thyroid disease; BMI, body mass index; CV, coefficient
of variation; FT
3
, free T
3
; FT
4
, free T
4
; HOMA-IR, homeostatic model of insulin resistance;
REE, resting energy expenditure; Tg, thyroglobulin; TgAb, thyroglobulin antibody; TPOAb,
thyroid peroxidase antibody; TSH-R, TSH receptor; TSH-RAb, TSH receptor antibody.
O R I G I N A L A R T I C L E
E n d o c r i n e R e s e a r c h
J Clin Endocrinol Metab, August 2010, 95(8):3965–3972 jcem.endojournals.org 3965
Particularly, high iodide intake accelerates autoimmune
thyroiditis in autoimmune-prone animal models (3), as
well as in individuals undergoing normal to high prophy-
lactic iodine intake (4). No main pathogenic determinants
have been isolated so far, but internalization of Tg anti-
body (TgAb) complexes or enhanced iodination of Tg in
extrathyroidal antigen-presenting cells have been associ-
ated with the pathogenesis of thyroiditis (5). Recently,
reviewed data disclosed that lymphocytic infiltration of
the thyroid gland is present in up to 40% of healthy
women, the prevalence of anti-TgAb and thyroid perox-
idase antibodies (TPOAb) inthe general populationis 10–
12%, whereas a suggestive ultrasound pattern may pre-
cede anti-TPOAbpositivity inAITD, andTPOAbmay not
be detected in more than 20% of individuals with ultra-
sound evidence of thyroid autoimmunity (6).
Little is known on the effects of obesity on AITD risk,
despite several evidences linking obesity to thyroid hor-
mones. Thyroid disorders may, in fact, impact body
weight in multiple ways (7), and hypothyroidism is as-
sumed to contribute to weight accrual via altered meta-
bolic efficiency (8). An association exists between TSH
levels and body mass index (BMI) independent of hypo-
thyroidism(9), with visceral adiposity playing a dominant
role (10). In obesity, TSH secretion is enhanced, likely as
a result of an endocrine loop relating the hypotalamo-
pituitary unit to the adipose tissue (11). Leptin, the main
product of the adipose tissue, has been experimentally
shown to stimulate pituitary TSHsecretion (12), but it has
also emerged as a potential regulator of several immune
processes involving the regulation of Th-1 lymphocyte
subsets (13).
This study aimed to explore the hypothesis that obesity
may increase the susceptibility to develop AITD through
a loop that involves leptin. To this end, we analyzed the
prevalence and characteristics of thyroid autoimmunity in
a population of obese men and premenopausal obese
women in relation to leptin levels and tested the associa-
tion between multiple weight-related variables and the oc-
currence of thyroid autoimmunity.
Patients and Methods
The study population consisted of 168 consecutive obese pa-
tients (68 males, age 35.8 Ϯ 9.7 yr, BMI of 43 Ϯ 8.1 kg/m
2
)
referred to our institution for workup of obesity. As controls,
134 age- and sex-matched subjects with normal BMI were se-
lected among the hospital employees (51 males, age 35.3 Ϯ 7.9
yr, BMI of 22.5 Ϯ2.6 kg/m
2
). In either group, exclusion criteria
comprised any prediagnosed thyroid or autoimmune disorder,
previous lithium or amiodarone medication, neck irradiation,
chronic steroid treatment, menopause, and age above 50 yr. No
patient had been prescribed hypocaloric diets or therapies for
weight control for at least 3 months before admission, and body
weight was stable for the same period. All subjects were enrolled
after written consent and approval by the Institution Ethic Com-
mittee. Hypothyroidism was classified as subclinical if TSH lev-
els were above the internal cutoff limits for obese patients (and
Ͻ10 mU/liter) with normal free thyroid hormones levels and
overt in the presence of elevated TSHlevels with reduced free T
4
(FT
4
) and/or free T
3
(FT
3
) levels. In obesity, the TSHcutoff limit
was 4.38 mU/ml, a value that reflected the mean Ϯ2 SD (1.96 Ϯ
1.21 mU/ml) obtained previously in a series of 114 obese pa-
tients with normal thyroid function as assessed by careful
clinical and laboratory estimation, i.e. no history of thyroid
diseases, normal FT
4
and FT
3
values, absence of antithyroid
antibodies and TSH receptor antibody (TSH-RAb), and nor-
mal ultrasound picture (14).
Body measurements
All subjects underwent body measurements wearing light un-
derwear, in fasting conditions after voiding. Weight and height
were measured to the nearest 0.1 kg and 0.1 cm, respectively.
BMI was expressed as weight (kilograms)/height (centimeters
2
).
Obesity was defined for any BMI over 30 kg/m
2
. Waist circum-
ference was measuredmidwaybetweenthe lowest ribandthe top
of the iliac crest after gentle expiration; hip was measured as the
greatest circumference around the nates. Anthropometric data
were expressed as the mean of two measurements. Fat mass and
free fat mass, expressed as percentage of total body mass, were
assessedby bio-impedance analysis (101/S; Akern, Firenze, Italy)
the morning after overnight fasting and after voiding. The two
vector components of impedance (i.e. resistance and reactance)
were obtained by single measurements; before each testing ses-
sion, the external calibration of the instrument was checked with
a calibration circuit of known impedance value. The mean co-
efficient of variation was 1%for within-day and 3%for weekly
intraindividual measurements in the steady-state condition in
either site and 2% for interoperator variability. Resting energy
expenditure (REE) (in kilocalories per 24 h) was determined in
a thermoregulated room (22–24 C) by computed open-circuit
indirect calorimetry, measuring resting oxygen uptake and rest-
ing carbon dioxide production by a ventilated canopy (Sensor-
medics, Milan, Italy) at 1-min intervals for 30 min and expressed
as 24 h value. Predicted REE was calculated by the Harris–Bene-
dict formula (15) and allowed to test for metabolic efficiency.
Insulin resistance was calculated by the homeostatic model of
insulinresistance (HOMA-IR) indexusingthe formuladescribed
by Matthews et al. (16): insulin (␮U/m) ϫ[glucose (mmol/liter)/
22.5]. A HOMA-IR value greater than 2.0 was considered in-
dicative of insulin resistance, as obtained in a sample of the Ital-
ian population (17).
Body weight
Individual patterns of body weight change were assessed
through a standardized interview, to determine the potential ef-
fect of weight variations on thyroid profile. Ascore was assigned
as follows: 1, childhood- or juvenile-onset obesity; 2, childhood-
or juvenile-onset obesity with less than two episodes of weight
loss of at least 10%; 3, adulthood-onset obesity; 4, adulthood-
onset obesity with less than two episodes of significant weight
loss; 5, weight-cycling syndrome (more than three episodes of
significant weight loss). Other evaluated variables included du-
ration of obesity, number of pregnancies, and previous use of
weight-control medications.
3966 Marzullo et al. Thyroid Autoimmunity and Leptin in Obesity J Clin Endocrinol Metab, August 2010, 95(8):3965–3972
Laboratory
Undiluted serum samples were assayed for FT
3
, FT
4
, TSH,
Tg, TPOAb, TgAb, and TSH-RAb using an automated chemi-
luminescence assay system (Immulite 2000; DPC, Los Angeles,
CA). The principle of the methodis atwo-site, solid-phase chemi-
luminescent immunometric assay or competitive immunoassay.
Normal values were as follows: FT
3
, 1.8–4.2 pg/liter (pg/liter ϫ
1.536 ϭ pmol/liter); FT
4
, 8.0–19.0 pg/liter (pg/liter ϫ 12.87 ϭ
pmol/liter); TSH, 0.4–4 mU/liter; Tg, 5–55 ␮g/liter (␮g/liter ϫ
1.515 ϭ pmol/liter); TPOAb, less than 35 IU/liter; TgAb, less
than 40 IU/liter; and TSH-RAb, less than 1.5 IU/liter. Serum
leptin levels were measured by commercial Linco RIA(Linco, St.
Louis, MO) having detection limit of 0.15 ␮g/liter, intraassay
coefficients of variation (CVs) of 2.2% at 6 ␮g/liter, 2.7% at 25
␮g/liter, and 5.9% at 62.8 ␮g/liter and interassay CVs of 4.3, 4,
and 6.9% at the concentration of 5.1, 21, and 56.2 ␮g/liter,
respectively. Insulinlevels were measuredby Immunite 2000(for
conversion, ␮U/ml ϫ 7.175 ϭ pmol/liter). Glucose, total cho-
lesterol (CHO), high-density lipoprotein-CHO, and triglycer-
ides were measured by enzymatic methods (Roche Molecular
Biochemicals, Mannheim, Germany). Ultrasensitive C-reactive
protein was measured by CRP (latex) HS Roche kit, having
sensitivity of 0.003 mg/dl, intraassay and interassay CVs of
2.51–5.35 and 4.25–5.79%, respectively, as reported by the
manufacturer.
Statistical analysis
All data are expressed as mean Ϯ SD. Differences between
obese patients and controls were calculated by Mann-Whitney
test. Two-way ANOVA was used to test for main effects of
AITD, hypothyroidism, and the interaction of both. Correlation
analyses were calculated with the Spearman’s coefficient. Logis-
tic regression analysis was used to test the association of multiple
variables with AITD. For significance, P Ͻ0.05 was considered
of statistical value. All the analyses were performedwiththe SPSS
11.0 (SPSS, Chicago, IL).
Results
Anthropometric and biochemical data are summarized
in Table 1. Atotal of 165 obese and 118 lean subjects had
full dataset and were used for comparative purposes.
Obese patients had nonsignificantly higher TSH with
lower FT
3
(P Ͻ 0.001) and FT
4
(P Ͻ 0.0001) levels than
lean subjects (Fig. 1). Elevated TSH levels were docu-
mented in 17 obese and five lean subjects (10.3 vs. 4.2%;

2
ϭ3.53; P ϭ0.06): hypothyroidism was overt in seven
obese andnocontrol (␹
2
ϭ5.39; PϽ0.05) andsubclinical
in 10 obese and 5 controls. Thyroid autoantibodies were
found in 39 obese and 15 controls (23.6 vs. 12.7%; ␹
2
ϭ
5.31; P Ͻ0.05), as follows: TPOAb in 28 obese and nine
controls (16.9 vs. 7.6%; ␹
2
ϭ5.28; P Ͻ0.01); TgAb in 25
obese and seven controls (13.9 vs. 5.9%; ␹
2
ϭ 4.75; P Ͻ
0.05); both TPOAb and TgAb in 17 obese and four con-
trols (10.3 vs. 3.3%; ␹
2
ϭ4.78; P Ͻ0.05); and TSH-RAb
in six obese and three controls (3.6 vs. 2.5%). In autoan-
tibody-negative subgroups, TSH was increased in eight
obese andfive leanindividuals (5.9vs. 4.7%). Adifference
was observed in REEvalues between obese and non-obese
subjects (Fig. 2).
Within the obese group, 114 of 165 patients (69%)
were severely obese (i.e. BMI Ͼ40 kg/m
2
). AITDpatients
(i.e. positive TPOAb) were mostlyseverelyobese (68%; ␹
2
ϭ
5.04; P Ͻ 0.05) with nonsignificantly higher TSH levels
than the AITD-negative counterparts (6.2 Ϯ9.2 vs. 1.9 Ϯ
1.3 mU/liter). TSH levels were increased in 10 AITD pa-
tients. The effect of AITD and hypothyroidism on total
and low-density lipoprotein cholesterol, as well as REE
TABLE 1. Summary data obtained in the study groups
Parameters Obese group (n ؍ 165) Control group (n ؍ 118) P
Age (yr) 35.7 Ϯ 9.6 (34) 35.3 Ϯ 7.9 (34) NS
Sex (male/female) 65/100 40/78 NS
BMI (kg/m
2
) 42.9 Ϯ 8.1 (42) 22.5 Ϯ 2.6 (23) 0.0001
FM (%) 45.5 Ϯ 6.9 (46) 24.9 Ϯ 6.5 (25) 0.0001
LM (%) 54.4 Ϯ 7 (54) 75.1 Ϯ 6.5 (75) 0.0001
REE (kcal/d) 2061 Ϯ 438 (2016) 1568 Ϯ 250 (1578) 0.0001
TSH (mU/liter) 2.7 Ϯ 4.5 (1.8) 1.9 Ϯ 1.1 (1.7) NS
FT
3
(pg/ml) 2.8 Ϯ 0.8 (2.7) 3.1 Ϯ 0.6 (3) 0.01
FT
4
(pg/ml) 11.7 Ϯ 2.2 (11.7) 12.7 Ϯ 2.1 (12.4) 0.0001
Tg (␮g/liter) 35.2 Ϯ 94.4 (17) 20.2 Ϯ 19.1 (14) NS
TPOAb (IU/ml) 98.6 Ϯ 252.2 (10) 23.4 Ϯ 77 (0) 0.01
TgAb (IU/ml) 101.2 Ϯ 412.4 (20) 10 Ϯ 45 (0) 0.0001
TSH-RAb (IU/liter) 0.5 Ϯ 0.7 (0.5) 0.5 Ϯ 0.4 (0) NS
HOMA-IR 3.6 Ϯ 2.3 (3.05) 1.9 Ϯ 1.4 (1.6) 0.0001
Leptin (␮g/liter) 34.3 Ϯ 16 (34) 9.5 Ϯ 8.9 (7) 0.0001
C-reactive protein (␮g/liter) 0.98 Ϯ 0.96 (0.75) 0.19 Ϯ 0.31 (0.1) 0.0001
Total CHO (mg/dl) 201.3 Ϯ 35.8 (199) 196.8 Ϯ 36.8 (194) NS
HDL-CHO (mg/dl) 46.4 Ϯ 14.5 (44) 63.5 Ϯ 16.9 (62) 0.0001
LDL-CHO (mg/dl) 134.8 Ϯ 33.3 (134) 129.1 Ϯ 78.1 (119.5) 0.01
Triglycerides (mg/dl) 162.8 Ϯ 116.1 (136) 94.4 Ϯ 47.4 (80) 0.0001
Data are indicated as mean Ϯ SD with median values in parentheses. Significance is calculated by Mann-Whitney test. FM, Fat body mass; LM, lean
body mass; CRP, C-reactive protein; HDL-CHO, high-density lipoprotein cholesterol; LDL-CHO, low-density lipoprotein cholesterol.
J Clin Endocrinol Metab, August 2010, 95(8):3965–3972 jcem.endojournals.org 3967
was significant (Table 2). Leptin levels were higher in
AITD-positive obese patients (42.8Ϯ14.6vs. 32.5Ϯ15.9
␮g/liter; P Ͻ 0.01) (Fig. 3), with a greater prevalence of
AITDoccurring among patients having their leptin above
a median of 33.8 ␮g/liter (24 vs. 8.6%; ␹
2
ϭ 6.87; P Ͻ
0.01). Spearman’s analysis documentedanassociationbe-
tween AITDand leptin (␳ ϭ0.26; P Ͻ0.001) that was, by
logistic regression, independent of fat mass and BMI (P Ͻ
0.001). Additionally, AITDwas correlated with TSH(␳ ϭ
0.42; P Ͻ0.0001) and FT
4
levels (␳ ϭϪ0.22; P Ͻ0.01),
female sex (␳ ϭ 0.25; P Ͻ 0.001), and REE (␳ ϭ Ϫ0.20;
P Ͻ0.05). Neither weight at birth, duration of obesity,
nor the pattern of weight accrual was correlated with
TSH, leptin, or AITD. In obese patients with a
HOMA-IR value less than 2, there was no correlation
between leptin and TSH.
Data analysis on the entire population is shown in Ta-
ble 3. Leptin levels were related to AITD (␳ ϭ 0.20; P Ͻ
0.001), TSH (␳ ϭ 0.12; P Ͻ 0.05), and, oppositely, FT
4
(␳ ϭ Ϫ0.31; P Ͻ 0.0001). By multiple logistic-regression
analysis, AITD was significantly associated with female
sex (male ϭ 0, female ϭ 1; P ϭ 0.003) and leptin levels
(Pϭ0.02). Neither obesity status (no ϭ0, yes ϭ1) nor fat
mass were significant in the model. The Hosmer-Leme-
showtest indicatedthat the model hadgoodfit (Pϭ0.68).
There were no interactions between or nonlinearity in the
continuous variables.
Discussion
Obesity is often the result of unbalanced calorie intake
and impaired energy expenditure acting on a predisposed
genetic setting. A common explanatory model encom-
passes the lipostatic regulation system, in which energy
stores generate signals that are compared with targets en-
codedinthe brain, anddifferences betweenthese drive our
food intake levels, activity patterns, and resting and active
metabolisms (18). Previous work fromour group showed
that subclinical hypothyroidismimpairs REEinobese sub-
jects and that TSH levels may provide a peripheral index
of thyroid hormone activity (14). Fat accumulation in-
creases TSH secretion as a result of a resetting of the hy-
pothalamo-pituitary thyrostat operatedby the adipose tis-
sue (10, 11, 19); thus, TSH elevation may not signify
authentic hypothyroidism. Some authors reported con-
comitant elevations in free thyroid hormones (20–25),
whereas others documented a decrease in FT
3
and FT
4
levels inmorbidlyobese euthyroidpatients comparedwith
controls (26). Our obese patients showed an increased
prevalence of hypothyroidism, a figure that approached
statistical significance and paralleled previous data (24–
26). In obese subjects, FT
4
and FT
3
levels decreased with
increasing adiposity, a circumstance suggestive of hypo-
metabolism at the peripheral level. In pooled analysis,
TSHlevels were unrelated to any parameter of body com-
position, glucose metabolism, or cardiovascular risk. Lit-
erature data inferred the following: the prevalence of
AITD variably ranges between 8 and 29%, according to
different assessment procedures (7); thyroid volume in-
creases with obesity (27); the association between thyroid
volume and autoantibodies is strong in subjects with ele-
FIG. 2. Individual REE values in the study groups as calculated by
indirect calorimetry (for description, see Results).
FIG. 1. Individual TSH (top), FT
3
(middle), and FT
4
(bottom) levels in
the study groups. NS, Not significant.
3968 Marzullo et al. Thyroid Autoimmunity and Leptin in Obesity J Clin Endocrinol Metab, August 2010, 95(8):3965–3972
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J Clin Endocrinol Metab, August 2010, 95(8):3965–3972 jcem.endojournals.org 3969
vated TSH (28); and no association links BMI to TPOAb
(9). The prevalence of AITDin obesity spans from12.4%
inchildrento10–16%inadults (25, 26), a figure that does
not seemto vary significantly fromour results. In fact, the
rate of AITD herein observed in obesity doubled that of
lean subjects, and nearly 60%of obese patients with high
TSHtested positive for AITD, therefore suggesting an un-
derlying autoimmune thyroid disorder. A recent study
(26) found a lower prevalence of AITD-associated hypo-
thyroidismcomparedwithhypothyroidismwithout AITD
(17 vs. 31 cases, respectively), a surprising circumstance
that questions the diagnostic value of abnormal TSH el-
evation in obesity. At variance with our study, however,
this latter investigation included patients with a wide age
range regardless of menopausal status and previous treat-
ment with T
4
. Importantly, we failed to document asso-
ciations between AITDand body composition, glucolipid
homeostasis, proinflammatory state, or any variable re-
lated to weight accrual and the development of obesity.
Although bio-impedance analysis-derived body composi-
tion cannot reflect body composition as well as dual x-ray
absorptiometry, our results appear toparallel those seenin
the general population (7, 9).
Althoughgenetic andenvironmental factors are known
contributors of AITD, the link between obesity and thy-
roid autoimmunity remains primarily undefined. It is
known that obesity enhances susceptibility to infections
(29), promotes a low-grade chronic proinflammatory
TABLE 3. Spearman’s correlation analysis on pooled data obtained from both study groups
Sex BMI Obesity %FM REE AITD Leptin TSH FT
3
FT
4
HOMA-IR
Age
␳ Ϫ0.02 0.02 0.01 Ϫ0.03 Ϫ0.03 0.1 0.02 Ϫ0.09 Ϫ0.1 Ϫ0.16 0.15
P 0.01 0.02
Sex
␳ Ϫ0.17 Ϫ0.08 0.31 Ϫ0.58 0.25 0.39 0.15 0.08 Ϫ0.07 Ϫ0.20
P 0.01 0.0001 0.0001 0.0001 0.0001 0.02 0.001
BMI
␳ 0.83 0.79 0.68 0.04 0.68 Ϫ0.21 Ϫ0.21 Ϫ0.21 0.56
P 0.0001 0.0001 0.0001 0.0001 0.001 0.001 0.001 0.0001
Obesity
␳ 0.82 0.57 0.08 0.73 0.07 Ϫ0.21 Ϫ0.22 0.44
P 0.0001 0.0001 0.0001 0.001 0.001 0.0001
FM (%)
␳ 0.33 0.13 0.87 0.13 Ϫ0.15 Ϫ0.20 0.41
P 0.0001 0.03 0.0001 0.03 0.02 0.001 0.0001
REE
␳ Ϫ0.05 0.21 0.04 Ϫ0.13 Ϫ0.13 0.50
P 0.001 0.05 0.05 0.0001
AITD
␳ 0.20 0.23 0.04 Ϫ0.21 Ϫ0.02
P 0.001 0.0001 0.001
Leptin
␳ 0.12 Ϫ0.1 Ϫ0.31 0.36
P 0.05 0.0001 0.0001
TSH
␳ 0.04 Ϫ0.08 0.02
P
FT
3
␳ 0.16 Ϫ0.03
P 0.01
FT
4
␳ Ϫ0.13
P 0.03
Any P Ͼ 0.05 or Ͻ0.0001 are not detailed. For categorical variables: male ϭ 0 and female ϭ 1; non-obese ϭ 0 and obese ϭ 1; AITD-negative ϭ 0
and AITD-positive ϭ 1. FM, Fat body mass.
FIG. 3. Cumulative leptin data obtained in obese (gray boxes) and
control (white boxes) subjects after exclusion of TSH-RAb-positive
subjects. Data are expressed as means Ϯ SD). NS, Not significant.
3970 Marzullo et al. Thyroid Autoimmunity and Leptin in Obesity J Clin Endocrinol Metab, August 2010, 95(8):3965–3972
state that favors metabolic complications (30), and acti-
vates inflammatory pathways ensuing a greater cancers
risk (31). The adipocytokines IL-6 and leptin inhibit reg-
ulatory T cells (32), and obesity alters cell-mediated Th-1
immune response thereby generating defects in CD3
ϩ
and
CD4
ϩ
T-helper and CD8
ϩ
T-suppressor/cytotoxic cells
(33–35). Leptin acts to regulate the Th-1 response (13, 36,
37) and has been shown recently to control T-cell energy
and, importantly, to regulate the proliferation of
CD4
ϩ
CD25
ϩ
T cells (38), a cell clone that is involved in
the apoptotic processes accompanying AITD(39). Aclin-
ical study in women with postpartum thyroiditis found
increasedleptinlevels for upto6months postpartum(40).
With current data documenting an association between
leptin and AITD independent of key variables related to
the development of obesity, we hypothesize that leptin
might play a role in thyroid autoimmunity, with genetic
and environmental variables playing a dominant role in
such context. We speculate that higher leptin levels may
have enhanced autoimmune thyroid injury in a substrate
(genetically or environmentally) prone to Th-1 immune
response.
Although our study was designed to reduce the selec-
tion bias (i.e. patients were exclusively admitted for obe-
sity and not enrolled if prediagnosed with thyroid disor-
ders or if postmenopausal), several caveats need to be
pondered: ultrasound was not used to assess altered thy-
roid echoic pattern; patients may have harbored AITD
before or in the process of becoming obese; thyroid dys-
function may per se have influenced leptin levels; previous
dieting may have enhanced susceptibility to AITD under
the influence of diverse genetic or environmental factors;
leptin elevation could depend on the underlying autoim-
mune process; other cytokines produced by the adipose
tissue or macrophages, i.e. IL-6andadiponectin, mayhave
influenced leptin levels; TPOAb elevation may be nonspe-
cific in the obese setting; and genetic or environmental
factors may have played a prominent role. These caveats
may have impacted the reliability of the study results.
In conclusion, the current study showed that obesity
can enhance the risk of thyroid autoimmunity, this being
associated with leptin levels as well as other known pre-
dictive factors. Future studies will be neededtounderstand
whether leptinmaycontribute topromote susceptibilityto
thyroid autoimmunity.
Acknowledgments
Address all correspondence and requests for reprints to: Paolo
Marzullo, M.D., Ospedale S. Giuseppe, Instituto di Ricovero e
Cura a Carattere Scientifico, Istituto Auxologico Italiano,
Casella Postale 1, 28921 Verbania, Italy. E-mail: paolo.marzullo@
med.unipmn.it.
Disclosure Summary: None of the authors has potential con-
flicts of interest to disclose.
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