Received: 1 April 2018 Revised: 31 December 2018 Accepted: 16 January 2019

DOI: 10.1002/hed.25691

ORIGINAL ARTICLE

Fasting serum glucose, thyroid-stimulating hormone, and thyroid

hormones and risk of papillary thyroid cancer: A case-control
study
Ming-Jun Hu MM1 | Chi Zhang MM1 | Ling Liang MD1 | Sheng-Ying Wang MM2 |
Xu-Cai Zheng MM2 | Qian Zhang MD1 | Chun-Xiao Jiang MM1 | Qi Zhong MM1 |
Fen Huang MD, PHD1

1
Department of Epidemiology and Biostatistics,
School of Public Health, Anhui Medical
University, Hefei, Anhui, China
2
Department of Head and Neck, Breast Surgery,
Anhui Provincial Cancer Hospital, West Branch of
Anhui Provincial Hospital, First Affiliated
Hospital of University of Science and Technology
of China, Hefei, Anhui, China
Correspondence
Fen Huang, Department of Epidemiology and
Biostatistics, School of Public Health, Anhui
Medical University, No. 81 Meishan Road,
Shushan Districts, Hefei 230032, Anhui, China
Email: fenh@ahmu.edu.cn
Funding information
the Project for Anhui Province Academic
Technology Leader Reserve Candidates’ Academic
Research Activities , Grant/Award Number:
2017H108; National Natural Science Foundation
of China, Grant/Award Number: 81373071
Abstract
Background: This study was to investigate the association of fasting serum glu-
cose (FSG), thyroid-stimulating hormone (TSH), and thyroid hormones with papil-
lary thyroid cancer (PTC).
Methods: A total of 649 participants were included in this case-control study. The
associations of FSG, TSH, free triiodothyronine (FT3) and free thyroxine (FT4)
with PTC were estimated using an unconditional logistic regression.
Results: Compared with the lowest quintile of TSH levels, odds ratios (ORs) and
95% confidence intervals (CIs) for association between PTC risk and highest quin-
tile of TSH levels were 1.67 (95% CI, 0.99-2.83). However, this risk correlation
was more significant in PTC cases with ≤1.0 cm tumor size (adjusted OR, 1.95;
95% CI, 1.08-3.54; adjusted P-trend, 0.05). The PTC risk was also inversely asso-
ciated with the serum FT3 level in all participants (adjusted P-trend, 0.001), but
positively associated with the serum FT4 (adjusted P-trend, 0.001) and FSG
(adjusted P-trend, 0.01) levels. Among the participants without diabetes, the indi-
viduals with high FSG levels and abnormal TSH concentration had an increased
PTC risk (adjusted OR, 3.38; 95% CI, 1.78-6.42).
Conclusion: The current study provides evidence for the association of FSG, TSH,
and thyroid hormones (FT3 and FT4) with PTC risk. However, larger relative studies
are needed.

KEYWORDS

glucose, papillary thyroid cancer, thyroid hormone, thyroid-stimulating

hormone, TSH

1 | INTRODUCTION
Recently, the high incidence of thyroid cancer has become
one of the important public health problems.1,2 Based on the
histopathological characteristics of thyroid cancer, papillary
thyroid cancer (PTC) is the most common subtype that
Ming-Jun Hu and Chi Zhang contributed equally to this study and should be
considered co-first authors.
accounts for 80% of all thyroid carcinomas.3 In fact, the rap-
idly increasing incidence of thyroid cancer is mostly driven
by PTC.4 The etiology of thyroid cancer remains unclear to
date. Numerous studies have identified a number of risk fac-
tors for PTC, such as old age, female sex, radiation expo-
sure, high body surface area and weight changes, and gene
BRAF V600E mutation.5–8 These factors are all reportedly
associated with poor clinical outcomes of PTC, including
extrathyroidal extension, lymph node metastasis, and distant

Head & Neck. 2019;1–8. wileyonlinelibrary.com/journal/hed © 2019 Wiley Periodicals, Inc. 1

2 HU ET AL.
metastasis. Several novel risk factors, such as vitamin D
deficiency, thyroid-stimulating hormone (TSH) and thyroid
hormones, and diabetes mellitus, have also been presented in
recent studies. However, no definite conclusions have been
made to date.9–13
Diabetes is related to many chronic diseases, such as
colorectal, prostate, bladder, and breast cancers.14–17 Hyper-
glycemia may be the primary risk factor. Some epidemiolog-
ical studies have investigated the association between blood
glucose concentrations and risk of cancer, including thyroid
cancer.18–21 A study that pooled six prospective cohorts in
the Metabolic Syndrome and Cancer Project suggested that
the risk of overall cancer incidence was positively associated
with blood glucose concentration, but the risk of thyroid
cancer was significantly increased only in men.19 However,
a large cohort study with a median followed up of 15.9 years
in the United States showed no significant associations
between thyroid cancer and diabetes.12 Numerous studies
have focused on the relationship of thyroid cancer and diabe-
tes. However, available data on the association between thy-
roid cancer and fasting serum glucose (FSG) are scarce.
The currently recognized carcinogenic mechanism of
hyperglycemia is the insulin—insulin-like growth factor-1
(IGF-1) signaling pathway. IGF-1 is an important somato-
medin, which can produce carcinogenesis by inducing mito-
sis and inhibiting apoptosis.18 High insulin levels associated
with hyperglycemia may motivate the production of TSH. A
previous study suggested that TSH and insulin or IGF-1
might synergistically promote thyroid cell proliferation.22
However, whether or not a high TSH level is a carcinogen
of thyroid cancer remains controversial.
TSH is a growth factor for thyroid cells and an important
indicator of thyroid function. In the normal hypothalamic-
pituitary-thyroid axis, TSH governs the thyroid hormone
(ie, triiodothyronine [T3] and thyroxine [T4]) production
and secretion and inversely regulates TSH release. After
hydrolysis, more than 99% of T3 and T4 form noncovalent
bonds with plasma proteins in circulating blood, leaving
only a small fraction of free T3 and T4 (ie, free triiodothyro-
nine [FT3] and free thyroxine [FT4]). FT3 and FT4 are
hormones that enter the target cell and bind to the receptor to
play a role. Thus, thyroid function should be assessed using
both TSH and FT4 comprehensive reference intervals.23
Current guides recommend TSH suppressive therapy
for differentiated thyroid cancer management, especially in
advanced and metastatic patients.24,25 High TSH levels can
predict the probability of malignant nodular thyroid dis-
ease.26,27 In animal experiments, high TSH concentrations can
induce PTC onset.28 The association between thyroid hor-
mones and cancer has also been investigated.29 However, in
the large European Prospective Investigation into Cancer and
Nutrition (EPIC) cohort study, the low TSH levels were found
to be associated with thyroid cancer oncogenesis.11
In the current case-control study, we examined the associ-
ation between PTC risk and FSG, TSH, and thyroid hormones
(FT3 and FT4). The combined effect of FSG and TSH for
PTC was also investigated. The primary purpose of this study
was to explore the novel risk association for the onset of PTC.
2 | M AT E RI A L S AN D M E T H O DS
2.1 | Study population
Participants were recruited from three general hospitals from
June 2016 to present, namely, the Anhui Provincial Cancer
Hospital, First Affiliated Hospital of Anhui Medical Univer-
sity, and Second Affiliated Hospital of Anhui Medical Uni-
versity. All cases were newly diagnosed with thyroid cancer
based on clear histopathological characteristics. Once the
case was confirmed, the controls were roughly matched on
sex, age, and habitat and were randomly selected immedi-
ately from the newly admitted patients in multiple depart-
ments of the three hospitals. The controls were free of cancer
and malnutrition and with no history of thyroid, liver, kid-
ney, or endocrine system diseases. Finally, a total of 649 par-
ticipants (320 PTC cases and 329 controls) were included in
this analysis. These participants provided all fasting blood
and urine samples for analysis and have complete epidemio-
logic information. All participants were Chinese Han people.
Approval for this study was obtained from Anhui Medical
University Biomedical Ethics Committee and each of the
hospitals. Written consent was obtained from all participants.
2.2 | Data collection
Epidemiologic data were acquired via face-to-face interview
by using a structured questionnaire at enrollment. The infor-
mation on the questionnaire included demographic charac-
teristics, lifestyle and behavior habits, family history of
thyroid disease and cancer, and personal medical history.
The anthropometric measurements of height, weight and
blood pressure were also collected. Blood pressure was mea-
sured twice after a quiet rest period of at least 15 minutes,
with a measurement interval of 5 minutes. We carefully
reviewed the patient's medical records before inclusion. This
process was helpful in excluding patients with major dis-
eases in the liver, kidney, gastrointestinal tract, and endo-
crine system. The clinical histopathological characteristics of
the patients with thyroid cancer were additionally recorded.
These characteristics included the subtype, tumor size,
lymph nodes and distant metastases, and extrathyroidal
extension.
2.3 | Samples collection and laboratory evaluations
All fasting blood and urine samples were collected in the next
morning after the patient's admission to hospital (between
6:00 and 8:00 AM). Patients were required to fast for at least
HU ET AL.
8 hours before sample collection. The serum was immedi-
ately separated. Then, the samples were stored at −80 C until
examination. Serum concentration of TSH, FT3, and FT4
were measured using an electrochemiluminescence immuno-
assay using Roche Cobas e 411 analyzer and whose manu-
facturer's reagents and calibrators (Roche Diagnostics
GmbH, Mannheim, Germany). FSG was determined by
hexokinase method using Roche Cobas 8000 modular ana-
lyzer and Glucose HK Gen.3 Kit (Roche Diagnostics GmbH
). All measurements were strictly in accordance with the
instructions of instruments and kits. Serum samples from
cases and controls were randomly mixed together to measure.
The assay reference ranges for TSH, FT3, FT4, and FSG
were 0.27-4.20 uIU/mL, 3.1-6.8 pmol/L, 12-22 pmol/L, and
3.9-6.1 mmol/L, respectively.
2.4 | Statistical analysis
Univariate analyses for selected characteristics were per-
formed using Student's t-test, Wilcoxon rank sum test, or
chi-squared test. Pearson and Spearman correlation coeffi-
cients were used to evaluate the correlation of FSG with
TSH, FT3, and FT4. The concentrations of TSH, FT3, FT4,
and FSG were categorized into quintiles based on the distri-
bution among controls. The odds ratio (OR) and 95% confi-
dence intervals (CIs) for the association of PTC risk with
TSH, FT3, FT4, and FSG were estimated using uncondi-
tional logistic regression. In the multivariate regression
model, TSH, FT3, FT4, and FSG were mutually adjusted to
obtain accurate risk assessments. However, additional
adjustment for FT3 and FT4 in risk assessments of TSH and
FSG did not significantly change the observed associations;
thus, FT3 and FT4 were excluded in final multivariate
models. P for trend was tested using the ordinal score on cat-
egory of TSH, FT3, FT4, and FSG. P for interaction was
tested using cross-product terms for FSG and TSH. Depend-
ing on the reference ranges of TSH, the serum concentra-
tions of TSH within the reference range were classified into
the normal group; then other concentration value was classi-
fied into abnormal group.
In the secondary analysis, we excluded the participants
with diabetes to conduct a sensitivity analysis. The median
FSG in the controls without diabetes was calculated (median
FSG, 4.9 mmol/L). On the basis of the median FSG and clin-
ical status of TSH (ie, normal and abnormal TSH concentra-
tion), FSG and TSH were combined to create four categories
as follows: FSG ≤ 4.90 mmol/L and TSH normal (BN),
FSG > 4.90 mmol/L and TSH normal (AN), FSG ≤ 4.90
mmol/L and TSH abnormal (BA), and FSG > 4.90 mmol/L
and TSH abnormal (AA). These categories were used to
estimate the combined effect of FSG and TSH on PTC risk.
Statistical significance was P <0.05 and all tests were
two-sided. All analyses were performed using IBM SPSS
Statistics for Windows (Version 23.0. IBM Corp., Armonk,
New York).
3
3 | RESULTS
3.1 | Descriptive characteristics of the study
participants
The descriptive characteristics of the PTC cases and controls
are shown in Table 1. The mean age of all study participants
was 47.5 years (SD was 15.0 years). Among the PTC cases,
the number of females was approximately thrice that of
males. The numbers of cases with ≤1.0 cm and >1.0 cm
tumor sizes were 117 and 203, respectively. The serum con-
centration of FSG was not correlated with TSH, FT3, and
FT4 both in cases and controls (data not shown).
3.2 | Association of PTC with serum TSH, FT3, FT4,
and FSG
The numbers (percentage) of study participants with abnor-
mal concentration of TSH, FT3, FT4 and FSG were
160 (24.7%), 13 (2.0%), 42 (6.5%), and 69 (10.6%), respec-
tively. The adjusted OR of the association between PTC and
TSH levels was not significant in all participants, whereas
the adjusted P for the trend was 0.15 (Table 2). Compared
with the lowest quintile of TSH levels, adjusted OR and 95%
CI for association between PTC risk and the highest quintile
of TSH levels was 1.67 (95% CI, 0.99-2.83). The PTC risk
was inversely associated with the serum FT3 levels in all
participants (adjusted P-trend, 0.001) but positively associ-
ated with the serum FT4 levels (adjusted P-trend, 0.001).
When all PTC cases were stratified by tumor size, high TSH
concentrations were significantly associated with increased
PTC risk with ≤1.0 cm tumor size (highest quintile vs lowest
quintile, adjusted OR, 1.95; 95% CI, 1.08-3.54; adjusted
P-trend, 0.05), see Supporting Information Table S1.
In addition, the FSG levels were positively associated with
PTC risk in all study participants (adjusted P-trend, 0.01;
Figure 1). When the participants were stratified according to
the clinical status of TSH, such association was still observed
among the participants with normal TSH concentration
(adjusted P-trend, 0.03) and was not modified by TSH con-
centration (adjusted P-interaction, 0.86; Table 3). However, a
positive association was observed between FSG concentra-
tions and PTC risk with >1.0 cm tumor size (adjusted P-trend,
0.03), see Supporting Information Table S1.
3.3 | Combined effect of fasting serum glucose and
TSH for PTC
A total of 307 PTC cases and 303 controls remained after
excluding the participants with diabetes. We combined FSG
and TSH results to estimate their effects on PTC risk. The
AA group had a greater risk effect on PTC (adjusted OR,
3.38; 95% CI, 1.78-6.42) than the BN group (Figure 2). This
effect was still significant on the PTC cases with ≤1.0 cm
tumor size (Table 4).
4 HU ET AL.

TABLE 1 Selected characteristics of papillary thyroid cancer cases and without diabetes (Supporting Information Figure S1). A posi-
controls tive association between FSG levels and PTC risk (adjusted
Cases Controls P-trend, 0.02) was also observed. A similar risk effect of FSG
Characteristics (n = 320) (n = 329) P valuea
concentration was also observed after stratification based on
Male/Female, n 84/236 124/205 0.002
the clinical status of TSH (Supporting Information Table S2).
Age, years, mean (SD) 45.6 (13.9) 49.3 (15.9) 0.002
And the positive association between FSG concentrations and
Weight, kg, mean (SD) 63.1 (11.2) 61.7 (9.7) 0.09
PTC risk with >1.0 cm tumor size was also remained
Body mass index, kg/m2, 23.7 (3.6) 22.9 (3.2) 0.004
mean (SD)
(adjusted P-trend, 0.04) (Supporting Information Table S3).
Average annual household income, RMB, n (%)
<30 000 53 (16.6) 83 (25.2) 0.004
4 | DISCUSSION
30 000-59 999 144 (45.0) 154 (46.8)
≥60 000 123 (38.4) 92 (28.0)
The current study showed a significant association between
Sleeping time, hours/day, n (%)
PTC risk and pre-diagnostic serum levels of TSH, FT3, FT4,
≤4 8 (2.5) 12 (3.6) 0.56
and FSG. Individuals with high TSH levels might have a high
4.1-6 64 (20.0) 70 (21.3)
risk of PTC onset. PTC risk was inversely associated with the
6.1-8 188 (58.8) 177 (53.8)
serum FT3 level, but positively associated with the FT4 level.
≥8.1 60 (18.8) 70 (21.3)
Although high FSG levels did not exert a significant effect on
Sleeping quality, n (%)
PTC risk, a positive trend was observed. The individuals with
Poor 55 (17.2) 49 (14.9) 0.14
high FSG levels and abnormal TSH concentration exhibited a
Impaired 96 (30.0) 81 (24.6)
more than threefold risk of PTC, compared with those with
Normal 169 (52.8) 199 (60.5)
low FSG levels and normal TSH concentration. These novel
Physical activity, n (%)
findings had major public health significance in the present
Inactive 183 (57.2) 207 (62.9) 0.007
situation of high PTC incidence.
Moderate 81 (25.3) 51 (15.5)
In this case-control study, some factors associated with
Active 56 (17.5) 71 (21.6)
PTC were investigated using univariate analyses. Among the
Smoking status, n (%)
PTC cases, it was not surprising that the number of females
Never 280 (87.5) 286 (86.9) 0.97
was approximately three times that of males. Thyroid cancer
Former 5 (1.6) 5 (1.5)
incidence rate in female is higher than that in male world-
Current 35 (10.9) 38 (11.6)
wide.30 Researchers had speculated that estrogen exerts an eti-
Drinking tea, n (%)
ologic effect on thyroid cancer oncogenesis.31 One of the
Never 168 (52.5) 185 (56.2) 0.25
mechanisms was that estrogen could augment the TSH levels
Moderately 90 (28.1) 74 (22.5)
in the human body.32 The functions of iodine on synthesis of
Frequently 62 (19.4) 70 (21.3)
TSH and thyroid hormones were well established. Therefore,
Current drinking, n (%) 50 (15.6) 50 (15.2) 0.88
we assessed the iodine levels of the subjects and conducted
History of X-ray, n (%) 151 (47.2) 151 (45.9) 0.74
correction to avoid the interference outside of the risk associa-
History of CT scans, n (%) 135 (42.2) 112 (34.0) 0.03
tion analysis. An association of PTC risk with high income
History of hypertension, n (%) 52 (16.2) 45(13.7) 0.36
and CT-scan exposure was observed in our study. Radiation
History of diabetes, n (%) 13 (4.1) 26 (7.9) 0.04
exposure had been reported to increase PTC risk.6 A higher
Family history 46 (14.4) 12 (3.6) <0.001
of thyroid diseases, n (%) radiation exposure is obtained during CT scan than during an
Family history 63 (19.7) 54 (16.4) 0.28 X-ray. A large cohort study of 11 million Australians demon-
of cancer, n (%) strated that CT-scan exposure in children and adolescents was
FSG, mmol/L, mean (SD) 5.2 (0.9) 5.3 (1.8) 0.50 related with increased thyroid cancer risk (relative risk [RR],
FT3, pmol/L, mean (SD) 4.56 (0.70) 4.76 (0.76) <0.001 1.40; 95% CI, 1.23-1.59).33 High-income individuals had
FT4, pmol/L, mean (SD) 17.11 (5.34) 16.20 (2.66) 0.007 more opportunities to undergo health examinations and medi-
TSH, μIU/mL, median (IQR) 2.56 (2.97) 2.42 (2.05) 0.09 cal radiation, which might augment the probability of thyroid
Urinary iodine/creatinine 313.12 (223.31) 178.16 (144.13) <0.001 cancer detection and onset, than low-income individuals.34 To
ratio, μg/g, median (IQR)
avoid these confounding, we performed multivariable models
Abbreviations: FSG, fasting serum glucose; FT3, free triiodothyronine; FT4, free in unconditional logistic regression.
thyroxine; TSH, thyroid-stimulating hormone; IQR, inter-quartile range.
a
P values (two-sided) were calculated by using the Student's t-test, Wilcoxon TSH is a two-subunit glycoprotein produced by the ante-
rank sum test or chi-squared test. rior pituitary gland. The main functions of TSH are regula-
tion of thyroid hormones, facilitation of thyroid cell growth,
3.4 | Sensitivity analysis
excitation of the sodium iodide symporter, and adjustment of
For a more accurate estimation of the effect of FSG levels on extrathyroidal effects. A study showed that long-term high
PTC risk, we conducted a risk assessment in the participants TSH levels leaded to hyperplasia and hypertrophy of the
HU ET AL. 5

TABLE 2 Odds ratios and 95% confidence intervals for the association between TSH and thyroid hormones and papillary thyroid cancer

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P-trend

TSH
Range (μIU/mL) <1.32 1.32-2.02 2.03-2.76 2.77-3.85 >3.85
Cases/controls (320/329) 59/67 60/65 51/66 47/66 103/65
Crude OR (95% CI) 1.0 (ref) 1.05 (0.64-1.72) 0.88 (0.53-1.46) 0.81 (0.49-1.35) 1.80 (1.13-2.87) 0.04
a
Adjusted OR (95% CI) 1.0 (ref) 0.98 (0.57-1.70) 0.99 (0.57-1.74) 0.64 (0.36-1.14) 1.67 (0.99–2.83) 0.15
FT3
Range (pmol/L) <4.18 4.18-4.54 4.55-4.95 4.96-5.42 >5.42
Cases/controls (320/329) 84/68 63/64 98/69 50/64 25/64
Crude OR (95% CI) 1.0 (ref) 0.80 (0.50-1.28) 1.15 (0.74-1.79) 0.63 (0.39-1.03) 0.32 (0.18-0.56) <0.001
Adjusted OR (95% CI)b 1.0 (ref) 0.97 (0.57-1.63) 1.11 (0.67-1.83) 0.66 (0.38-1.15) 0.28 (0.14-0.54) 0.001
FT4
Range (pmol/L) <14.37 14.37-15.58 15.59-16.57 16.58-17.99 >17.99
Cases/controls (320/329) 53/67 54/65 60/67 57/66 96/64
Crude OR (95% CI) 1.0 (ref) 1.05 (0.63-1.75) 1.13 (0.69-1.87) 1.09 (0.66-1.81) 1.90 (1.17-3.06) 0.01
Adjusted OR (95% CI)b 1.0 (ref) 1.36 (0.75-2.45) 1.35 (0.76-2.40) 1.53 (0.85-2.74) 2.52 (1.44-4.40) 0.001

Abbreviations: TSH, thyroid-stimulating hormone; FT3, free triiodothyronine; FT4, free thyroxine; OR, odds ratio; CI, confidence interval. .
a
Adjusted for sex, age, average annual household income, body mass index, physical activity, history of CT scan, history of diabetes, family history of thyroid diseases,
fasting serum glucose, and urinary iodine/creatinine ratio.
b
Additionally adjusted for serum concentration of TSH.

thyroid gland.35 A previous meta-analysis of 28 studies sug-
gested that an increased thyroid neoplasm risk was related to
high TSH concentrations.36 However, a genome-wide asso-
ciation study (GWAS) of 22 single nucleotide polymor-
phisms presented that common variants with low TSH
concentrations were positively associated with thyroid can-
cer.37 In a recent nested case-control study among 741 US
military personnel and 741 matched controls, Huang et al.
showed that a high TSH level within the reference range was
a protective factor for PTC, whereas a TSH level above the
reference range was positively associated with PTC.10 This
finding was similar to our results, especially in PTC cases
with a ≤1.0 cm tumor size. Similar efficacies of thyroid hor-
mones (FT3 and FT4) were found in our study. One of the
possible mechanisms involved the up-regulation of TSH by
abnormal thyroid hormone levels. Thyroid hormones were
also reportedly associated with cellular transformation,
tumorigenesis, and metastasis; the angiogenesis promoting
effect of thyroid hormones was mainly caused by the binding
of T4 to the integrin αvβ3 membrane receptor.38
Impaired fasting glucose, as a marker of prediabetes,
draws considerable attention for its ability to intervene with
the progression of diabetes initially. Long-term chronic hyper-
glycemia is a key factor in diabetes and is also related to the

FIGURE 1 Odds ratios and 95% confidence intervals for PTC risk according to fasting serum glucose levels. OR (95%CI) from unconditional logistic
regression analysis adjusted or unadjusted for sex, age, average annual household income, body mass index, physical activity, history of CT scan, history of
diabetes, family history of thyroid diseases, urinary iodine/creatinine ratio, and TSH. Abbreviations: CI, confidence interval; OR, odds ratio; PTC, papillary
thyroid cancer; TSH, thyroid-stimulating hormone [Color figure can be viewed at wileyonlinelibrary.com]
6 HU ET AL.

TABLE 3 Odds ratios and 95% confidence intervals for PTC risk according to fasting serum glucose levels stratified by the clinical status of TSH

Fasting serum glucose levels

Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 P-trend P-interaction
Range (mmol/L) < 4.51 4.51-4.80 4.81-5.10 5.11-5.50 > 5.50
Normal TSH concentration
Cases/controls (217/272) 27/60 42/54 54/57 60/50 34/51
Crude OR (95% CI) 1.0 (ref) 1.73 (0.94-3.17) 2.11 (1.17-3.79) 2.67 (1.48-4.81) 1.48 (0.49-2.78) 0.06 0.89
Adjusted OR (95% CI)a 1.0 (ref) 1.63 (0.83-3.18) 1.93 (1.00-3.74) 2.33 (1.18-4.62) 1.99 (0.94-4.18) 0.03 0.86
Abnormal TSH concentration
Cases/controls (103/57) 20/14 19/15 18/6 27/14 19/8
Crude OR (95% CI) 1.0 (ref) 0.89 (0.34-2.32) 2.10 (0.67-6.63) 1.35 (0.53-3.46) 1.66 (0.57-4.86) 0.22
Adjusted OR (95% CI)a 1.0 (ref) 0.67 (0.22-2.10) 2.93 (0.78-11.00) 1.25 (0.42-3.73) 1.86 (0.48-7.27) 0.22

Abbreviations: PTC, papillary thyroid cancer; TSH, thyroid-stimulating hormone; OR, odds ratio; CI, confidence interval.
a
Adjusted for sex, age, average annual household income, body mass index, physical activity, history of CT scan, history of diabetes, family history of thyroid diseases,
urinary iodine/creatinine ratio, and TSH.

onset of cancer.18 In a cohort study that included 1 298 385
Koreans, the 10-year followed up showed that the overall can-
cer risk was associated with increased FSG levels (highest
quintile vs lowest quintile, hazard ratio [HR], 1.22; 95% CI,
1.16-1.27).21 In another cohort of more than 140 000 adults
in Austria, a positive association was found between thyroid
cancer risk and glucose concentrations of >5.3 mmol/L.20 A
study that pooled six prospective cohorts in the Metabolic
Syndrome and Cancer Project suggested that a high blood
glucose concentration was associated with an increased risk of
overall cancer incidence, but the risk of thyroid cancer was
significantly increased only in men.19 Epidemiological studies
have demonstrated that hyperglycemia is related to an
increased risk of both thyroid nodule and goiter.22,39 Although
the high FSG levels did not show any significant effect on
PTC risk in our study, the positive trend of FSG and risk
effect of the combination of high FSG levels and abnormal
TSH concentration was definite. This result was a novel find-
ing and required more longitudinal studies to confirm.
Hyperglycemia produces high insulin levels during the
metabolic process, followed by insulin resistance. Aside
from the carcinogenic effect of IGF-1 from the insulin, IGF-
1 signaling pathway, the independent carcinogenic effects of
early hyperinsulinemia in diabetes should also be consid-
ered.40 Long-term hyperglycemia will lead to capillary base-
ment membrane thickening, decreased permeability, and
mitochondrial respiratory enzyme damage, which enhance
the anaerobic glycolysis and produce more reactive oxygen
species (ROS).41 ROS accumulation can cause oxidative
stress within the target tissue, which can damage DNA,
reduce DNA repair, and consequently induces tumorigene-
sis.42 Anaerobic glycolysis may provide energy for cancer

FIGURE 2 Odds ratios and 95% confidence intervals for PTC risk according to the combination of FSG and TSH in subjects without diabetes. OR (95%CI)
from unconditional logistic regression analysis adjusted or unadjusted for sex, age, average annual household income, body mass index, physical activity,
history of CT scan, family history of thyroid diseases, urinary iodine/creatinine ratio, and TSH. Abbreviations: AA, FSG > 4.90 mmol/L and TSH abnormal;
AN, FSG > 4.90 mmol/L and TSH normal; BA, FSG ≤ 4.90 mmol/L and TSH abnormal; BN, FSG ≤ 4.90 mmol/L and TSH normal; CI, confidence
interval; FSG, fasting serum glucose; PTC, papillary thyroid cancer; TSH, thyroid-stimulating hormone; OR, odds ratio [Color figure can be viewed at
wileyonlinelibrary.com]
HU ET AL. 7

TABLE 4 Odds ratios and 95% confidence intervals for the association between the combination of FSG and TSH and papillary thyroid cancer stratified by
tumor size in subjects without diabetes
The combination of FSG and TSH
BN AN BA AA
Tumor size ≤1.0 cm
Cases/controls (200/303) 57/135 71/115 33/30 39/23
Crude OR (95% CI) 1.0 (ref) 1.46 (0.95-2.24) 2.61 (1.45-4.67) 4.02 (2.20-7.33)
Adjusted OR (95% CI)a 1.0 (ref) 1.45 (0.88-2.38) 4.34 (2.00-9.42) 6.15 (2.83-13.33)
Tumor size >1.0 cm
Cases/controls (107/303) 33/135 46/115 14/30 14/23
Crude OR (95% CI) 1.0 (ref) 1.64 (0.98-2.73) 1.91 (0.91-4.00) 2.49 (1.16-5.36)
Adjusted OR (95% CI)a 1.0 (ref) 1.71 (0.96-3.04) 1.31 (0.56-3.05) 1.71 (0.29-4.26)

Abbreviations: FSG, fasting serum glucose; TSH, thyroid-stimulating hormone; OR, odds ratio; CI, confidence interval; BN, FSG ≤ 4.90 mmol/L and TSH normal;
AN, FSG > 4.90 mmol/L and TSH normal; BA, FSG ≤ 4.90 mmol/L and TSH abnormal; AA, FSG > 4.90 mmol/L and TSH abnormal.
a
Adjusted for sex, age, average annual household income, body mass index, physical activity, history of CT scan, family history of thyroid diseases, urinary iodine/-
creatinine ratio, and TSH.

cell and may further promote cell canceration; this process is
known as the Warburg effect.43 Recently, molecular biology
research illuminated that hyperglycemia could adversely
affect the DNA 5-hydroxymethylation (5hmC).44 High
blood glucose levels firstly inhibited the activity of AMP
activated kinase (AMPK), resulting in a decrease in phos-
phorylation at serine 99, which indicated that the stability of
10 to 11 translocation 2 (TET2) protein would becomes
more and more unreliable, and directly leaded to its acceler-
ated rate of degradation. In epigenetics, it had been estab-
lished that TET2 plays an important role in regulating DNA
methylation,45 including catalysis of the conversion of DNA
methylation (5mC) to 5hmC. However, numerous studies
had proved that 5hmC reduction in DNA is one of the hall-
marks of cancer.46,47
To our knowledge, the present study is the first to evalu-
ate the association between PTC risk and the combined effect
of FSG and TSH. All blood and urine samples were collected
the second morning after the patients' admission. At that time,
no definite histopathological examination was completed for
the case group. This step ruled out the potential clinical fac-
tors that may interfere with the concentrations of the analyti-
cal indicators. In addition, accurate risk assessments were
obtained after correcting some important covariates, namely
BMI, CT scans exposure, and urinary iodine/creatinine ratio.
However, several limitations should be mentioned. First, the
limited sample size did not allow for a comprehensive strati-
fied analysis, such as stratification by sex. But sex correction
was performed in our multivariate regression model. Second,
a single measurement of the analytical indicators may influ-
ence the authenticity of the result. We preferred to use multi-
ple measurements to reduce accidental errors. Finally, this
work was a retrospective study, and the results should be con-
firmed with longitudinal studies.
In summary, the current study provided evidence for the
association of FSG, TSH, and thyroid hormones (FT3 and
FT4) with PTC risk. Individuals with high FSG levels and
abnormal TSH concentration should receive corresponding
interventions to prevent the occurrence of thyroid cancer.
Although the novel findings of our study help identifying
the population in most need of prevention and screening,
more relevant studies are necessary.
ACKNOWLEDGMENTS
This work was supported by National Natural Science Foun-
dation of China (No. 81373071) and the Project for Anhui
Province Academic Technology Leader Reserve Candidates'
Academic Research Activities (2017H108).
CONFLICT OF IN TER EST
The authors declare that they have no conflicts of interests
with the contents of this article.
OR CID
Fen Huang https://orcid.org/0000-0003-2127-3668
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SUPPORTING I NFORMATION
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
How to cite this article: Hu M-J, Zhang C, Liang L,
et al. Fasting serum glucose, thyroid-stimulating hor-
mone, and thyroid hormones and risk of papillary thy-
roid cancer: A case-control study. Head & Neck.
2019;1–8. https://doi.org/10.1002/hed.25691