Severely low serum magnesium is associated with increased risks of positive anti-thyroglobulin antibody and hypothyroidism: A cross-sectional study

Abstract

Trace elements, such as iodine and selenium, are closely related to autoimmune thyroiditis and thyroid function. Low serum magnesium is associated with several chronic diseases; however, its associations with autoimmune thyroiditis and thyroid function are unclear. We investigated the relationships between low serum magnesium, autoimmune thyroiditis, and thyroid function in 1,257 Chinese participants. Demographic data were collected via questionnaires, and levels of serum thyroid stimulating hormone, anti-thyroid peroxidase antibody, anti-thyroglobulin antibody (TGAb), free thyroxine, serum magnesium, serum iodine, and urinary iodine concentration were measured. Participants were divided into serum magnesium level quartiles (≤0.55, 0.551-0.85, 0.851-1.15, and >1.15 mmol/L). The median serum magnesium level was 0.89 (0.73-1.06) mmol/L; levels ≤0.55 mmol/L were considered severely low (5.9% of participants). The risks of TGAb positivity and Hashimoto thyroiditis (HT) diagnosed using ultrasonography in the lowest quartile group were higher than those in the adequate magnesium group (0.851-1.15 mmol/L) (p < 0.01, odds ratios [ORs] = 2.748-3.236). The risks of total and subclinical-only hypothyroidism in the lowest quartile group were higher than those in the adequate magnesium group (0.851-1.15 mmol/L) (p < 0.01, ORs = 4.482-4.971). Severely low serum magnesium levels are associated with an increased rate of TGAb positivity, HT, and hypothyroidism.

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Severely low serum magnesium
is associated with increased risks
of positive anti-thyroglobulin
antibody and hypothyroidism: A
cross-sectional study
Kunling Wang1, Hongyan Wei1, Wanqi Zhang2, Zhen Li3, Li Ding1, Tong Yu4, Long Tan 2,
Yaxin Liu1, Tong Liu1, Hao Wang1, Yuxin Fan1, Peng Zhang1, Zhongyan Shan5 & Mei Zhu1
Trace elements, such as iodine and selenium, are closely related to autoimmune thyroiditis and
thyroid function. Low serum magnesium is associated with several chronic diseases; however, its
associations with autoimmune thyroiditis and thyroid function are unclear. We investigated the
relationships between low serum magnesium, autoimmune thyroiditis, and thyroid function in
1,257 Chinese participants. Demographic data were collected via questionnaires, and levels of serum
thyroid stimulating hormone, anti-thyroid peroxidase antibody, anti-thyroglobulin antibody (TGAb),
free thyroxine, serum magnesium, serum iodine, and urinary iodine concentration were measured.
Participants were divided into serum magnesium level quartiles (≤0.55, 0.551–0.85, 0.851–1.15, and
>1.15 mmol/L). The median serum magnesium level was 0.89 (0.73–1.06) mmol/L; levels ≤0.55 mmol/L
were considered severely low (5.9% of participants). The risks of TGAb positivity and Hashimoto
thyroiditis (HT) diagnosed using ultrasonography in the lowest quartile group were higher than those
in the adequate magnesium group (0.851–1.15 mmol/L) (p < 0.01, odds ratios [ORs] = 2.748–3.236).
The risks of total and subclinical-only hypothyroidism in the lowest quartile group were higher than
those in the adequate magnesium group (0.851–1.15 mmol/L) (p < 0.01, ORs = 4.482–4.971). Severely
low serum magnesium levels are associated with an increased rate of TGAb positivity, HT, and
hypothyroidism.
Magnesium is the fourth most abundant essential mineral in the human body aer sodium, potassium, and
calcium1, and is a cofactor for more than 300 enzymes that regulate a variety of biochemical processes, such
as DNA/RNA synthesis, protein synthesis, oxidative phosphorylation, and glycolysis1,2. Magnesium is mainly
absorbed through the diet, and high-magnesium foods include nuts, seeds, whole grains, and leafy greens.
Epidemiological surveys show that magnesium deciency exists in many regions worldwide3–5. According to data
from the National Health and Nutrition Examination (2001–2010) in the United States, the magnesium intakes
of only 18.8% of male participants and 24.8% of female participants met the recommended dietary allowance3.
e Nutrition and Health Survey in Taiwan (NAHSIT) also showed that the daily intakes of magnesium in 75% of
male participants and 81% of female participants were lower than the dietary reference intakes (DRIs)4. It is esti-
mated that the prevalence of low serum magnesium in the population is 2.5–15%5. Insucient magnesium intake
and low serum magnesium are associated with a variety of chronic diseases, including insulin resistance and type
1Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, No154 Anshan Road,
Heping District, Tianjin, 300052, China. 2Department of Nutrition and Food Hygiene, School of Public Health, Tianjin
Medical University, No22 Qixiangtai Road, Heping District, Tianjin, 300070, China. 3Department of Nuclear Medicine,
Zhujiang Hospital of Southern Medical University, No 253 Gongye Road, Guangzhou, Guangdong Province, 510282,
China. 4Department of Endocrinology, Huaihe Hospital of Henan University, Kaifeng, No 8 Baobei Road, Henan
Province, 475000, China. 5Department of Endocrinology and Metabolism and Institute of Endocrinology, The First
Hospital of China Medical University, Shenyang, Liaoning Province, 110001, China. Correspondence and requests for
materials should be addressed to M.Z. (email: meichuqin@163.com)
Received: 23 January 2018
Accepted: 21 June 2018
Published: xx xx xxxx
OPEN
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2 diabetes mellitus6,7, metabolic syndrome3,8, hypertension9, cardiovascular disease10, stroke11, migraine12, atten-
tion decit disorder13, Alzheimer’s disease14, and asthma15.
Magnesium is closely related to the immune system; in vitro experiments have showed that intracellular free
magnesium ions are an important second messenger in the immune activation of T lymphocytes16 and B lym-
phocytes17, and magnesium channels and transport proteins play an important role in normal immune func-
tion16,18,19. Moreover, magnesium is also associated with cellular oxidative stress and inammatory reactions20.
e homeostasis of magnesium ions in mitochondria is important for cellular energy metabolism and for the
ability to respond to oxidative stress21. e synthesis of glutathione, which is an important cellular antioxidant,
is an ATP-dependent reaction and is therefore critically dependent on magnesium1. Studies have found that
magnesium intake was inversely associated with levels of C-reactive protein, interleukin-6, and other inamma-
tory factors6,22, and that magnesium citrate supplementation can downregulate genes related to metabolic and
inammatory pathways23.
Autoimmune thyroiditis is a common endocrine disorder that is caused by a variety of environmental factors
and is based on genetic susceptibility. A range of trace elements are related to the pathogenesis of autoimmune
thyroiditis, among which the most important is iodine, followed by iron, selenium, and others24,25. ere are few
studies on the relationship between magnesium and thyroid disease. For example, a study on patients with Graves’
disease found that they exhibited a lower serum magnesium concentration than normal control participants, and
that the serum magnesium concentration was negatively correlated with lymphocyte activation26. An Austrian
study found that low serum magnesium was associated with abnormal thyroid function, which was improved
aer supplemental magnesium therapy27. To further clarify the relationship between serum magnesium levels and
autoimmune thyroiditis, as well as thyroid function, we performed a cross-sectional study among the permanent
residents of Tianjin.
Results
Demographic data of participants in different serum magnesium level groups. The demo-
graphic data of the study’s participants are shown in Table1. A total of 1,257 participants were included, among
whom the median serum magnesium level was 0.89 (0.73–1.06) mmol/L. e mean age of the participants was
42.5 ± 15.2 years and 49.2% were male. e proportion of elderly participants in the serum magnesium concen-
tration ≤0.55 mmol/L quartile group was signicantly higher than in the other groups. e 0.551–0.85 mmol/L
quartile group had the lowest proportion of female participants. In terms of education and income levels, serum
magnesium levels tended to increase gradually with increasing education and income levels (p < 0.0001). e
proportion of non-smokers was lowest in the 0.551–0.85 mmol/L quartile group and increased gradually in the
higher and lower quartile groups (p = 0.004). ere were no signicant dierences in the proportions of body
mass index (BMI) values among the groups.
Iodine nutrition state. e median urinary iodine concentration (UIC) of the subjects was 148.0 (quartile
range, 89.9–227.4) μg/L, indicating that the iodine-related nutritional status of the population was at an appro-
priate level.
Serum magnesium levels in the euthyroidism and hypothyroidism groups. e median serum
magnesium level in the euthyroidism group was 0.88 (0.73–1.06) mmol/L, and that in the hypothyroidism group
(including subclinical hypothyroidism) was 0.87 (0.61–1.09) mmol/L; there was no signicant dierence between
the two groups (Z = −1.712, p = 0.087). e median serum magnesium level in the subclinical hypothyroid-
ism group was 0.89 (0.60–1.10) mmol/L, which was not signicantly dierent from that in the euthyroidism
group (Z = −1.289, p = 0.197). e median serum magnesium level in the TPOAb-negative group was 0.88
(0.73–1.05) mmol/L, while that in the TPOAb-positive group was 0.90 (0.66–1.09) mmol/L; again, there was no
signicant dierence between the two groups (Z = −0.663, p = 0.507). e median serum magnesium level in the
TGAb-negative group was 0.88 (0.73–1.05) mmol/L, and that in the TGAb positive group was 0.91 (0.67–1.11)
mmol/L, with no signicant dierence (Z = −0.221, p = 0.825).
Relationship between serum magnesium level and thyroid disorders. e TPOAb positivity rate
in the lowest serum magnesium level (≤0.55 mmol/L) quartile group was 29.7%, which was signicantly higher
than the rates in the other groups (χ2 = 10.703, p = 0.013). Moreover, the TGAb positivity rate in the lowest quar-
tile group was 28.4%, which was also signicantly higher than the rates in the other quartile groups (χ2 = 23.148,
p = 0.000) (Table2). e prevalence of Hashimoto thyroiditis (HT) diagnosed using ultrasonography in the
lowest quartile group was 27.0%, which was signicantly higher than in the other quartile groups (χ2 = 21.785,
p = 0.000) (Table2). e prevalence of subclinical hypothyroidism in the lowest quartile group was 32.4%, which
was signicantly higher than in the other quartile groups (χ2 = 40.490, p = 0.000); the prevalence of hypothy-
roidism overall (both clinical and subclinical) in the lowest quartile was 40.5%, which was also signicantly
higher than in the other groups (χ2 = 54.527, p = 0.000) (Table2). e proportion of patients with clinical and
subclinical hyperthyroidism was highest in the quartile 3 (0.851–1.15 mmol/L), while there were no patients with
hyperthyroidism in the lowest quartile group. However, statistical analysis of patients with hyperthyroidism was
not possible owing to their small number.
Aer performing logistic regression analysis to adjust for confounding factors, the TGAb positivity rates in
the lowest serum magnesium level (≤0.55 mmol/L) quartile group were higher than those in the quartile 3 group
(0.851–1.15 mmol/L), (odds ratios [ORs]: 3.036–3.236); the prevalence of HT in the lowest serum magnesium level
(≤0.55 mmol/L) quartile group was higher than that in the quartile 3 group (0.851–1.15 mmol/L), (ORs: 2.748–
2.847); however, the serum magnesium level was not a statistically signicant risk factor for TPOAb positivity
(p > 0.05). e risks of hypothyroidism in the lowest serum magnesium level (≤0.55 mmol/L) quartile group were
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higher than those in the quartile 3 group (0.851–1.15 mmol/L), (ORs: 4.482–4.841); e risks of subclinical hypothy-
roidism in the lowest serum magnesium level (≤0.55 mmol/L) quartile group were higher than those in the quartile
3 group (0.851–1.15 mmol/L), (ORs: 4.517–4.971). e logistic regression analysis results are shown in Tables3, 4
and 5. e results using the forward method, backward method, or all arguments analysed together were consistent.
Variables All
participants
Serum magnesium (mmol/L)
p
value
Quartile
1 ≤ 0.55 Quartile 2
0.551–0.85 Quartile 3
0.851–1.15 Quartile
4 > 1.15
No. of participants (%) 1257 (100) 74 (5.9) 493 (39.2) 492 (39.1) 198 (15.8)
Median of serum magnesium
(quartile range, mmol/L) 0.89
(0.73–1.06) 0.50
(0.47–0.52) 0.73
(0.67–0.79) 0.98
(0.91–1.05) 1.26
(1.19–1.39)
Age (years) 42.5 ± 15.2 46.0 ± 20.1 39.0 ± 14.6 43.5 ± 14.7 47.7 ± 13.4 0.000
Age group, %
Young (18–39 years) 48.0 48.6 58.8 43.5 31.8 0.000
Middle-aged (40–64 years) 42.5 28.4 33.7 47.2 58.6
Elderly (≥65 years) 9.5 23.0 7.5 9.3 9.6
Sex (%)
Male 49.2 44.6 60.9 56.1 33.8 0.000
Female 50.8 55.4 39.1 43.9 66.2
Income
(×1000 RMB/year, %)
<10 4.5 14.9 4.5 4.3 1.0 0.000
10–50 49.6 56.8 54.2 47.0 42.4
50–100 32.0 23.0 28.6 32.5 42.4
≥100 13.9 5.4 12.8 16.3 14.1
Smoking status (%)
Never 71.0 75.7 64.2 74.6 77.3 0.004
Occasionally 1.5 0.0 1.8 1.4 1.0
Frequently 27.5 24.3 33.9 24.0 21.7
BMI (kg/m2) 24.7 ± 3.7 25.0 ± 4.6 24.4 ± 3.7 24.7 ± 3.7 25.1 ± 3.6 0.183
BMI (kg/m2) constitution, %
<18.5 (marasmus) 3.3 4.1 3.2 3.3 3.5 0.379
18.5–23.9 (moderate) 42.7 44.6 44.8 41.1 40.5
24–26.9 (overweight) 28.9 21.6 29.6 30.7 24.7
≥27 (obese) 25.1 29.7 22.3 25.0 31.3
Education
Junior school or below 18.1 32.4 18.7 18.5 10.6 0.000
High s chool 54.2 56.8 58.6 50.4 52.0
Junior college or above 27.7 10.8 22.7 31.1 37.4
Table 1. Characteristics of participants according to quartiles of serum magnesium. BMI: body mass index.
All (%)
Serum magnesium (mmol/L)
χ2p value
Quartile
1 ≤ 0.55 Quartile 2
0.551–0.85 Quartile 3
0.851–1.15 Quartile
4 > 1.15
n1257 (100) 74 (5.9) 493 (39.2) 492 (39.1) 198 (15.8)
Positive TPOAb 206 (16.4) 22 (29.7) 74 (15.0) 76 (15.4) 34 (17.2) 10.703 0.013
Positive TGAb 166 (13.2) 21 (28.4) 56 (11.4) 53 (10.8) 36 (18.2) 23.148 0.000
HTa140 (11.1) 20 (27.0) 43 (8.7) 55 (11.2) 22 (11.1) 21.785 0.000
Hypothyroidismb161 (12.8) 30 (40.5) 49 (9.9) 55 (11.2) 27 (13.6) 54.527 0.000
Subclinical hypothyroidism 136 (10.8) 24 (32.4) 40 (8.1) 48 (9.8) 24 (12.1) 40.490 0.000
Clinical hypothyroidism 25 (2.0) 6 (8.1) 9 (1.8) 7 (1.4) 3 (1.5) 10.090 0.012
Hyperthyroidismc19 (1.5) 06 (1.2) 10 (2.0) 3 (1.5) 4.008 0.216
Subclinical hyperthyroidism 6 (0.5) 01 (0.2) 3 (0.6) 2 (0.1)
Clinical hyperthyroidism 13 (1.0) 05 (1.0) 7 (1.4) 1 (0.5)
Table 2. Prevalence of thyroid disorders according to quartiles of serum magnesium. aHT: Hashimoto
thyroiditis, which was diagnosed using ultrasonography; bincluding clinical and subclinical hypothyroidism;
cincluding clinical and subclinical hyperthyroidism; TPOAb: anti-thyroid peroxidase antibody; TGAb: anti-
thyroglobulin antibody.
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Discussion
Magnesium in the human body is mostly located in the cells and bone tissues; only 1% of total body magnesium
is located in extracellular uids, and only 0.3% of total body magnesium is present in serum1. However, the
detection of intracellular magnesium ions is dicult, while the detection of serum magnesium ions is simple
and convenient. erefore, serum magnesium is still used to assess individuals’ magnesium nutritional statuses1.
Hypermagnesaemia and magnesium poisoning are rare in clinical practice, and only occur in patients with severe
renal failure. e main clinical manifestation of magnesium nutrition imbalance is low serum magnesium, the
denition of which varies among dierent populations and methods of detection. Recent evaluations of serum
magnesium as an indicator of magnesium status have indicated that individuals with serum magnesium values
>0.85 mmol/L most likely have adequate magnesium levels20,28,29. erefore, in our study, serum magnesium
levels ≤0.85 mmol/L were considered low. Additionally, serum magnesium levels ≤0.55 mmol/L were considered
severely low in our study, as previously described in the literature30,31.
Moreover, the median serum magnesium level was 0.89 (0.73–1.06) mmol/L in our study; the proportion
of subjects with inadequate magnesium levels (≤0.85 mmol/L) was 45.1%, while the proportion of people with
severely low serum magnesium was 5.9%. e NAHSIT4 showed that the mean serum magnesium levels of male
and female participants were 0.861 and 0.866 mmol/L, respectively; furthermore, 12.3% and 23.7% of male and
female participants had low serum magnesium levels (dened as <0.8 mmol/L in the NAHSIT), which were
lower rates than in our study. Using the Food Frequency Questionnaire, the NAHSIT found that the daily mag-
nesium intakes of 75% in male participants and 81% in female participants were lower than the DRI; the daily
magnesium intake of middle-aged individuals (ages 45–64 years) was the highest, while that of elderly individuals
Serum magnesium
(mmol/L)
Model 1 aModel 2bModel 3cModel 4d
OR (95% CI) pOR (95% CI) pOR (95% CI) pOR (95% CI) p
Positive TPOAb
Serum magnesium 0.075 0.071 0.066 0.056
≤0.55 2.099 (1.162–3.792) 0.014 2.071 (1.146–3.744) 0.016 2.127 (1.167–3.874) 0.014 2.208 (1.222–3.990) 0.009
0.551–0.85 1.103 (0.759–1.605) 0.607 1.121 (0.770–1.633) 0.551 1.119 (0.764–1.638) 0.563 1.075 (0.740–1.563) 0.704
0.851–1.15 1.00 1.00 1.00 1.00
>1.15 0.927 (0.586–1.468) 0.747 0.896 (0.565–1.422) 0.642 0.885 (0.552–1.417) 0.611 0.960 (0.607–1.519) 0.862
Positive TGAb
Serum magnesium 0.002 0.003 0.002 0.001
≤0.55 3.084 (1.690–5.629) 0.000 3.036 (1.663–5.544) 0.000 3.236 (1.751–5.980) 0.000 3.171 (1.730–5.812) 0.000
0.551–0.85 1.186 (0.780–1.803) 0.425 1.190 (0.782–1.811) 0.417 1.211 (0.792–1.851) 0.377 1.158 (0.761–1.760) 0.494
0.851–1.15 1.00 1.00 1.00 1.00
>1.15 1.586 (0.990–2.541) 0.055 1.557 (0.971–2.497) 0.066 1.484 (0.916–2.405) 0.109 1.484 (0.916–2.405) 0.043
Table 3. Relative risk of TPOAb and TGAb positivity according to quartiles of serum magnesium as
determined using multiple logistic regression analyses. TPOAb: anti-thyroid peroxidase antibody; TGAb: anti-
thyroglobulin antibody; OR: odds ratio; CI: condence interval. aModel 1: adjusted for age, sex, smoking status,
and serum iodine concentration; bModel 2: additionally adjusted for body mass index; cModel 3: adjusted for all
covariates in model 2 as well as income and education; dModel 4: adjusted for all covariates in model 1, but age
was used as classication variable according to youth, middle age, and old age (as shown in Table1). Regression
analyses using the forward method, backward method, and all arguments simultaneously were performed; the
results were similar.
Serum magnesium
(mmol/L)
Model 1 aModel 2bModel 3cModel 4d
OR (95% CI) pOR (95% CI) pOR (95% CI) pOR (95% CI) p
HT using ultrasonography
Serum magnesium 0.002 0.002 0.003 0.001
≤0.55 2.748 (1.489–5.070) 0.001 2.847 (1.533–5.287) 0.001 2.763 (1.470–5.193) 0.002 2.944 (1.590–5.450) 0.001
0.551–0.85 0.884 (0.568–1.376) 0.585 0.916 (0.588–1.428) 0.700 0.900 (0.575–1.408) 0.644 0.871 (0.559–1.355) 0.539
0.851–1.15 1.00 1.00 1.00 1.00
>1.15 0.806 (0.472–1.378) 0.430 0.785 (0.457–1.349) 0.381 0.755 (0.434–1.313) 0.320 0.832 (0.487–1.420) 0.499
Table 4. Relative risk of Hashimoto thyroiditis (HT) diagnosed using ultrasonography according to quartiles
of serum magnesium as determined using multiple logistic regression analyses. HT: Hashimoto thyroiditis;
OR: odds ratio; CI: condence interval. aModel 1: adjusted for age, sex, smoking status, and serum iodine
concentration; bModel 2: additionally adjusted for body mass index; cModel 3: adjusted for all covariates in
model 2 as well as income and education; dModel 4: adjusted for all covariates in model 1, but age was used as
a classication variable according to youth, middle age, and old age (as shown in Table1). Regression analyses
using the forward method, backward method, and all arguments simultaneously were performed; the results
were similar.
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(≥65 years) was the lowest. Our study also found that the proportion of elderly subjects (≥65 years) was signi-
cantly higher in the lowest serum magnesium quartile group. Moreover, the proportion of young people (18–39
years) tended to decrease in the higher (>0.55 mmol/L) quartile groups, while the proportion of individuals
≥40 years old tended to increase. On the one hand, this might be related to the intake level of magnesium in the
diet; on the other hand, these results can also be explained by the decline of intestinal absorption capacity in the
elderly vs. rapid metabolism in young individuals. Our study also found that individuals with lower educational
and income levels were more likely to exhibit low serum magnesium; this might be related to dietary structure as
well as food aordability. In a cross-sectional study of 13,226 American participants, the proportion of individuals
with serum magnesium levels <0.75 mmol/L was 26.5%, while that of individuals with levels <0.70 mmol/L was
10.3%. In that study, participants with lower education and income levels were more likely to have low serum
magnesium levels32, which was consistent with our data.
Logistic regression analysis revealed that the morbidity risk owing to clinical and subclinical hypothyroidism
was increased in the lowest serum magnesium level (≤0.55 mmol/L) quartile group. Early studies on magne-
sium and thyroid function revealed that serum magnesium levels in patients with hyperthyroidism are decreased
while those in patients with hypothyroidism are increased; this change might be related to thyroid hormones
causing increased magnesium excretion in the urine33. However, subsequent studies have produced contrasting
ndings; animal model34 and clinical studies35,36 found hypothyroidism to be associated with decreased serum
magnesium levels, and the role of thyroid hormones on the magnesium urinary excretion rate was mainly related
to their eect on the degree of urinary concentration. ere were no dierences in the levels of urinary magne-
sium or creatinine levels in patients with varying thyroid functionality35. Furthermore, a previous study showed
that the inhibition of mitochondrial oxidative phosphorylation may lead to decreased iodine uptake by thyroid
cells, as such uptake is achieved by a sodium iodide cotransporter that requires a mitochondrial energy supply37.
Magnesium, as an enzyme cofactor, plays a critical role in mitochondrial oxidative phosphorylation and ATP
synthesis, and its deciency can aect these functions and lead to decreased iodine uptake by thyroid cells and
a subsequent drop in thyroid hormone synthesis, thereby causing the secretion of thyroid-stimulating hormone
(TSH). Animal experiments have shown that magnesium supplementation can signicantly increase radioactive
iodine uptake by thyroid cells, while its deciency does the opposite34. Notably, the majority of participants with
hypothyroidism in this study exhibited subclinical hypothyroidism; those with clinical hypothyroidism were too
few in number to analyse separately using logistic regression analysis. erefore, our conclusions are mainly
applicable to subclinical hypothyroidism.
Our study found that serum magnesium levels ≤0.55 mmol/L were related to the risk of TGAb positivity and
prevalence of HT. ere are at least two explanations for this: rst, severely low serum magnesium can increase
TGAb via the abnormal activation of immune cells and induction of an autoimmune response. A study on patients
with Graves’ disease found that their serum magnesium concentrations were lower than in normal individuals, and
that the serum magnesium concentration was inversely related to the activation levels of CD3+, CD4+, CD8+T, and
CD19+B cells. It was speculated that low serum magnesium might lead to decreased immune tolerance and abnor-
mal activation of immune cells26. Second, given its function as a coenzyme, magnesium is involved in a variety of
antioxidant metabolism pathways, such as glutathione synthesis; low serum magnesium could therefore reduce the
antioxidant response capacity in cells and allow the accumulation of free radicals, resulting in oxidative stress and
tissue damage21,38,39. Epidemiological studies have shown that insucient magnesium intake is associated with a
variety of chronic inammatory diseases and elevated serum C-reactive protein levels6,22,23,40.
Model 1 aModel 2bModel 3cModel 4d
OR (95% CI) pOR (95% CI) pOR (95% CI) pOR (95% CI) p
Hypothyroidism
Serum magnesium 0.000 0.000 0.000 0.000
≤0.55 4.482 (2.438–8.239) 0.000 4.544 (2.468–8.369) 0.000 4.841 (2.584–9.070) 0.000 4.785 (2.582–8.866) 0.000
0.551–0.85 0.982 (0.627–1.535) 0.935 0.999 (0.636–1.570) 0.997 1.024 (0.647–1.621) 0.918 0.995 (0.634–1.559) 0.981
0.851–1.15 1.00 1.00 1.00 1.00
>1.15 0.954 (0.561–1.623) 0.863 0.916 (0.536–1.565) 0.747 0.847 (0.491–1.461) 0.551 0.973 (0.572–1.657) 0.920
Subclinical hypothyroidism
Serum magnesium 0.000 0.000 0.000 0.000
≤0.55 4.517 (2.382–8.567) 0.000 4.531 (2.382–8.617) 0.000 4.971 (2.557–9.666) 0.000 4.654 (2.435–8.896) 0.000
0.551–0.85 0.885 (0.540–1.451) 0.629 0.919 (0.558–1.512) 0.739 0.951 (0.572–1.580) 0.846 0.890 (0.543–1.461) 0.646
0.851–1.15 1.00 1.00 1.00 1.00
>1.15 1.066 (0.608–1.872) 0.823 1.038 (0.589–1.831) 0.897 0.903 (0.505–1.613) 0.730 1.087 (0.619–1.910) 0.772
Table 5. Relative risk of hypothyroidism (including clinical and subclinical hypothyroidism) and subclinical
hypothyroidism-only according to quartiles of serum magnesium determined using multiple logistic regression
analyses. aModel 1: adjusted for age, sex, anti-thyroid peroxidase antibody, anti-thyroid globulin antibody, and
serum iodine concentration. bModel 2: additionally adjusted for smoking status, and body mass index. cModel
3: adjusted for all covariates in model 2 as well as income and education. dModel 4: adjusted for all covariates in
model 1, but age was used as a classication variable according to youth, middle age, and old age (as shown in
Table1). Regression analyses using the forward method, backward method, and all arguments simultaneously
were performed and the results were similar. OR: odds ratio; CI: condence interval.
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Our study revealed that severely low serum magnesium levels were not related to increased TPOAb positivity.
e clinical signicance of TPOAb is distinct from that of TGAb, as it is the most sensitive and specic index for
the diagnosis of autoimmune thyroiditis and is closely related to hypothyroidism41. However, as a serological
marker of autoimmune thyroiditis, TGAb does not damage the thyroid gland42. e dierent eects of severely
low serum magnesium on the two autoantibodies examined in our study indicated that its eect on the thyroid
autoantibody might primarily be caused by inammation and oxidative stress, rather than by activating auto-
immune responses. In other words, severely low serum magnesium is not the initiating factor of autoimmune
thyroiditis, but might be an aggravating factor via inammation.
is study found that non-severely low serum magnesium (0.551–0.85 mmol/L) is not associated with thyroid
autoantibody levels or thyroid function. Another study on the relationship between low serum magnesium and
metabolic syndrome with low-grade inammation also found that inammatory factors were elevated only when
magnesium levels were severely low (<0.5 mmol/L)31. Animal studies found that the inammatory response
caused by mild-to-moderate magnesium deciency could be compensated for, or aggravated, by other factors39.
Hegsted et al. found that reducing the magnesium intake in rats to 50% of their required levels did not inhibit
their growth; however, placing these rats in a cold environment (13 degrees) reduced their growth rate signi-
cantly compared with control rats with normal magnesium intake43. is indicated that the eects of mild versus
moderate magnesium deciency in dierent individuals might be more complex; therefore, studies of dierent
populations may well produce dierent results. Additionally, results can dier based on dierent denitions of
low serum magnesium levels and varying cut-o points.
is study included some limitations. First, because most of the body’s magnesium content is intracellular,
serum magnesium does not fully represent the body’s magnesium nutritional status. However, in a large-scale epi-
demiological investigation, serum magnesium is still the most feasible and representative index. Second, dietary
magnesium intake was not investigated in this study. If serum magnesium and the nutritional questionnaire were
analysed together, more comprehensive data on the nutritional status of magnesium may have been obtained.
ird, all subjects included in this study were residents of Tianjin; while the background data in each group were
relatively consistent, other confounding factors might still be present. Lastly, as an observational study, our results
could only reveal the associations between severely low serum magnesium levels, TGAb, HT, and thyroid func-
tion; prospective interventional studies are required to conrm the conclusion and reveal any cause-and-eect
relationships.
Conclusions
Our cross-sectional survey revealed that the proportion of Tianjin residents with inadequate magnesium status
(serum magnesium levels ≤0.85 mmol/L) was 28.2%, and that with severe magnesium deciency (serum mag-
nesium levels ≤0.55 mmol/L) was 5.9%. Serum magnesium levels ≤0.55 mmol/L were associated with increased
risks of TGAb positivity, the prevalence of HT, and (mainly subclinical) hypothyroidism, indicating that serum
magnesium levels should be evaluated in patients with autoimmune thyroiditis and hypothyroidism. Increased
magnesium intake or magnesium supplementation may be benecial for patients with severely low blood magne-
sium who are diagnosed with these disorders.
Methods
Subjects. e “yroid Disorders, Iodine Status and Diabetes: a National Epidemiological Survey-2014” is a
cross-sectional study of thyroid disease, iodine nutrition status, and diabetes mellitus performed across 31 prov-
inces, municipalities, and autonomous regions of China; the Tianjin portion was conducted between June and
September, 2015. A total of 2,650 participants were enrolled using stratied multi-stage cluster random sampling.
e serum magnesium levels of 1,257 participants whose blood samples were kept intact were examined in this
study; all participants were older than 18 years and were of Han ethnicity. All participants had lived in the local
area for more than ve years; none received any examination involving iodinated contrast agent or took any drugs
containing iodine during the previous three months. Pregnant women and patients with chronic diarrhoea and
kidney disease were excluded. e research project was approved by the ethics committee of e First Hospital of
China Medical University and was conducted in accordance with the Declaration of Helsinki II. All participants
signed informed consent forms.
Specimen and data acquisition. Demographic data, smoking history (including passive smoking), and
income and education levels were collected via questionnaires. e heights and weights of all participants were
measured by a single investigator using a standardized measurement method, and the BMI was then calculated.
Fasting venous blood (5 mL) was collected from all participants in the morning, and blood was allowed to coag-
ulate. Serum was separated within 6 h and stored in a −80 °C freezer; the levels of TSH, TPOAb, TGAb, serum
iodine, and serum magnesium were detected uniformly. Free thyroxine (FT4) was also detected for participants
with TSH elevation; FT4 and free triiodothyronine (FT3) were also detected in participants with decreased TSH lev-
els. Fasting morning urine (5 mL) was collected from all participants and stored at −80 °C for urinary iodine tests.
Laboratory testing. Roche cobas e601 reagent kits were used for the detection of FT3, FT4, TSH, TPOAb,
and TGAb; all were detected using chemiluminescence immunoassays according to the manufacturer’s instruc-
tions. e kits were subjected to quality control tests; the intra-assay coecients of variation for the measured
parameters were 1.1–6.3%, while the inter-assay coecients of variation were 1.9–9.5%. Serum iodine and serum
magnesium were detected using inductively coupled plasma mass spectrometry. e UIC was detected by urine
iodine arsenic cerium catalytic spectrophotometry (WS/T-2006). e levels of serum iodine, serum magne-
sium, and UIC were the averages of triplicate measurements. e intra-assay coecients of variation for serum
iodine and serum magnesium were 1.4–4.5%, while the inter-assay coecients of variation were 2.7–6.4%. e
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intra-assay coecient of variation for UIC (66 μg/L) was 3–4%, while the inter-assay coecients of variation were
4–6%; the intra-assay coecients of variation for UIC (230 μg/L) were 2–5%, while the inter-assay coecients of
variation were 3–6%.
Ultrasonography. yroid ultrasonography was performed by the same experienced physician using com-
mercially available ultrasound equipment (LOGIQα100, GE Company, United States) equipped with a 7.5 Hz
linear transducer. Patients were examined in a supine position with their neck hyperextended in accordance with
a standard sonographic protocol. Markedly decreased echogenicity, heterogeneity, and brous septation inltra-
tion were considered indicative of HT according to the literature44,45.
Diagnostic criteria. Using the normal ranges provided by the testing kits as references, the normal range of
TSH was 0.27–4.20 mIU/L, while the reference range of FT4 was 12.00–22.00 pmol/L. Patients with TSH eleva-
tion and decreased FT4 combined with positive thyroid autoantibodies or ultrasound performance of HT were
deemed to have clinical hypothyroidism; those with TSH elevation and normal FT4 were considered to have
subclinical hypothyroidism. e reference ranges for TPOAb and TGAb were 0–34 IU/L and 0–115 IU/L, respec-
tively. TPOAb >34 IU/L and TGAb >115 IU/L were deemed to be elevated (i.e., positive).
Statistical analysis. e SPSS 19.0 soware (IBM, Chicago, Illinois) was used to analyse the data. e meas-
urements and normal distributions are expressed as means ± standard deviations, while values with skewed dis-
tributions are expressed as medians (interquartile ranges); enumerated values are represented as percentages. e
participants were divided into four groups based on serum magnesium concentration: quartile 1, serum magne-
sium concentration ≤0.55 mmol/L; quartile 2, 0.551–0.85 mmol/L; quartile 3, 0.851–1.15 mmol/L; and quartile 4,
>1.15 mmol/L corresponding to severe magnesium deciency, deciency, adequate level, and excess, respectively.
e adequate magnesium group (0.851–1.15 mmol/L) was taken as the control group. Sex, TPOAb, TGAb, smok-
ing history, annual income level, education level, and BMI were used as classication variables; distributions are
shown in Table1. Age was used as both a continuous and classication variable. BMI categories were determined
according to the overweight and obesity standards in China46. e data in each group were analysed using single
factor analysis of variance and rank sum tests; the chi-square and Fisher exact probability tests were used to com-
pare the rates among groups.
A logistic regression model was used to adjust for the inuence of confounding factors. When analysing the
dependent variables TPOAb, TGAb, and HT, the independent variables sex, age, serum iodine concentration,
serum magnesium concentration, and smoking history were incorporated into model 1. Model 2 incorporated
model 1 and additionally adjusted for BMI; furthermore, model 3 incorporated model 2 while adding the inde-
pendent variables of income and education levels. When analysing the dependent variables (all hypothyroidism
and subclinical hypothyroidism-only), the independent variables sex, age, TPOAb, TGAb, serum iodine concen-
tration, and serum magnesium concentration were incorporated into model 1. Model 2 incorporated model 1
plus the independent variables smoking history and BMI, while model 3 incorporated model 2 in addition to the
independent variables of income and education levels. Age and serum iodine concentration were continuous var-
iables, whereas the remaining variables were categorical. e forward and backward methods, as well as all argu-
ments analysed simultaneously, were used for regression analysis; p < 0.05 was considered statistically signicant.
Availability of data and materials. e datasets analysed during the current study are available from the
corresponding author on reasonable request.
Ethics Approval and Consent to Participate. Ethical approval for this study was obtained from the
Ethics Committee of e First Hospital of China Medical University, Shenyang, China. Informed consent was
obtained from all participants.
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Acknowledgements
is work was supported by the National Natural Science key project foundation of China (Grant 81330064), the
National Natural Science foundation of China (Grant 71774115), the Technology Plan Key Projects of Tianjin
(Grant 14ZCZDSY00022), the Popular Science Projects of Tianjin (Grant 15KPXM01SF037), and the Major
Project of Tianjin Municipal Education Commission (Grant 2017JWZD35).
Author Contributions
Kunling Wang wrote the manuscript. Kunling Wang, Hongyan Wei, Wanqi Zhang, Zhongyan Shan, and Mei Zhu
were involved in the design and execution of the study. Kunling Wang, Hongyan Wei, Zhen Li, Li Ding, Tong Yu,
Long Tan, Yaxin Liu, Tong Liu, Hao Wang, and Yuxin Fan were involved in collecting materials. Zhen Li, Long
Tan, and Peng Zhang were involved in laboratory measurements. Mei Zhu was involved in data interpretation and
manuscript writing. All authors read and approved the nal manuscript.
Additional Information
Competing Interests: e authors declare no competing interests.
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and
institutional aliations.
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