Effects of Altitude on Thyroid Disorders according to Chinese Three-Rung, Ladder-like Topography：National Cross- Sectional Study

doi:10.21203/rs.3.rs-2741936/v1

Download PDF

Research Article

Effects of Altitude on Thyroid Disorders according to Chinese Three-Rung, Ladder-like Topography：National Cross- Sectional Study

https://doi.org/10.21203/rs.3.rs-2741936/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 02 Jan, 2024

Read the published version in BMC Public Health →

You are reading this latest preprint version

Background: Chinese topography appears a three-rung ladder-like distribution of decreasing elevation from northwest to southeast, which is divided by two sloping edges. To explore the association between three-rung ladder-like regions and thyroid disorders according to unique Chinese topographic features, we conducted an epidemiological cross-sectional study from 2015–2017 that covered all 31 mainland Chinese provinces.

Methods: A total of 78,470 participants aged ≥18 years from a nationally representative cross-sectional study were included. Serum thyroid peroxidase antibody, thyroglobulin antibody, and thyroid-stimulating hormone levels; urine iodine concentration; and thyroid volume were measured. The three-rung ladder-like distribution of decreasing elevation from northwest to southeast in China was categorized into three topographic groups according to elevation: first ladder, >3000 m above sea level; second ladder, descending from 3000 - 500 m; and third ladder, descending from 500 m to sea level. The third ladder was further divided into groups A (500-100 m) and B (<100 m). Associations between geographic factors and thyroid disorders were assessed using linear and binary logistic regression analyses.

Results: Participants in the first ladder group were associated with lower thyroid peroxidase (β=-4.69; P=0.00) , thyroglobulin antibody levels (β=-11.08; P=0.01), and the largest thyroid volume (β=1.74; P=0.00), compared with the other groups. The second ladder group was associated with autoimmune thyroiditis (odds ratio=1.30, 95% confidence interval [1.18-1.43]) and subclinical hypothyroidism (odds ratio=0.61, 95%confidence interval [0.57-0.66]) (P<0.05) compared with the first ladder group. Group A (third ladder) (500-100 m) was associated with thyroid nodules and subclinical hypothyroidism (P<0.05). Furthermore, group B (<100 m) was positively associated with autoimmune thyroiditis, thyroid peroxidase and thyroglobulin antibody positivity, and negatively associated with overt hypothyroidism, subclinical hypothyroidism, and goiter compared with the first ladder group(P<0.05).

Conclusion: We are the first to investigate the association between different ladder regions and thyroid disorders according to unique Chinese topographic features. The prevalence of thyroid disorders varied among the three-rung ladder-like topography groups in China, with the exception of overt hyperthyroidism.

high altitude

geographic variation

thyroid disorders

Chinese topography

thyroid antibody

China is located in East Asia on the western shores of the Pacific Ocean. The immense Chinese territory is approximately 9.6 million km2. Chinese topography has a three-step ladder-like distribution that slopes downward from northwest to southeast (Fig. 1)(1). The Kunlun, Qilian, and Hengduan and Great Khingan, Taihang, Wushan, and Xuefeng Mountains are the boundaries for the first and second and second and third ladders, respectively(2). Over 66% of China consists of upland hills, mountains, and plateaus, and the highest mountains and plateaus are located mainly in the first ladder region, including the highest and largest plateau, the Qinghai-Tibet Plateau, which is known as the “roof of the world”(3). The second ladder region is mainly comprised of the Inner Mongolia, Loess, and Yunnan-Guizhou Plateaus. The third ladder region is mainly comprised of the Yangtze Plain, Northeast China Plateau, Liaodong Hills, and North China Plain. The relationship between Chinese three-rung, ladder-like topography and thyroid disorders has yet to be systematically reported.

Thyroid hormones play important roles in cell growth and differentiation, and elevated thyroid antibody levels are involved in the progression of many autoimmune thyroid diseases(4, 5). Several previous studies have reported thyroid status changes at different altitudes(6, 7). Endocrine system responses to chronic high-altitude exposure were significantly different from those in sea-level areas or low-altitude plain regions. Free thyroxine (FT4) levels reportedly significantly increased after 3 weeks at 4300 m without any change in thyroid-stimulating hormone (TSH) levels(8). Moreover, the hypothalamic-pituitary-thyroid (HPT) axis was reportedly altered to adapt to high-altitude environments, including hypoxic conditions, hypohydration, and nutrition alterations(9–12).

Recently, a few small, population-based studies explored the association between thyroid status and the first ladder region of Tibet, although these studies did not compare thyroid status with the other two Chinese ladder regions(13). Furthermore, an Ethiopian study reported that altitude correlated with goiter prevalence, with the peak prevalence observed in the highlands(14). Here, we used data from the Thyroid disorders, iodine status, and Diabetes, a national epidemiological cross-sectional study (TIDE) conducted from 2015–2017 that covered all 31 mainland Chinese provinces to explore the association between thyroid status and different ladder-like altitude regions, as well as the prevalence of thyroid disorders considering unique Chinese topographic features.

Study design and population

This study included 80,937 people who were random selected fulfilling the inclusion criteria from urban and rural regions, including all 31 provinces of mainland China. The ration of age and sex urban, or rural population in each region was calculated based on data from the 2010 China census. We used a multiple stratified sampling method to select one representative city per province according to population size and economic level. The inclusion criteria were: 18 years or older, resident of a selected community for at least five years, no iodine drugs or contrast agents within the previous 3 months, and not pregnant. Moreover, 2,467 participants were excluded because of missing sex, age, or thyroid function test data. Ultimately, 78,470 participants (38,182 men and 40,288 women) were included in the analysis. This study was approved by the Medical Ethics Committee of the China Medical University. All participants provided written informed consent after we explained all research procedures. Participants did not receive a stipend and all research complied with the declaration of Helsinki. More details of the TIDE study design have been published previously(15).

China’s territory slopes downward from the northwest to southeast similar to a three-step ladder, which is divided by two sloping edges. The first ladder is > 3000 m above sea level (ASL), the second ladder descends from 3000 to 500 m, and the third ladder is < 500 m ASL(16, 17). Therefore, geographically speaking, we divided all residents into three groups by two sloping edges, where two steps meet. (Figure S1). The average altitude of each region was based on the national standards of the People’s Republic of China (GB50009-2012)(18).

Laboratory tests

Venous blood samples were collected from each participant and transported via a cold chain system to the Central Laboratory in Shenyang for unified testing of thyroid parameters. Serum TSH, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) levels were measured using an electrochemiluminescence immunoassay on a Cobas 601 analyzer (Roche Diagnostics, Basel, Switzerland) at the Central Laboratory in Shenyang. The sensitivity and specificity of the TSH assay was 0.01 µIU/mL. Free triiodothyronine (FT3) and FT4 levels were measured only if TSH levels were outside the reference range (0.27–4.20 mIU/L). The normal ranges for TPOAb, TgAb, and TSH provided by the manufacturers were < 34.00 IU/mL, < 115.00 IU/mL, and 0.27–4.20 mIU/L, respectively. Urine iodine concentration (UIC) was determined using inductively coupled plasma mass spectrometry (Agilent 7700x; Agilent Technologies Inc., Santa Clara, CA, USA). Certified reference material (GBW09108, GBW9109, and Cmeasurement quality. Comprehensive quality control was implemented to ensure the data was valid and well defined.

Thyroid ultrasonography

All participants underwent thyroid ultrasonography by qualified observers, who had specially trained and passed examination in the project center, using a portable instrument (LOGIQ 100PRO; GE, Milwaukee, WI with a 7.5 MHz linear array transducer). Thyroid volume was calculated as the sum of both lobes volumes estimated according to the formula: V (ml) = 0.479×width (cm) ×depth (cm) ×length (cm), without isthmus. Two trained quality control personnel beyond the sonographers were responsible for supervising the accuracy and reliability of the ultrasound results.

Clinical diagnosis

The diagnostic criteria for thyroid disorders are listed in Table S1.

Covariates

Demographic information, including age, sex, ethnicity, region of residence, education level, and smoking status, was collected using a standard questionnaire. Ethnicity was categorized as Han or other. Education level was categorized as junior school and below or high school and above. Participants who smoked at least one cigarette per day were defined as current smokers. Body mass index (BMI) was calculated according to World Health Organization criteria.

Statistical analyses

All statistical analyses were performed using SPSS software (version 23.0; IBM Corp., Armonk, NY, USA). We performed a descriptive analysis of BMI, UIC, TPOAb, TgAb, TSH levels, and thyroid volume which were not normally distributed using quartile stratification and compared the medians for differences using the Kruskal-Walls test. The chi-square test was used for categorical data and presented as percentages or counts to compare the thyroid disorder prevalence and related diseases (Table S2). Line chart was used to visually present the results of the prevalence of different thyroid disease among successive three ladder groups. We used linear regression analyses to estimate the TPOAb, TgAb, TSH levels and thyroid volume among the three ladder groups. Linear regression analyses were adjusted for age and sex in model 1 and age, sex, ethnicity, location, education level, smoking status, BMI, and UIC in model 2. Binary logistic regression analyses were adjusted for age and sex in model 1 and age, sex, ethnicity, location, education level, smoking status, BMI, and UIC in model 2, which were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and evaluate the risk factors for thyroid disorders and related diseases according to the three ladder groups. Statistical significance was defined as P < 0.05. Corrected P values were used for pairwise comparisons of multiple groups.

3.1 Population characteristics according to three-rung, ladder-like topographic groups

Table 1 summarizes the general participant characteristics from the TIDE study by geographic distribution according to the three-rung, ladder-like topographic groups, which revealed that China’s population is mainly concentrated in eastern China, possibly owing to topographic patterns and natural resources(19). Among 78,470 participants, 60.55% lived in the third ladder region at elevations below 500 m ASL, which was significantly higher than that of the second (32.97%) and first ladder groups (6.47%). People of Han ethnicity were more likely to live in the second and third ladder regions. The median TSH value among participants from the first ladder group was 2.84 mIU/L, which was significantly higher than that in participants from the second ladder (2.51) and the third ladder (2.20) (P<0.05). Moreover, among all three ladder groups, the median thyroid volume in the first ladder group was the largest than the other ladder groups (200.18 μg/L) (P<0.05).

3.2 Associations between ladder regions and clinical thyroid parameters

Table 2 shows the associations between the three ladder regions and TPOAb, TgAb, TSH, and thyroid volume values using linear regression analysis. After adjustments for age, sex, ethnicity, location, education level, smoking status, BMI, and UIC, participants in the second ladder (β=-0.82 [95% CI -0.96 to -0.68] and third ladder (β=-1.24 [95% CI -1.38 to -1.10] were associated with lower serum TSH concentration, compared to the first ladder group. The median TSH value was higher among participants in the first ladder group than that of the other groups (P<0.025). Participants in the second ladder and third ladder group were associated higher TPOAb and TgAb levels compared to the first ladder group after adjustments for confounding factors (P<0.05). Besides, the median thyroid volume among participants in the first ladder group was significantly larger than that in the other ladder groups (P<0.001). As shown in Table 2, thyroid volume was negatively associated with the second ladder group (β=-2.50 [95% CI -2.66 to -2.33]) and the third ladder group (β=-1.37 [95% CI -1.54 to -1.20]) compared to the first ladder group (P<0.05).

3.3 Hyperthyroidism

No significant association was found between the three successive ladder regions and the prevalence of overt hyperthyroidism and subclinical hyperthyroidism (P>0.05). The prevalence of Graves’ disease (GD) in the first ladder group was lower than that in the other ladder groups (P<0.025) (Figure 2). Compared with the first ladder group, significant associations were found between the third ladder group (OR=2.06 [CI=1.21-3.52]) and GD after adjustments for confounding factors (P<0.05), while no significant difference was found with the second ladder group by binary logistic regression (p>0.05) (Table 3).

3.4 Hypothyroidism

Both overt hypothyroidism and subclinical hypothyroidism prevalence decreased with descending altitude from the first to the third ladder regions. Participants in the first ladder group had a significantly higher overt hypothyroidism prevalence (1.83%) than that in the second ladder group (1.40%), and the third ladder group (1.02%) (P<0.001) (Figure 2). Compared with the first ladder group, the third ladder showed a significant association with overt hypothyroidism (OR=0.77 [CI=0.60-0.99]) (P<0.05). However, no significant association was found between the second ladder group and overt hypothyroidism (P>0.05) (Table 3). Participants in the first ladder group had a higher prevalence of subclinical hypothyroidism than that in the other ladder groups (P<0.001). After adjustments for confounding factors, the OR of the second ladder group was 0.57 [CI 0.52-0.61], and that of the third ladder was 0.34 [CI 0.31-0.31], compared with that of the first ladder group.

3.5 Autoimmune thyroiditis

The autoimmune thyroiditis (AIT) prevalence and TPOAb and TgAb positivity increased with descending altitude. The AIT prevalence was 12.20%, 15.21%, and 14.55% for the first ladder group to the third ladder group. The prevalence of TPOAb and TgAb positivity in the second ladder group and the third ladder group were higher than that in the first ladder group (all P<0.001) (Figure 2). After adjustments for confounding factors, the ORs [CIs] of AIT in the second ladder group and the third ladder group were 1.33 [CI=1.21-1.47], 1.25 [CI=1.14-1.38], respectively, compared with that of the first ladder group (P<0.05). Furthermore, compared with the first ladder group, the second ladder group showed a significant association with TPOAb (OR=1.30 [CI=1.16-1.46]) and TgAb positivity (OR=1.35 [CI=1.20-1.51]) (P<0.05) (Table 3).

3.6 Goiter

The goiter prevalence of the overall population and women was significantly higher in the first ladder group than that in the second and third ladder groups, along with the prevalence in men (Figure 2). Compared with the first ladder group, the second ladder group (OR=0.56 [CI=0.44-0.71]) showed negative associations with goiter, while no significant association was observed between the third group and goiter prevalence (OR=0.83 [CI=0.66-1.08]) (P>0.05) after adjustments for confounding factors (Table 3).

3.7 Thyroid nodule

Figure 2 illustrates a thyroid nodule prevalence of 18.54% in the first ladder group, which was significantly lower than that in the second ladder groups (20.86%) and the third ladder group (21.35%) (P<0.001). The prevalence of thyroid nodule increased with descending altitude from the first to the third ladder regions. Both men and women showed a similar trend. Table 3 shows the binary logistic regression model results which revealed ORs for the second ladder group of 1.43 [CI 1.32-1.56] and 1.58 [CI 1.45-1.72] for the third ladder group, respectively, compared with that for the first ladder group, after adjustments for confounding factors (P<0.05).

Thyroid disease is a prevalent health problem with potential health consequences with increasing prevalence worldwide(20). Thyroid disease can occur alone or in the context of other autoimmune diseases such as celiac disease and type 1 diabetes mellitus(21, 22). Undiagnosed or uncontrolled thyroid disease can lead to adverse outcomes, including cardiovascular disease, osteoporosis or fractures, pregnancy problems, and all-cause mortality(23–25). The TIDE study explored the relationship between iodine status and thyroid disorders, while differences in topographic conditions and altitude, which may affect thyroid status, still need to be clarified(15, 26). To the best of our knowledge, this is the first cross-sectional study with a large sample size investigating the association between three ladder regions with different altitudes and thyroid disorders according to unique Chinese three-rung, ladder-like topography.

Here, we found that China’s population distribution was mainly concentrated in eastern China, and fewer people lived in the first ladder region at extremely high altitudes. As the famous “Hu Line” set by Chinese geographer Hu Huanyong described, the region southwest of the Hu Line accounts for 36% of China’s total land mass although 96 percent of its total population(2). Moreover, among these three successive ladder regions, people of Han ethnicity mainly lived in the second and third ladder regions. The thyroid disorder prevalence differed significantly among the three ladder regions of China (P < 0.05). We found that the prevalence of GD, AIT, TPOAb positivity, TgAb positivity, and thyroid nodule increased while the overt hypothyroidism, subclinical hypothyroidism, and goiter prevalence decreased with elevation descending from the first to third ladder regions. After adjusting for confounding factors, significant associations were found between the three-rung, ladder-like regions and thyroid disorders, whereas no significant association was found between the three successive ladder regions and overt hyperthyroidism and subclinical hyperthyroidism prevalence.

GD is one of the most common causes of hyperthyroidism(27). We found no significant association between the three ladder regions and overt hyperthyroidism and subclinical hyperthyroidism (P > 0.05). The third ladder group showed a positive association with GD compared with the first ladder group. Study have pointed out that the diagnosis and treatment of GD differs by various geographic area(28). A Swedish study reported that 75% of patients with hyperthyroidism had GD, and geographic differences were observed(29). Taylor et al(20). reviewed the global hyperthyroidism incidence and prevalence and highlighted the effects of geographic differences and environmental factors. Considering China’s unique ladder-like terrain, we aimed to describe the hyperthyroidism prevalence based on topographic factors. Several studies explored the thyroid status and thyroid disorder prevalence in Tibet (first ladder) with a small sample size(13, 30, 31). Furthermore, they only investigated Tibetan regions without comparisons with the other two ladder regions of China with a limited population. We included all three ladder regions and found that the GD prevalence was significantly lower in the first ladder group than the other ladder groups.

TSH concentration is one of the most sensitive indices of HPT axis function(32). Studies have shown that the adrenal, thyroid, and gonadal axes are affected by increased altitude, and the HPT axis is altered to adapt to hypoxic conditions(33). Animal studies have concluded that high altitude exposure results in a decreased requirement for thyroid hormones and concomitant hormone genesis(34). Several studies investigated thyroid status at different altitudes. Hanckney found that TSH and FT3 concentrations were significantly lower among 15 mountain climbers who climbed Mt. Denali in Alaska(35). Another study conducted at Mount HimlungHimal revealed that the thyroid axis was directly activated by increased altitude and that FT4 increased above baseline at an altitude of 4844 m ASL, although results were unclear for FT3 and TSH(36). Another study found a significant negative correlation between FT3 level and the FT3/FT4 ratio by geographic factors, including temperature and sunshine duration, and a positive correlation with humidity and atmospheric pressure(37). Here, TSH levels decreased with descending elevation from high altitude to sea level.

AIT is characterized by thyroid-specific autoantibodies and is one of the most common autoimmune disorders(38). To date, our study is the first to research the AIT prevalence among the three-rung, ladder-like regions in China. According to unique Chinese geographic features, we found that participants in the first ladder group, with an average altitude above 3000 m, had the lowest prevalence of AIT and thyroid antibody positivity. The diagnosis of AIT mainly relies on circulating antibodies to thyroid antigens (TPOAb and TgAb). The prevalence of AIT and TPOAb and TgAb positivity showed a similar trend, which like a A-shaped curve. Compared with the first ladder group, the other two ladder groups showed a significant association with AIT by binary logistic regression analysis.

A study among schoolchildren in high- and low-altitude areas of Saudi Arabia reported that children living at high altitudes (3150 m ASL) were 2.5 times more likely to develop goiter than their counterparts at low altitudes (500 m ASL)(39). Another community-based, cross-sectional survey in Ethiopia found that altitude was correlated with goiter prevalence, with peak prevalence observed in the highlands(14). We also found that the goiter prevalence in the first ladder group was higher than that in other ladder groups, with the lowest prevalence observed in the second ladder group. A meta-analysis of 26 articles assessed the thyroid nodule prevalence in mainland China and found that participants living at elevations below 200 m ASL had a higher prevalence compared with other elevation subgroups(40). Similarly, we found that the third ladder group had a higher prevalence of thyroid nodules than that of other two ladder groups.

Our study has several strengths. First, we selected participants from all 31 Chinese provinces, including the first through the third ladder regions, which comprehensively revealed the association between thyroid disorders and different altitudes based on Chinese topographic features. Second, most previous studies only detected thyroid hormones, including TSH, FT3, and FT4; however, we also detected thyroid volume and thyroid antibodies, including TPOAb and TgAb. Third, previous studies mainly included mountaineers at high altitudes and observed a transient change in thyroid hormone levels.(9) We selected residents from each ladder region who had lived there for at least five years to determine the geographic variations in thyroid status changes.

This study has several limitations. First, since our study excluded pregnant women and only included adults, the findings are not generalizable for the full distribution of thyroid disorders and thyroid status among the entire Chinese population. Second, environmental factors, such as temperature, humidity, and sunshine duration, as well as iodine intake, genetic and other factors, may influence disease outcomes. Finally, since this was a cross-sectional study, mechanisms involved in the observed phenomena cannot be explained; thus, further studies with larger sample sizes are needed to reveal the mechanism of geographic variation in thyroid status based on the three-rung, ladder-like topography of China.

In conclusion, we investigated the association between altitude and thyroid disorders according to unique Chinese topographic features providing evidence of the correlation between geographic factors and thyroid disorders and highlight geographic differences and environmental factors in thyroid health research. Owing to the limitations of this cross-sectional study, we did not include individual changes over time; thus, further cohort studies are needed to evaluate temporal changes.

Ethics approval and consent to participate:

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Committee of China Medical University (protocol code 2014-103-2, serial number: IRB [2008]115). All authors read and approved the final manuscript for publication. Informed consent was obtained from all subjects involved in the study after we explained all research procedures. Participants did not receive a stipend. All methods were performed in accordance with the relevant guidelines and regulations.

Consent for publication:

Not applicable

Availability of data and materials: The data presented in this study are available on reasonable request from the corresponding author. The data are not publicly available due to reasons of sensitivity of human data.

Competing Interests:

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported and no part of this manuscript has been published or is under consideration for publication elsewhere.

Funding: This work was funded by the Research Fund for public Welfare from the National Health and Family Planning Commission of China (Grant Number. 201402005)

Author Contributions: Conceptualization, B.S.G. and Z.Y.S., methodology, Y.M.W and J.A.Z., software, Q.Z and X.C.W., validation, J.J.Z., B.S.G. and J.S.L., formal analysis, Y.T.H, investigation, Z.W.Y, resources, Y.M.X, data curation, C.Y.Z, writing—original draft preparation, B.S.G., writing—review and editing, B.C.P. and Q.X.L. and P.W., visualization, Y.Z.L., supervision, W.P.T., project administration, Y.M.W and J.J.Z., funding acquisition, W.P.T and Z.Y.S. All authors have read and agreed to the published version of the manuscript.

Acknowledgments: This work was supported by the Research Fund for public Welfare from the National Health and Family Planning Commission of China (Grant No. 201402005). We thank the participants of this study. For continuous support, assistance, and cooperation, we thank Caiping Li and Jian Huangfu (The Affiliated Hospital of Inner Mongolia University), Wuquan Deng and Fang Deng (Third Military Medical University), Qingling Lu (Cardiovascular and Cerebrovascular Disease Hospital of Ningxia Medical University), Guodong Liu (The First Affiliated Hospital of Harbin Medical University), Yanping Wang (Fujian Medical University Union Hospital), Weihua Linle and Tuanyu Fang (Hainnan General Hospital), Jingfang Liu and Songbo Fu (The First Hospital of Lanzhou University), Ben Niu (The First People’s Hospital of Yunnan Provience), Chenglin Sun (The first Hospital of Jilin University), Jun Yue and Jia Song (People’s Hospital of Tibet Autonomous Region), Yanan Li and Wei Luo (Qinghai Provincial People’s Hospital), Nianchun Peng and Liuxin Shi (Affiliated Hospital of Guiyang Medical University), Yong Fan (The First Affiliated Hospital of Xinjiang Medical University General Hospital).

Zhang X-H, Wang Z-L, Hou F-H, Yang J-Y, and Guo X-W. Terrain Evolution of China Seas and Land Since the Indo-China Movement and Characteristics of the Stepped Landform. Chin J Geophys (USA) 58: 54-68, 2015.
Ping A, Tao B, Qingchao C, Lianfu D, Peiqin D, Hong D, Tunzi G, Dao G, yi H, bottanzzi J, Husan J, zhiguo J, Shi J, Shan K, Boshen L, Qingsong L, Yide L, Ruizhu L, Jian L, and Jin Z. Chinese National Geography the People's Republic of China: Foreign Language Press, 2006.
Wu J, Duan D, Lu J, Luo Y, Wen X, Guo X, and Boman BJ. Inorganic pollution around the Qinghai-Tibet Plateau: An overview of the current observations. The Science of the total environment 550: 628-636, 2016.
Caturegli P, De Remigis A, and Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmunity reviews 13: 391-397, 2014.
Babić Leko M, Gunjača I, Pleić N, and Zemunik T. Environmental Factors Affecting Thyroid-Stimulating Hormone and Thyroid Hormone Levels. International journal of molecular sciences 22: 2021.
Nepal O, Pokhrel BR, Khanal K, Gyawali P, Malik SL, Koju R, and Kapoor BK. Thyroid hormone levels in highlanders- a comparison between residents of two altitudes in Nepal. Kathmandu University medical journal (KUMJ) 11: 18-21, 2013.
Wright AD, Black EG, Fletcher RF, and Bradwell AR. Thyroid function at high altitude. The New England journal of medicine 310: 1334, 1984.
Barnholt KE, Hoffman AR, Rock PB, Muza SR, Fulco CS, Braun B, Holloway L, Mazzeo RS, Cymerman A, and Friedlander AL. Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. American journal of physiology Endocrinology and metabolism 290: E1078-1088, 2006.
Benso A, Broglio F, Aimaretti G, Lucatello B, Lanfranco F, Ghigo E, and Grottoli S. Endocrine and metabolic responses to extreme altitude and physical exercise in climbers. European journal of endocrinology 157: 733-740, 2007.
Basu M, Pal K, Prasad R, Malhotra AS, Rao KS, and Sawhney RC. Pituitary, gonadal and adrenal hormones after prolonged residence at extreme altitude in man. International journal of andrology 20: 153-158, 1997.
Sawhney RC, and Malhotra AS. Thyroid function in sojourners and acclimatised low landers at high altitude in man. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 23: 81-84, 1991.
Gunga HC, Kirsch K, Röcker L, and Schobersberger W. Time course of erythropoietin, triiodothyronine, thyroxine, and thyroid-stimulating hormone at 2,315 m. Journal of applied physiology (Bethesda, Md : 1985) 76: 1068-1072, 1994.
Ma C, Zhong J, Zou Y, Liu Z, Li H, Pang J, Liu X, Zejipuchi, Tian L, Hou L, Wang D, Cheng X, and Qiu L. Establishment of Reference Intervals for Thyroid-Associated Hormones Using refineR Algorithm in Chinese Population at High-Altitude Areas. Frontiers in endocrinology 13: 816970, 2022.
Mekonen E. Prevalence of goitre in Sekota district, Ethiopia. East African medical journal 73: 264-267, 1996.
Li Y, Teng D, Ba J, Chen B, Du J, He L, Lai X, Teng X, Shi X, Li Y, Chi H, Liao E, Liu C, Liu L, Qin G, Qin Y, Quan H, Shi B, Sun H, Tang X, Tong N, Wang G, Zhang JA, Wang Y, Xue Y, Yan L, Yang J, Yang L, Yao Y, Ye Z, Zhang Q, Zhang L, Zhu J, Zhu M, Ning G, Mu Y, Zhao J, Shan Z, and Teng W. Efficacy and Safety of Long-Term Universal Salt Iodization on Thyroid Disorders: Epidemiological Evidence from 31 Provinces of Mainland China. Thyroid : official journal of the American Thyroid Association 30: 568-579, 2020.
Chang N, Zhang Q, Wang Q, Luo L, Wang XC, Xiong J, and Han J. Current status and characteristics of urban landscape lakes in China. The Science of the total environment 712: 135669, 2020.
Zhao J, Chen Y, Han Y, Li Z, Liu Y, and Li W. The Physical Geography of China. Beijing, China: Higher Education Press, 1995.
Cheng K, Yao J, Lv G, Liu N, and Zhang Y. Research on Reliability of Structural Members Subjected to Snow or Wind Load for Design Working Life of 100 Years in China. Sustainability 14: 13, 2022.
Guan XL, Wei HK, Lu SS, and Su HJ. Mismatch distribution of population and industry in China: Pattern, problems and driving factors. Appl Geogr 97: 61-74, 2018.
Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM, and Okosieme OE. Global epidemiology of hyperthyroidism and hypothyroidism. Nature reviews Endocrinology 14: 301-316, 2018.
Starchl C, Scherkl M, and Amrein K. Celiac Disease and the Thyroid: Highlighting the Roles of Vitamin D and Iron. Nutrients 13: 2021.
Frommer L, and Kahaly GJ. Type 1 Diabetes and Autoimmune Thyroid Disease-The Genetic Link. Frontiers in endocrinology 12: 618213, 2021.
Moon S, Kim MJ, Yu JM, Yoo HJ, and Park YJ. Subclinical Hypothyroidism and the Risk of Cardiovascular Disease and All-Cause Mortality: A Meta-Analysis of Prospective Cohort Studies. Thyroid : official journal of the American Thyroid Association 28: 1101-1110, 2018.
Korevaar TIM, Medici M, Visser TJ, and Peeters RP. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nature reviews Endocrinology 13: 610-622, 2017.
Iglesias P, Bajo MA, Selgas R, and Díez JJ. Thyroid dysfunction and kidney disease: An update. Reviews in endocrine & metabolic disorders 18: 131-144, 2017.
Teng D, Yang W, Shi X, Li Y, Ba J, Chen B, Du J, He L, Lai X, Li Y, Chi H, Liao E, Liu C, Liu L, Qin G, Qin Y, Quan H, Shi B, Sun H, Tang X, Tong N, Wang G, Zhang JA, Wang Y, Xue Y, Yan L, Yang J, Yang L, Yao Y, Ye Z, Zhang Q, Zhang L, Zhu J, Zhu M, Shan Z, and Teng W. An Inverse Relationship Between Iodine Intake and Thyroid Antibodies: A National Cross-Sectional Survey in Mainland China. Thyroid : official journal of the American Thyroid Association 30: 1656-1665, 2020.
Graves' disease. Nature reviews Disease primers 6: 53, 2020.
Moon JH, and Yi KH. The diagnosis and management of hyperthyroidism in Korea: consensus report of the korean thyroid association. Endocrinology and metabolism (Seoul, Korea) 28: 275-279, 2013.
Abraham-Nordling M, Byström K, Törring O, Lantz M, Berg G, Calissendorff J, Nyström HF, Jansson S, Jörneskog G, Karlsson FA, Nyström E, Ohrling H, Orn T, Hallengren B, and Wallin G. Incidence of hyperthyroidism in Sweden. European journal of endocrinology 165: 899-905, 2011.
Ning P, Ren Q, Teng D, Zhang Z, Lv X, Meng S, Shi X, Lou Z, Wu C, Yang P, Zhang W, Zhou L, Luo Y, Zhuoma Z, Yang L, and Teng W. Current Iodine Nutrition Status and Prevalence of Thyroid Disorders in Tibetan Adults in an Oxygen-Deficient Plateau, Tibet, China: A Population-Based Study. Thyroid : official journal of the American Thyroid Association 30: 759-766, 2020.
Zou Y, Li H, Pang J, Liu X, Zejipuchi, Tian L, Yu S, Wang D, Hou L, Yin Y, Ma C, Xie S, Cheng Q, Guo X, Cheng X, Xia L, Yang H, and Qiu L. An evaluation of urine and serum iodine status in the population of Tibet, China: No longer an iodine-deficient region. Nutrition (Burbank, Los Angeles County, Calif) 82: 111033, 2021.
Fröhlich E, and Wahl R. MECHANISMS IN ENDOCRINOLOGY: Impact of isolated TSH levels in and out of normal range on different tissues. European journal of endocrinology 174: R29-41, 2016.
Keenan DM, Pichler Hefti J, Veldhuis JD, and Von Wolff M. Regulation and adaptation of endocrine axes at high altitude. American journal of physiology Endocrinology and metabolism 318: E297-e309, 2020.
Galton VA. Some effects of altitude on thyroid function. Endocrinology 91: 1393-1403, 1972.
Hackney AC, Feith S, Pozos R, and Seale J. Effects of high altitude and cold exposure on resting thyroid hormone concentrations. Aviation, space, and environmental medicine 66: 325-329, 1995.
von Wolff M, Nakas CT, Tobler M, Merz TM, Hilty MP, Veldhuis JD, Huber AR, and Pichler Hefti J. Adrenal, thyroid and gonadal axes are affected at high altitude. Endocrine connections 7: 1081-1089, 2018.
Mahwi TO, and Abdulateef DS. Relation of Different Components of Climate with Human Pituitary-Thyroid Axis and FT3/FT4 Ratio: A Study on Euthyroid and SCH Subjects in Two Different Seasons. International journal of endocrinology 2019: 2762978, 2019.
Yin L, Zeng C, Yao J, and Shen J. Emerging Roles for Noncoding RNAs in Autoimmune Thyroid Disease. Endocrinology 161: 2020.
Abu-Eshy SA, Abolfotouh MA, and Al-Naggar YM. Endemic goitre in schoolchildren in high and low altitude areas of Asir region, Saudi Arabia. Saudi medical journal 22: 146-149, 2001.
Liu X, Sun J, Fang W, Xu Y, Zhu Z, and Liu Y. Current Iodine Nutrition Status and Morbidity of Thyroid Nodules in Mainland China in the Past 20 Years. Biological trace element research 199: 4387-4395, 2021.

Table 1. General Characteristics of Study Population

AIT, autoimmune thyroiditis, BMI, body mass index, SD, standard deviation, TgAb, thyroglobulin antibodies, TPOAb, thyroid peroxidase antibodies, TSH, thyroidstimulatinghormone, UIC, urinary iodine concentration. 1st ladder: the first ladder, 2nd ladder: the second ladder, 3rd ladder: the second ladder. There were 75 missing values of smoke and 332 missing values of education. *Compared with the first ladder group, P<0.05.

Table 2. Associations Between Three-rung ladder-like Group and Thyroid Clinical Parameters by linear regression analysis

Groups

TPOAb (IU/mL)

TgAb (IU/mL)

TSH (mIU/L)

Thyroid volume

Model 1

Model 2

Model 1

Model 2

Model 1

Model 2

Model 1

Model 2

β [CI]

The 1^stladder

Reference

The 2^ndladder

6.47[3.72-

3.72-9.21]

0.00

5.18[2.31- 8.06]

0.00

17.59[8.66-26.52]

0.00

15.31[5.91-24.71

0.00

-0.74[-0.87-

-0.61]

0.00

-0.82[-0.96-

-0.68]

0.00

-2.20[-2.36-

-2.04]

0.00

-2.50[-2.66-

-2.33]

0.00

The 3^rdladder

5.75[3.11-8.39]

0.00

4.57[1.73-7.42]

0.00

11.14[2.55-19.73]

0.01

8.14[-1.18-17.46

0.09

-1.13[-1.26-

-1.01]

0.00

-1.24[-1.38-

-1.10]

0.00

-1.06[-1.21-

-0.90]

0.00

-1.37[-1.54-

-1.20]

0.00

The linear regression Model 1: Adjusted for age and sex

The linear regression Model 2: Adjusted for age, sex, ethnicity, location, education level, smoking status, BMI, UIC

CI, 95% confidence interval.

Table 3. Odds Ratio of Thyroid Disorders Among the Three-rung Ladder-like Groups by binary logistic regression analysis

The 1^st ladder

The 2^nd ladder

The 3^rd ladder

Altitude

>3000

3000-500

<500

Overt hyperthyroidism

Model1

Model2

Ref.

0.95

0.66-1.38

0.91

0.64-1.29

1.19

0.82-1.71

1.11

0.79-1.55

Subclinical hyperthyroidism

Model1

Model2

Ref.

1.66

0.95-2.90

2.57^*

1.40-4.74

1.69

0.98-2.90

3.00^*

1.63-5.53

Graves’ disease

Model1

Model2

Ref.

1.50

0.89-2.54

1.65

0.96-2.84

1.85^*

1.12-3.07

2.06^*

1.21-3.52

Overt hypothyroidism

Model1

Model2

Ref.

0.77^*

0.61-0.97

0.96

0.75-1.23

0.56^*

0.45-0.70

0.77^*

0.60-0.99

Subclinical hypothyroidism

Model1

Model2

AIT

Model1

Model2

Ref.

0.62^*

0.58-0.67

0.57^*

0.52-0.61

1.35^*

1.23-1.48

1.33^*

1.21-1.47

0.39^*

0.36-0.42

0.34^*

0.31-0.37

1.28^*

1.17-1.40

1.25^*

1.14-1.38

TPOAb positive

Model1

Model2

Ref.

1.34^*

1.21-1.50

1.30^*

1.16-1.46

1.32^*

1.19-1.47

1.28^*

1.14-1.43

TGAb positive

Model1

Model2

Ref.

1.40^*

1.26-1.57

1.35^*

1.20-1.51

1.31^*

1.18-1.46

1.24^*

1.10-1.39

Goiter

Model1

Model2

Ref.

0.50^*

0.39-0.62

0.56^*

0.44-0.71

0.69^*

0.56-0.85

0.85

0.66-1.08

Thyroid nodule

Model1

Model2

Ref.

1.17^*

1.08-1.27

1.43^*

1.32-1.56

1.21^*

1.12-1.31

1.58^*

1.45-1.72

Binary logistic regression Model: Adjusted for age, sex, ethnicity, location, education level, smoking status, BMI, UIC. CI, 95% confidence interval, *Compared with the first ladder group (P<0.05). (A) Binary logistic regression analyses of overt hyperthyroidism. (B) Binary logistic regression analyses of subclinical hyperthyroidism. (C) Binary logistic regression analyses of Graves’ disease. (D) Binary logistic regression analyses of overt hypothyroidism. (E) Binary logistic regression analyses of subclinical hypothyroidism. (F) Binary logistic regression analyses of AIT. (G) Binary logistic regression analyses of TPOAb positivity. (H) Binary logistic regression analyses of TgAb positivity. (I) Binary logistic regression analyses of goiter. (J) Binary logistic regression analyses of thyroid nodule.

No competing interests reported.

additionalfile1.pdf

Download PDF

Journal Publication

published 02 Jan, 2024

Read the published version in BMC Public Health →

Editorial decision: Revision requested
02 Nov, 2023
Reviews received at journal
24 Oct, 2023
Reviewers agreed at journal
20 Oct, 2023
Reviewers agreed at journal
18 Sep, 2023
Reviewers agreed at journal
17 Sep, 2023
Reviewers invited by journal
14 Sep, 2023
Editor assigned by journal
11 May, 2023
Editor invited by journal
10 Apr, 2023
Submission checks completed at journal
10 Apr, 2023
First submitted to journal
27 Mar, 2023

You are reading this latest preprint version

Effects of Altitude on Thyroid Disorders according to Chinese Three-Rung, Ladder-like Topography：National Cross- Sectional Study

Status:

Journal Publication

Version 1

Abstract

Figures

1. Introduction

2. Materials And Methods

3. Results

4. Discussion

5. Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1