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Prevalence of Goiter and Thyroid Nodules before and after Implementation of the Universal Salt Iodization Program in Mainland China from 1985 to 2014: A Systematic Review and Meta-Analysis

  • Wei Zhao ,

    Contributed equally to this work with: Wei Zhao, Cheng Han, Xiaoguang Shi

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Cheng Han ,

    Contributed equally to this work with: Wei Zhao, Cheng Han, Xiaoguang Shi

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Xiaoguang Shi ,

    Contributed equally to this work with: Wei Zhao, Cheng Han, Xiaoguang Shi

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Chuhui Xiong,

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Jie Sun,

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Zhongyan Shan,

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

  • Weiping Teng

    twp@vip.163.com

    Affiliation Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China

Prevalence of Goiter and Thyroid Nodules before and after Implementation of the Universal Salt Iodization Program in Mainland China from 1985 to 2014: A Systematic Review and Meta-Analysis

  • Wei Zhao, 
  • Cheng Han, 
  • Xiaoguang Shi, 
  • Chuhui Xiong, 
  • Jie Sun, 
  • Zhongyan Shan, 
  • Weiping Teng
PLOS
x

Abstract

Objectives

We comprehensively estimated the prevalence of goiter and thyroid nodules (TNs) before and after the implementation of the Universal Salt Iodization (USI) program in mainland China and provided information for creating effective health policies.

Methods

PubMed, Google Scholar, CNKI, Chinese Wanfang and Chongqing VIP databases were searched for relevant studies from Jan 1985 to Feb 2014. Data from eligible citations were extracted by two independent reviewers. All analyses were performed with Stata 11.0 and SPSS 17.0.

Results

Eligible articles (N = 31; 4 in English and 27 in Chinese) included 52 studies (15 about goiter rates made before 1996 and 14 afterwards, and 23 about TNs). Our meta-analysis suggests a pooled prevalence for goiter before and after 1996 and for TNs of 22.8% (95% CI: 15.3%, 30.3%), 12.6% (95% CI: 9.4%, 15.8%) and 22.7% (95% CI: 18.3%, 27.0%), respectively. Egger's test of three independent categories revealed no evidence of publication bias (p = 0.101, 0.148 and 0.113, respectively).

Conclusions

The prevalence of goiter was reduced by almost half after 1996 in mainland China, so the USI program was considered beneficial. However, subgroup analysis suggests that both insufficient and excess iodine may be associated with goiter. The prevalence of goiter and TNs increased significantly after 2002, suggesting a risk of excessive iodine intake. Thus, salt iodization standardizations should be set according to local conditions.

Introduction

Iodine is an essential trace element required for the normal thyroid hormone activity, specifically that of thyroxine and tri-iodothyronine. Both insufficient and excessive iodine intake can cause thyroid-hormone disorders [1][4] and the presence of goiter and thyroid nodules (TNs) represents thyroid diseases. The term goiter describes the enlargement of the thyroid gland and the goiter prevalence of this condition is considered an important and sensitive long-term indicator of iodine intake [1], [5]. The prevalence of goiter in school-age children is related to the severity of iodine deficiency. For example, a prevalence of 0.0–4.9% suggests no iodine deficiency; 5.0–19.9% indicates mild deficiency; 20.0–29.9% reveals moderate deficiency; and severe deficiency is observed at ≥30% [1]. Excessive iodine, however, can also lead to goiter [1].

TNs are discrete structurally distinct lesions within the thyroid gland, separate from the surrounding parenchyma [6]. Previous work indicates that the frequency of TNs vary considerably among the general population—4–7% are detected by palpation [7], 20–76% are found with ultrasound [8], [9], and 19–67% are documented from autopsy data [10][12]. Although most TNs are benign, cancer should be suspected with the presence of TNs [6], [13], because 5–15% may be malignant (carcinomas) [14]. Thus, goiter and TNs are common thyroid disorders with an intimate association with iodine intake.

China was once an iodine-deficient country; prior to the 1970s, 370 million people lived in iodine-deficient areas [15]. Iodine deficiencies manifested various ways, including goiter, cretinism, endemic mental retardation, and decreased fertility rates [1], all of which are generally classified as iodine deficiency disorders (IDDs) [1], [16]. To reduce IDDs, in 1979, a program of local iodine fortification was introduced into these iodine-deficient areas; and in 1996, China launched the Universal Salt Iodization (USI) program [17]. Although the USI program reduced the prevalence of goiter, the median urinary iodine concentration (UIC) in school-age children simultaneously rose sharply—reaching 330 µg/L in 1997 and 306 µg/L in 1999. For this reason, in 2002, national standards for iodized salt were revised to reduce the iodine concentration at the production level [5]. In 2012, global data identified China as a region with more than adequate iodine intake [18]. Meanwhile, since the implementation of the USI program, a growing number of Chinese clinical endocrinologists have reported an increasing incidence of thyroid diseases, especially in recent years [19][25].

China has diverse environments with varied populations and socio-economic conditions, complicating unified epidemiological investigations for prevalence of goiter and TNs, most of which were limited to specific geographic areas or populations. Thus, data may not accurately represent these two diseases especially in light of the implementation of the USI program which may skew data for the epidemiology of goiter and TNs. Thus, to formulate appropriate local public health policies and criteria, we must document the epidemiology and distribution of both diseases and use the few previous studies to provide comprehensive analyses of detailed explorations and secular trends, geographic properties, and iodine status.

Here, we describe a systematic review and meta-analysis of the prevalence of goiter and TNs before and after implementation of the USI program in mainland China from 1985 to 2014.

Materials and Methods

Search Strategy

Goiter and TNs are independent diseases and iodine intake in China changed markedly after 1996 after the implementation of USI. Therefore, we conducted three meta-analyses—one on the prevalence of goiter before 1996 and one after 1996 and one analysis of the prevalence of TNs. We searched all English-language reports of population-based studies on the prevalence of goiter and TNs using PubMed and Google Scholar, and searched all Chinese reports manually and on-line using the CNKI (Chinese National Knowledge Infrastructure), Chinese Wanfang and Chongqing VIP databases, from Jan 1985 to Feb 2014. Search key words were “goiter,” “thyroid nodule(s),” “thyroid disorder(s),” “epidemiology” and “prevalence(s)”. We also scanned relevant reference lists and reviews to find additional studies. Attempts were made to contact authors of the identified papers for necessary details not given in the original texts. The PRISMA guideline for systematic reviews and meta-analyses was followed closely [26], see Checklist S1.

Inclusion and Exclusion Criteria

The following inclusion criteria were adopted for paper selection: (1) Data were acquired through population-based studies instead of hospital-based studies; (2) study participants were recruited from a random community-based sample, rather than from volunteers or those receiving routine-health examinations, and the subjects had to be living in mainland China; (3) the studies contained sufficient information to conduct pooled analysis of the prevalence; (4) if the same study data were reported in both English and Chinese, the English publication was included.

Studies were excluded if: (1) they were reviews or case reports; (2) the participants suffered from any related diseases or took medicines known to affect thyroid structure or function; (3) the study focused on participants with one underlying condition (such as pregnant women and smokers) or a certain occupation; (4) they were duplicate publications.

Data Extraction

The literature was searched independently by two reviewers. Any discrepancies between the extracted data of the two reviewers were reconciled through discussion. The literature-search process is shown in Figure 1. For all included studies, the first author's name, publication date, study year, age, location, sample size, events data and prevalence were recorded.

Iodine Status

Median UIC is recognized as the most practical biochemical marker for iodine nutrition [27]. Using the criteria from WHO/UNICEF/ICCIDD [1], the iodine status was identified based on the median UIC, where the median UIC ≤99 µg/L is insufficient, 100–199 µg/L is adequate, 200–299 µg/L is more than adequate and a median UIC ≥300 µg/L is considered to be excessive.

Statistical Analysis

The pooled prevalence and 95% confidence intervals (CIs) were used to estimate the prevalence of goiter and TNs in mainland China. All meta-analyses were calculated for heterogeneity using the Chi-square based Q test and the I2 test (25, 50 and 75% were considered low, moderate and high levels of heterogeneity, respectively) [28]. For a moderate or high level of heterogeneity we adopted a random-effects meta-analysis rather than using a fixed-effects model. Addressing heterogeneity and performing a secondary analysis required subgroup analysis. Publication bias was estimated through Egger's test. A p-value less than 0.05 indicated statistical significance. Meta-analyses were carried out in Stata Version 11.0 (Stata Corp LP, TX). Differences in prevalence among different groups were analyzed using the Chi-square test with SPSS Version 17.0 (SPSS Software, Chicago, IL).

Results

Characteristics of Papers

Figure 1 provides a schematic representation of the process for identifying, screening, and including studies in the review. The search strategy resulted in 31 articles (4 published in English and 27 in Chinese), reporting 52 studies—29 studies reporting goiter prevalence estimates (15 before 1996 and 14 after) and 23 on TNs. Table 1 provides a descriptive summary of these studies.

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Table 1. Characteristics of studies on the prevalence of goiter and TNs.

https://doi.org/10.1371/journal.pone.0109549.t001

All studies were based on general population samples. Before 1996, 436,182 people met the inclusion criteria for goiter; the criteria for diagnosis were in line with those of WHO, which was based on palpations. Another 14,359 people met the criteria for goiter after 1996. Goiter diagnosis after 1996 was based on palpation or ultrasound. After a diagnose with ultrasound, 59,098 people met the inclusion criteria for TNs.

Pooled Prevalence of Goiter and TNs

As shown in Figs 2 and 3, the pooled prevalence of goiter before 1996 was 22.8% (95% CI: 15.3%, 30.3%), with the actual numbers ranging from 3.11 to 50.89%; after 1996, the pooled prevalence, 12.6% (95% CI: 9.4%, 15.8%) in the range of 4.27–30.31%, was significantly lower compared with the prevalence prior to 1996 (χ2 = 532.56, p<0.001). Figure 4 shows a pooled prevalence of 22.7% (95%CI: 18.3%, 27.0%) for TNs with individual studies ranging from 10.12–46.56%. Individual disease conditions of the provinces and municipalities are shown in the maps in Figs 57.

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Figure 2. Forest plot displaying the pooled goiter prevalence in mainland China before 1996.

https://doi.org/10.1371/journal.pone.0109549.g002

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Figure 3. Forest plot displaying the pooled goiter prevalence in mainland China after 1996.

https://doi.org/10.1371/journal.pone.0109549.g003

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Figure 4. Forest plot of the pooled prevalence of TNs in mainland China.

https://doi.org/10.1371/journal.pone.0109549.g004

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Figure 5. Regional distribution of pooled goiter prevalence in mainland China before 1996.

https://doi.org/10.1371/journal.pone.0109549.g005

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Figure 6. Regional distribution of pooled goiter prevalence in mainland China after 1996.

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Figure 7. Regional distribution of pooled prevalence of TNs in mainland China.

https://doi.org/10.1371/journal.pone.0109549.g007

Subgroup Analysis

Goiter prevalences before and after 1996 and TNs were analyzed in subgroups, divided by location (North, South, East, West and Central China) and the type of area (rural, urban and mixed), as shown in Tables 24.

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Table 2. Prevalence of goiter before 1996 in mainland China by different stratification factors.

https://doi.org/10.1371/journal.pone.0109549.t002

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Table 3. Prevalence of goiter after 1996 in mainland China by different stratification factors.

https://doi.org/10.1371/journal.pone.0109549.t003

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Table 4. Prevalence of TNs in mainland China by different stratification factors.

https://doi.org/10.1371/journal.pone.0109549.t004

As shown in Table 2, before 1996, rural area (χ2 = 48054.05, p<0.001), inland area (χ2 = 1479.00, p<0.001), high altitude (χ2 = 52150.24, p<0.001), small study sample size (χ2 = 255.52, p<0.001), location in West China (χ2 = 2023.41, p<0.001), and both low and high levels of iodine intake (χ2 = 8809.32, p<0.001) might indicate a high prevalence of goiter.

As shown in Table 3, after 1996, subgroups including rural area (χ2 = 448.82, p<0.001), diagnosis using ultrasound (χ2 = 101.98, p<0.001) and study year 2002–2014 (χ2 = 421.05, p<0.001) had a greater prevalence of goiter. Of note, iodine nutrition may also be associated with this greater prevalence. Among the four iodine intake categories, the prevalence of goiter was lowest in the subgroup with adequate iodine, 4.3% (95% CI: 2.6%, 5.9%), and prevalence data for the insufficient subgroup was 23.2% (95% CI: 20.3%, 26.1%) and for excess iodine subgroup was 14.5% (95% CI: 8.8%, 20.1%), both of which were higher (χ2 = 190.17, p<0.001).

For TNs, prevalence among subgroups of location and study year was very different (Table 4). Prevalence rates for North, East and West China were 11.0% (95% CI: 9.7%, 12.3%), 25.5% (95% CI: 21.2%, 29.8%) and 18.3% (95% CI: 7.6%, 28.9%) (χ2 = 800.56, p<0.001), respectively. In terms of the study year, 11.0% (95% CI: 9.7%, 12.3%) of people investigated between 1999 and 2001 were diagnosed with TNs and this increased to 24.4% (95% CI: 20.2%, 28.7%) after 2002 (χ2 = 538.27, p<0.001).

Analysis of Heterogeneity and Publication Bias

We noted a significant overall heterogeneity within the studies (p<0.001, I2 = 97.4–100.0%), which decreased through subgroup analyses. Egger's test for the three independent research categories revealed no evidence of publication bias (p = 0.101, 0.148 and 0.113, respectively).

Discussion

We examined 52 epidemiological research studies covering 14 provinces, municipalities and autonomous regions in China. We systematically analyzed the prevalence of goiter and TNs prior to and after 1996, when China implemented the USI program. To our knowledge this is one of the first studies of this kind.

Research indicates that the prevalence of goiter in children 8–10 years-of-age is an indicator of local iodine consumption [1]. Our analysis, however, focused on the general population, to provide epidemiological information concerning the disease itself. Iodine nutrition is certainly an important factor for goiter, and the association between iodine intake and goiter prevalence has been investigated extensively.

Indian researchers reported that the prevalence of goiter was 65.9% in an iodine-deficient area [59], which decreased to 27.7% two decades after the USI program [60]. In Denmark, the goiter prevalence was 13.4% in an area with mild iodine deficiency and 19.7% in an area with moderate iodine deficiency, indicating that even a modest increase in iodine intake might significantly reduce IDDs [61]. In China, the USI program was launched in 1996 to prevent IDDs, establishing an important time boundary for our study. We observed a trend similar to the study in India. The overall goiter prevalence was 22.8% prior to 1996 and this was halved (declined to 12.6%). Thus, the USI program might be beneficial in China.

Also, iodine excess may increase thyroid volume [1]. In our subgroup analyses, both before and after 1996, the prevalence of goiter significantly changed with iodine status, with data suggesting hormesis—emphasizing that overdoses of iodine, as well as deficiencies may be associated with high prevalence of goiter. Meanwhile, previous studies suggest a goitrogenic effect of excess iodine in school-age children and adults [62][67]. In areas with high iodine content in the drinking water, school-age children had elevated median UIC and endemic goiter, suggesting that, in addition to adjusting the iodine content of salt, improving water quality is also necessary [62], [63]. In a prospective study, 10 normal men accepted daily oral intake of excess iodine for 1 month. At the end of this treatment, their mean thyroid volume increased, which eventually returned to baseline within 4 weeks after iodine withdrawal [64]. LeMar reported that excess iodine from tetraglycine hydroperiodide tablets caused a reversible thyroid stimulating hormone (TSH)-dependent thyroid enlargement [65]. For Peace Corps volunteers, after the removal of excess iodine from water, the mean serum iodine declined sharply, and the goiter rate fell from 44 to 30% [66]. In animal models, excessive iodine intake has been shown to lead to thyroid enlargement [67]. Thus, iodine excess should be scrutinized. In agreement with this concern, we observed that after 1996, the pooled goiter prevalence increased from 10.7% before 2002 to 25.1% afterwards, indicating an impending problem.

We also observed that altitude correlated with goiter: the plateau environment was associated with higher goiter frequency than residence in the plains and hills, a finding similar to trends in previous surveys that may be explained by deficiencies in natural iodine at high altitudes and limited educational and economic support for the people who reside there [68][70].

There is a longstanding controversy regarding the relationship between the prevalence of TNs and iodine nutrition because of the varied epidemiological situation across the globe. Among a Swedish population with adequate iodine, the rate of TNs was only 2.6% [71]. German data from a previously iodine deficient area revealed a 20.2% prevalence of TNs, with a smaller rate for men [72]. Mexico, which formerly was mildly iodine deficient, now consumes more than normal iodine intake and here the locally-identified TNs frequency was 19.6% [73]. Overall, the prevalence of TNs in mainland China was similar to that of other countries and regions of historic iodine deficiency and present states of iodine sufficiency. In addition, our data indicate that the prevalence of TNs after 2002 was higher than the rate prior to 2002—11.0% of those investigated from 1999–2001 were diagnosed with TNs, and this increased to 24.4% between 2002 and 2014.

Unlike goiter, which has a strong etiological relationship with iodine nutrition, the prevalence of TNs also depends on sex, age and head-and-neck radiation exposure history [74], [75]. According to the present information, TNs are more common in cities than in the country, which may be explained by lifestyle choices [76], [77]. Furthermore, females were at greater risk for TNs and this difference was not changed when females were further divided into rural, mixed and urban groups.

In conclusion, we report that the USI program in China successfully reduced the prevalence of goiter after 1996. However, the program might cause excesses iodine intake that may be associated with a high prevalence of goiter. The prevalence of TNs also increased over time. Also, 5% of TNs may be malignant [14], so an increased prevalence of TNs might predict more thyroid carcinoma patients. In view of this information, in 2012, China adjusted the iodized salt concentration to 20–30 mg/kg (previously 35 mg/kg) and provincial governments and health administrative departments were allowed to formulate local standards within ±30% of recommended concentrations based on data for their area [78], [79].

Our study has several limitations. First, variations in the quality of the selected papers exist. Uncertain data will confound investigations into potential influences on heterogeneity. Secondly, primary TNs articles did not use a completely unified diagnostic criterion, but they did diagnose with ultrasound. Third, data from qualified articles failed to cover most of mainland China provinces. Still, we included all available information about goiter and TNs from the past three decades and this report is the first to document the epidemiological status of both diseases before and after the USI program in mainland China. In addition, our work underscores the need for additional population-based studies in areas excluded from this analysis.

Our data show that the implementation of USI program is beneficial but may pose iodine risks; therefore, salt iodization standards should be set according to local conditions. Also, some epidemiology studies remain to be undertaken, and these are essential for comprehensive original data on the epidemiology and distribution of thyroid diseases. Our future work will include a national baseline study on thyroid diseases which will be implemented from 2014 to 2016 and these data will provide broad and accurate information for other researchers.

Supporting Information

Acknowledgments

We are grateful to Jianming Zhang (Department of Clinical Epidemiology and Evidence-based Medicine, the First Affiliated Hospital of China Medical University), Yongze Li (Key Laboratory of AIDS Immunology of Ministry of Health, Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) and Guangcong Liu (School of Public Health, China Medical University) for methodological support. We also thank the authors of the included studies.

Author Contributions

Conceived and designed the experiments: WPT ZYS. Performed the experiments: WZ CH XGS. Analyzed the data: WZ CH CHX JS. Contributed reagents/materials/analysis tools: WPT. Wrote the paper: WZ CH. Revised the language/article: WPT WZ CH XGS.

References

  1. 1. World Health Organization, United Nations Children's Fund, International Council for the Control of Iodine Deficiency Disorders (2007) Assessment of iodine deficiency disorders and monitoring their elimination: A guide for program managers. Geneva, Switzerland: World Health Organization.
  2. 2. FAO/WHO (2005) Vitamin and mineral requirements in human nutrition, 2nd ed. Geneva: World Health Organization. Available: http://whqlibdoc.who.int/publications/2004/9241546123.pdf
  3. 3. Zimmermann MB (2009) Iodine deficiency. Endocr Rev 30: 376–408.
  4. 4. Ozpinar A, Kelestimur F, Songur Y, Can O, Valentin L, et al. (2014) Iodine status in Turkish populations and exposure to iodide uptake inhibitors. PLoS One 9: e88206.
  5. 5. Delange F, Bürgi H, Chen ZP, Dunn JT (2002) World status of monitoring iodine deficiency disorders control programs. Thyroid 12: 915–924.
  6. 6. Polyzos SA, Kita M, Avramidis A (2007) Thyroid nodules-Stepwose diagnosis and management. Hormones (Athens) 6: 101–119.
  7. 7. Singer PA, Cooper DS, Daniels GH, Ladenson PW, Greenspan FS, et al. (1996) Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 156: 2165–2172.
  8. 8. Mazzaferri EL (1992) Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am J Med 93: 359–362.
  9. 9. Tan GH, Gharib H (1997) Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 126: 226–231.
  10. 10. Hull OH (1955) Critical analysis of two hundred twenty-one thyroid glands: study of thyroid glands obtained at necropsy in Colorado. AMA Arch Pathol 59: 291–311.
  11. 11. Mortensen JD, Woolner LB, Bennett WA (1955) Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 15: 1270–1280.
  12. 12. Oertel JE, Klinck GH (1965) Structural changes in the thyroid glands of healthy young men. The Med Ann Dist Columbia 34: 75–77.
  13. 13. Gharib H, Papini E, Paschke R, Duick DS, Hegedus L, et al. (2010) American Association of Clinical Endocrinologists, Associazione Medicie Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest 33: 51–56.
  14. 14. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19: 1167–1214.
  15. 15. Endemic Disease Control Department in Ministry of Public Health (1989) China national programme 1989–1995 for the control of iodine deficiency disorders (Article in Chinese). Chin J Endemiol 8: 252–254.
  16. 16. Luton D, Alberti C, Vuillard E, Ducarme G, Oury JF, et al. (2011) Iodine deficiency in northern Paris area: impact on fetal thyroid mensuration. PLoS One 6: e14707.
  17. 17. Ministry of Health of the People's Republic of China, Ministry of Light Industry of the People's Republic of China (1994) Outline of eliminating iodine deficient disorders in China in 2000 (Article in Chinese). Beijing.
  18. 18. Zimmermann MB, Andersson M (2012) Update on iodine status worldwide. Curr Opin Endocrinol Diabetes Obes 19: 382–387.
  19. 19. Zhou RH, Zhu HM, Du YG, Dong XJ (2000) Investigation on residents' iodine-nutritional status after supplementation of iodine salt in Shijiazhuang City (Article in Chinese). Chin J Endemiol 19: 191–193.
  20. 20. Tan J, Fang PH, Lu TZ, Chen BZ, Gao S, et al. (2001) Investigation on iodine nutritional status and thyroid goiter prevalence of residents in Tianjin after salt iodination (Article in Chinese). Chin J Endocrinol Metab 17: 75–78.
  21. 21. Jin Y, Teng WP, Yuan B, Zhang YG, Yin CC (2001) Thyroid autoimmunity in members from multiplex families with Grave's disease and effect of iodine intake on its incidence (Article in Chinese). Chin J Endocrinol Metab 17: 79–82.
  22. 22. Yang F, Teng WP, Shan ZY, Wang ZY, Jin Y, et al. (2001) A comparative epidemiologic survey of hyperthyroidism in areas with different iodine intake (Article in Chinese). Chin J Endocrinol Metab 17: 197–201.
  23. 23. hang KZ, Lin YC, Fang ZP, Luo CR, Liu XY, et al. (2002) The effect of salt iodization for 10 years on the prevalence of endemic goiter and hyperthyroidism (Article in Chinese). Chin J Endocrinol Metab 18: 342–344.
  24. 24. Hou X, Wang J, Qi Q, Zhu LX, Xue XF, et al. (2003) Epidemiologic comparative study of hyperthyroidism before and after salt iodization in different iodine intake regions of Jilin Province (Article in Chinese). Chin J Endocrinol Metab 19: 104–105.
  25. 25. Wu MY, Zhang JW, Zhao JK, Zhang QL, Xie YQ, et al. (2004) Retrospective study on thyroid diseases after universal salt iodization in mild iodine deficiency area (Article in Chinese). Chin J Endocrinol Metab 20: 104–106.
  26. 26. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, et al. (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Medicine 6: e1000100.
  27. 27. Zou SR, Wu F, Guo CY, Song J, Huang CH, et al. (2012) Iodine nutrition and the prevalence of thyroid disease after salt iodization: a cross-sectional survey in Shanghai, a coastal area in China. PLoS One 7: e40718.
  28. 28. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560.
  29. 29. Wang LF, Wang SL, Aihaidi, Wang XZ, Lin FF, et al. (1992) Iodine deficiency disorders and geographical environment: an investigation in the diluvia-alluvial plain in front of the Kunlun Mountains (Article in Chinese). Endemic Diseases Bulletin 7: 56–64.
  30. 30. Dou DX, Li ZP, Zhu HF, Lv XC (1992) Control of endemic goiter with iodine bricks (Article in Chinese). Mil Med Sci 16: 256–259.
  31. 31. Chen HM, Ke GY, Li DL, Zheng XX, Cui SL, et al. (2000) An observational study on the control of endemic goiter by water improvement to reduce iodine level (Article in Chinese).Chin J Endemiol. 19: 275–276.
  32. 32. Zhang JL, Kang XP, Li QM, Ma LJ, Ping F, et al. (1992) A report on the effect of the prevention and treatment of endemic goiter at the basic control stage in Linyi area (Article in Chinese). J Linyi Med School 14: 327–331.
  33. 33. Wu WY, Wang XL, Wu LP (2002) The epidemiology, control and elimination of endemic goiter in Qingyuan County (Article in Chinese). Occupation and Health 18: 94–95.
  34. 34. Zhang Z, Lin YC, Fang ZP, Luo CR, Liu XY, et al. (2002) The effect of salt iodization for 10 years on the prevalence of endemic goiter and hyperthyroidism (Article in Chinese). Chin J Endocrinol Metab 18: 342–344.
  35. 35. Bao Y, Shu HS, Yu MJ, Chen T, Liu RJ, et al. (1994) An epidemiological investigation of endemic goiter in Xuzhou areas (Article in Chinese). Endemic Diseases Bulletin 9: 58–61.
  36. 36. Su MY, Yilixiati, Tang PC, Jiang XM, Kelimu, et al (1989) A preliminary study on the difference of the incidence of endemic goiter between the agricultural areas and pasture-lands of Tekesi County, Xinjiang (Article in Chinese). Chin J Endemiol 8: 375–406.
  37. 37. Zheng HB, Feng JL, Li GQ, Qin ZQ (1988) An investigation on goiter caused by high concentration of water iodine in Cangzhou areas (Article in Chinese). Endemic Diseases Bulletin 3: 61–65.
  38. 38. Yu J, Liu SJ, Su M, Zhang SB, Ye YX, et al. (2004) A Survey of IDDs surveillance in Jixian Village of Huangchuan County, Heilongjiang Province in 2003 (Article in Chinese). Chin J Ctrl Endem Dis 19: 114–116.
  39. 39. Yu XH, Fan CL, Shan ZY, Teng XC, Guan HX, et al. (2008) A five-year follow-up study of goiter and thyroid nodules in three regions with different iodine intakes in China. J Endocrinol Invest 31: 243–250.
  40. 40. Zhao SH, Wang YG, Yan SL, Wang YH, Han L, et al. (2004) A survey of present status of thyroid goiter and urine iodine status of residents in the coastal regions of Shandong Province (Article in Chinese). Med J Qilu 19: 221–223.
  41. 41. Zhu WY, Hu XF, Zhou SQ, Wang HK, Zheng XJ, et al. (2009) An epidemiological investigation on goiter in the town residents of Zhoushan Archipelago (Article in Chinese). Zhejiang Prev Med 21: 1–3.
  42. 42. Chen ZX, Xu WM, Huang YM, Jin XY, Deng J, et al. (2013) Associations of noniodized salt and thyroid nodule among the Chinese population: a large cross-sectional study. Am J Clin Nutr 98: 684–692.
  43. 43. Lou XM, Mo Z, Zhu WM, Zhou JS, Mao GM, et al. (2011) An epidemiological analysis of thyroid nodules among population with different levels of iodine nutrition (Article in Chinese). Chin J Public Health 27: 1564–1565.
  44. 44. Feng SY, Liu C, Liu XY, Duan Y, Liu CP (2006) An epidemiological study of thyroid nodules among a community-based population in Gaochun and Chuzhou of Jiangsu (Article in Chinese). Acta Universitais Medicinalis Nanjing (Natural Science) 26: 717–720.
  45. 45. Li SJ, Cao YS, Sun S, Wang XM (2012) An analysis of the prevalence of thyroid nodules and the risk factors among population (Article in Chinese). Zhejiang Prev Med 24: 4–10.
  46. 46. Chi HY, Zhou YP, Li YB, Wang Y, Zhang HR (2013) The age distribution and thyroid function of thyroid nodules patients (Article in Chinese). Chin J Prac Med 40: 24–25.
  47. 47. Chen LD, Chen P, Lei JM (2011) An analysis on thyroid ultrasonography results of residents in Lishui, Zhejiang Province (Article in Chinese). Chin Rural Health Service Administration 31: 981–982.
  48. 48. Wang XD, Bu RF, Peng W, Duan Y, Liu XY, et al. (2008) An epidemiological study of thyroid nodules among population in Wuxi of Jiangsu Province (Article in Chinese). Chin J Prac Int Med 28: 860–862.
  49. 49. Liu F, Chen HB, Ye TY (2012) An epidemiological survey of thyroid nodules in Ruian, Zhejiang Province (Article in Chinese). Chin J Prim Med Pharm 19: 3400–3401.
  50. 50. Yang NZ, Chen Y, Yang WY, Bao XJ, Hao W, et al. (2012) A survey on iodine nutrition condition of residents in Jiaojiang District, Taizhou City, Zhejiang Province (Article in Chinese). J Environ Occup Med 29: 148–153.
  51. 51. Liu ZY, Zhou JS, Lin Q, Zhang YL (2012) An analysis on thyroid ultrasonography results of residents in Zhoushan islands (Article in Chinese). Chin J Ctrl Endem Dis 27: 57–59.
  52. 52. Zhu WY, Zhou SQ, Wang HK, Hu XF, Zheng XJ, et al. (2010) An investigation of iodine nutrition and prevalence of thyroid nodules in Zhoushan Archipelago (Article in Chinese). Chin Prev Med 11: 113–116.
  53. 53. Guo HW, Sun M, He W, Chen HH, Li W, et al. (2014) The prevalence of thyroid nodules and its relationship with metabolic parameters in a Chinese community-based population aged over 40 years. Endocrine 45: 230–235.
  54. 54. Zhang JL, Tuo SJ, Song HP, Zhou XD, Liu XY, et al. (2013) An epidemiological survey of thyroid diseases in Yan'an City (Article in Chinese). Chin J Clin Med 20: 548–550.
  55. 55. Liu Y, Yan Z, Tong NW, Lv GQ (2012) An epidemiological survey of thyroid diseases in a community-based population in Chengdu (Article in Chinese). Proceedings of the 11th Annual Meeting of Chinese Society of Endocrinology pp. 114.
  56. 56. Yang YX, Shi LX (2011) A survey of the prevalence of thyroid nodules in a community-based population in Guiyang (Article in Chinese). Proceedings of the 10th Annual Meeting of Chinese Society of Endocrinology pp. 162–163.
  57. 57. Shen Y, Zhang YY, Yuan H, Sun SF, Tao MY, et al. (2013) A survey of iodine nutritional status of the residents in Jiading District of Shanghai (Article in Chinese). Chin Tropical Med 13: 307–309.
  58. 58. Zhang SG, Jiao L, Gong Y, Cai KY, Lu MQ, et al. (2010) The epidemiological characteristics and analysis of subclinical thyroid diseases in Xuzhou coalmine areas (Article in Chinese). Acta Academiae Med Xuzhou 30: 65–67.
  59. 59. Pandav CS, Kochupillai N (1982) Endemic goitre in India: prevalence, etiology, attendant disabilities and control measures. Indian J Pediatr 49: 259–271.
  60. 60. Yadav S, Gupta SK, Godbole MM, Jain M, Singh U, et al. (2010) Persistence of severe iodine-deficiency disorders despite universal salt iodization in an iodine-deficient area in northern India. Public Health Nutr 13: 424–429.
  61. 61. Knudsen N, Bülow I, Jorgensen T, Laurberg P, Ovesen L, et al. (2000) Goitre prevalence and thyroid abnormalities at ultrasonography: a comparative epidemiological study in two regions with slightly different iodine status. Clin Endocrinol (Oxf) 53: 479–485.
  62. 62. Zhao J, Wang P, Shang L, Sullivan KM, van der Haar F, et al. (2000) Endemic goiter associated with high iodine intake. Am J Public Health 90: 1633–1635.
  63. 63. Liu P, Liu L, Shen H, Jia Q, Wang J, et al. (2014) The standard, intervention measures and health risk for high water iodine areas. PLoS One 9: e89608.
  64. 64. Namba H, Yamashita S, Kimura H, Yokoyama N, Usa T, et al. (1993) Evidence of thyroid volume increase in normal subjects receiving excess iodide. J Clin Endocrinol Metab 76: 605–608.
  65. 65. LeMar HJ, Georgitis WJ, McDermott MT (1995) Thyroid adaptation to chronic tetraglycine hydroperiodide water purification tablet use. J Clin Endocrinol Metab 80: 220–223.
  66. 66. Pearce EN, Gerber AR, Gootnick DB, Khan LK, Li R, et al. (2002) Effects of chronic iodine excess in a cohort of long-term American workers in West Africa. J Clin Endocrinol Metab 87: 5499–5502.
  67. 67. Yu JS, Shan ZY, Chong W, Mao JY, Geng YX, et al. (2011) Vitamin E ameliorates iodine-induced cytotoxicity in thyroid. J Endocrinol 209: 299–306.
  68. 68. Harris NS, Crawford PB, Yangzom Y, Pinzo L, Gyaltsen P, et al. (2001) Nutritional and health status of Tibetan children living at high altitudes. N Engl J Med 344: 341–347.
  69. 69. Abuye C, Berhane Y, Ersumo T (2008) The role of changing diet and altitude on goitre prevalence in five regional states in Ethiopia. East Afr J Public Health 5: 163–168.
  70. 70. Abu-Eshy SA, Abolfotouh MA, Al-Naggar YM (2001) Endemic goiter in schoolchildren in high and low altitude areas of Asir region, Saudi Arabia. Saudi Med J 22: 146–149.
  71. 71. Takahashi T, Fujimori K, Simon SL, Bechtner G, Edwards R, et al. (1999) Thyroid nodules, thyroid function and dietary iodine in the Marshall islands. Int J Epidemiol 28: 742–749.
  72. 72. Völzke H, Lüdemann J, Robinson DM, Spieker KW, Schwahn C, et al. (2003) The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area. Thyroid 13: 803–810.
  73. 73. Hurtado-Lopez LM, Basurto-Kuba E, Montes de Oca-Duran ER, Pulido-Cejudo A, Vazquez-Ortega R, et al. (2011) Prevalence of thyroid nodules in the Valley of Mexico. Cir Cir 79: 114–117.
  74. 74. Rojeski MT, Gharib H (1985) Nodular thyroid disease: evaluation and management. N Engl J Med 313: 428–436.
  75. 75. Gharib H (1997) Changing concepts in the diagnosis and management of thyroid nodules. Endocrinol Metab Clin North Am 26: 777–800.
  76. 76. Leng S, Liu Y, Liu HX, Zhao H, Sun GH, et al. (2011) Epidemiology of thyroid nodules in health examination participants in Dalian (Article in Chinese). Medicine and Philosophy 32: 22–24.
  77. 77. Wang CY, Mi GL, Si RH, Tao L, Wang X, et al. (2012) Epidemiology of thyroid nodules in teachers of distinction in Shijiazhuang (Article in Chinese). Hebei Med J 34: 1402–1403.
  78. 78. Ministry of Health of the People's Republic of China (2011) National Guideline for food safety: iodine concentration in table salt (Article in Chinese). Available: http://wenku.baidu.com/view/7db4f3de6f1aff00bed51eae.html. Accessed 8 August 2013.
  79. 79. Meng F, Zhao R, Liu P, Liu L, Liu S (2013) Assessment of iodine status in children, adults, pregnant women and lactating women in iodine-replete areas of China. PLoS One 8: e81294.