Current Iodine Nutrition Status and Morbidity of Thyroid Nodules in Mainland China in the Past 20 Years

The aim of this study was to comprehensively assess the prevalence of goiter and thyroid nodules (TNs) in relation to China’s iodine nutrition level over the past 20 years and provide an effective reference for developing health policies. PubMed, EMBASE, Chinese National Knowledge Infrastructure, Chongqing VIP, and Chinese Wan Fang databases were searched for relevant studies from Jan 1996 to Feb 2020. Two reviewers extracted valid data from the eligible citations to determine the morbidity of TNs in different urinary iodine concentrations (UICs) and in patients of different genders, of different ages, who live in different geographic regions, and who live at different altitudes, as well as the P values of interactions between groups. There were 26 articles (34 studies) included in this analysis. The overall morbidity of TNs in mainland China was 23.4%. Morbidity was higher in urban areas (P < 0.001) than in rural and mixed areas. Coastal areas (P < 0.001), female patients (P < 0.001), high-altitude areas (P < 0.001), and residence in south China (P < 0.001) were all associated with higher morbidity of TNs. The lowest morbidity value of TNs, 16%, was in the more-than-adequate iodine subgroup. The highest morbidity, 27.2%, was in the adequate iodine subgroup. The morbidity of TNs increases with age, and women are more likely to have TNs. We also need to perform more epidemiological studies, and in the future, we should cultivate better understanding of the relationship between other thyroid diseases and provide more comprehensive and useful information for other researchers.

performed in China shows that excess iodine can induce and promote the incidence and development of hypothyroidism and autoimmune thyroiditis [4].
China implemented universal salt iodization (USI) regulations to prevent IDDs in 1996, involving all 31 provinces of mainland China. In 2011, the standard of salt iodization concentration in China was adjusted to household salt iodine content of 20-30 mg/kg, and provinces were allowed to choose salt iodization concentrations according to local conditions. During the two decades in which USI standards have been used, the population of China has been consecutively exposed to an iodine nutrition status of excessive iodine intake from 1996 to 2001, more-than-adequate iodine intake from 2002 to 2011, and adequate iodine intake from 2012 to 2016 [15].
Thus, we here present a systematic review and meta-analysis to analyze the morbidity of TNs after enforcement of the USI project in mainland China over the course of two decades.

Literature Search Strategy
We artificially retrieved all of the literature concerning population-based studies on the morbidity of thyroid nodules from January 1996 to September 2020 making use of the PubMed, EMBASE, Chinese National Knowledge Infrastructure, Chongqing VIP, and Chinese Wan Fang databases. The keywords "thyroid disorder(s)," "thyroid nodule(s)," "TN(s)," and "iodine" or the terms "prevalence(s)" or "incidence(s)," or "epidemiology" and "China" or "Chinese" were used to search for relevant studies. We also checked the reference list of identified studies in order to find more additional studies.

Selection Criteria
Our inclusion criteria were as follows: (1) the people were from stochastic community-oriented samples rather than voluntary acceptors or patients undergoing routine medical examinations; (2) the research design was population-based rather than hospital-based; (3) research results covered enough information (e.g., research geographic region, survey methodology, number of cases, sample size, diagnostic criteria, and urinary iodine concentration). Studies were removed if they met any of the following exclusion criteria: (1) case reports or reviews; (2) the people had any relevant sickness or took drugs or therapy known to influence thyroid structure or function; (3) the study centered on people in a specific subpopulation (such as smokers or gestational women) or who shared a specific career; (4) they were the same studies republished.

Data Extraction
Two reviewers separately extracted information, specifically the first author, the date of publication, the starting year of the work, age of the participants, geographic region, sample size, outcomes, and prevalence. The literature-retrieval process is shown in Fig. 1. Any differences were resolved by consensus. In our study, the median UIC was used to sort subjects into four subgroups: insufficient group (median UIC ≤ 99 μg/L); adequate group (median UIC between 100 and 199 μg/L); more-than-adequate group (median UIC between 200 and 299 μg/L); excessive group (median UIC ≥ 300 μg/L).

Statistical Analysis
We summarized the frequency of TNs along with 95% confidence intervals (CIs) to evaluate the morbidity of TNs in mainland China. The χ 2 -based test and the 2 test were used to calculate the heterogeneity of the studies. The low, moderate, and high levels of heterogeneity were set as 25%, 50%, and 75%, respectively [16]. We used a random-effects meta-analysis model to replace the fixed-effects model. We used the Egger's test to estimate for publication bias (P < .05 was considered of statistical significance) when the level of heterogeneity was moderate or high. Stata Version 16.0 (Stata Corp LP, TX, USA) was used to perform meta-analyses. We analyzed the differences in epidemiology among distinct groups utilizing the χ 2 test in SPSS Version 23.0 (SPSS Software, Chicago, IL, USA).

Literature Retrieval and Study Characteristics
A total of 1788 articles are initially planned to be included in this study, and 1654 were eliminated after screening the titles and abstracts. A total of 108 articles were excluded after more detailed evaluation. As a result, 26 articles (34 studies)  were brought into this meta-analysis. The characteristics of the 34 joined studies are listed in Table 1, based on general population samples. The total number of participants in the included studies was 72,319, from 16
In the four levels of iodine intake, the lowest level of morbidity of TNs was in the more-than-adequate iodine subgroup, 16% (95% CI: 12-20%). The highest level of morbidity was in the adequate iodine subgroup, 27.2% (95% CI: 23.531%).
As shown Fig. 3, the morbidity of TNs increased with age, and the highest, 53.3%, was in the group over 60 years old (95% CI: 42.

Evaluation of Potential Bias
For the estimated overall incidence of TNs, we did not detect any significant publication bias using the Egger's test. The funnel plot was shown in

Discussion
Thyroid nodules are frequently found in the thyroid gland. Because small nodules can be detected by ultrasound, the morbidity of TNs has been reported as high as 67% in the general population [43]. Because approximately 10-15% of nodules are cancerous, TNs should be observed closely in clinical practice [44,45]. In our study, on the basis of the inclusion and exclusion criteria, a total of 26 original epidemiological studies were included in this study. After the merger, the sample size reached 18,189 cases and 72,319 patients with TNs, covering 16 provinces. Through a systematic review and meta-analysis of these previous works, an updated estimate of the overall morbidity of TNs was obtained.
The morbidity of TNs in China has been rising over the past 20 years, from 2.73% in 1999 to 17.50% in 2010, and the morbidity rate in 2017 reached 20.43% [46]. The results of our meta-analysis revealed that the morbidity of TNs in mainland China was 23.4%. In the years 2012-2020, the morbidity of TNs was greater than in the years 1999-2011. Teng et al. showed that the morbidity of TNs was 20.43%, which was very high. Furthermore, they also determined that the morbidity of TNs decreased with increases in iodine intake, suggesting that insufficient iodine is a risk factor for TNs and that adequate iodine and more-than-adequate iodine are protective factors for TNs [15]. They supported the conclusion that AI and MAI could be merged as an indicator of an optimal iodine intake for the general population, that is, iodine intake within the range of 100-299 μg/L. But the WHO reported that the optimal urinary iodine concentration was 100-200 μg/L, corresponding approximately to a daily intake of 150-300 μg for adults. We find the optimal median range of urinary iodine recommended by the WHO may need to be broadened. The incidence of TNs and iodine intake formed U-shaped curves, indicating that insufficient and excessive iodine intake both increase the morbidity of TNs. A study from South Korea showed that when the range of UIC was 100-199 μg/L, the morbidity rate of TNs was highest, reaching 19.4%, while the morbidity of TNs decreased with the increase of iodine intake, which further proves that the morethan-adequate iodine is the protective factor of thyroid nodules [47]. In our study, more-than-adequate iodine intake had the  [15,39].
Several articles have shown that high-resolution thyroid ultrasound can allow discovery of TNs in 19-68% of stochastically specific individuals, with more women and the elderly suffering from TNs [7,48]. In our study, a subgroup analysis was carried out by gender, and the morbidity of TNs in males was 18% and 27.6% in females. Women were found to be more likely to experience higher morbidity of TNs than men, which is consistent with the results of earlier studies [49][50][51]. Possible reasons for this are as follows: (1) thyroid growth factors are susceptible to sex hormones, such as estrogen [52] and 17 beta-estradiol, so women are more likely to be diagnosed with thyroid disease than men [53]. (2) It may also be related to the increased demand for thyroxine during menstruation, pregnancy, and other factors that lead to periodic endocrine changes [54]. According to the subgroup analysis of different ages, as age increases, the morbidity of TNs gradually increases. This may be related to hypothyroidism, dyslipidemia, hormone levels, and other factors. It also indicates that age is one of the factors affecting the occurrence of TNs [55]. We also found high altitude, urban location, and coastal location to be correlated with TNs. Plateau and coastal environments were found to be associated with higher rates of TNs. This finding is similar to that observed for previous studies, and it may be caused by insufficient iodine intake at high altitudes. Excessive iodine in coastal areas necessitates education and economic remedies for the residents who live there [56,57].
There are two limitations to this research. First, the studies included here covered 16 provinces, mainly in eastern China. Second, we rightly limited the research to mainland China, considering no other countries.

Conclusion
Our research shows that it is beneficial to formulate iodized salt standards according to local conditions, but there may be some dangerous factors, and these must be considered with care. We need to perform more epidemiological studies, and in the future, we should develop further understanding of the relationship between other thyroid diseases and provide more comprehensive and useful information for other researchers.
Data Availability All data used during the study appear in the submitted article and availability.

Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.