Age-specific association between thyroid autoimmunity and hypothyroidism in Chinese adults aged over 65 years: a cross-sectional study

Background The correlation between thyroid autoimmune (TAI) disease and hypothyroidism in the elderly of different ages remains unclear. This study aimed to investigate the epidemiological characteristics of hypothyroidism, including subclinical hypothyroidism (Shypo) and overt hypothyroidism (Ohypo) in those aged ≥65 years from iodine-adequate areas and reveal the correlation between TAI and hypothyroidism in the elderly of different ages. Methods It was a cross-sectional study involving 2,443 subjects aged ≥65 years from two iodine-adequate areas in China by cluster sampling. They were assigned to the 65–69-, 70–79-, and ≥80-year-old age group. All subjects were surveyed by questionnaires and received physical examinations, laboratory testing, and thyroid ultrasound. Epidemiological characteristics of thyroid diseases in the elderly were compared among the three groups. Risk factors for hypothyroidism were predicted by binary logistic regression analysis. Results The median urinary iodine level was 238.70 (197.00, 273.70) μg/L. Thyroid peroxidase antibody or thyroglobulin antibody positivity (11.87%) and Shypo (9.13%) were common in the elderly. The prevalence of hypothyroidism in the elderly increases with age. TAI was a risk factor for Shypo (OR, 1.94; 95% CI, 1.35, 2.80; p < 0.01) and Ohypo (OR, 7.64; 95% CI, 3.40, 17.19; p < 0.01) in elderly Chinese. There was an age-specific correlation between TAI and hypothyroidism in the elderly. However, a significant correlation was not identified between TAI and hypothyroidism in ≥80-year-old age group (p > 0.05). Conclusion Hypothyroidism, particularly Shypo, is common in the elderly from iodine-adequate areas in China. TAI serves as a risk factor for hypothyroidism in the elderly, with an age-specific correlation with hypothyroidism.


Introduction
The aging of the global population has accelerated over the past several decades (1). Overall, the incidence of thyroid diseases in the elderly is higher than that in adults (2)(3)(4)(5)(6). Our study has also found that hypothyroidism is common in the Chinese elderly, with a prevalence of 10.28% (7).
As the most sensitive index of thyroid function, serum thyroid stimulating hormone (TSH) levels can be influenced by multiple factors like iodine nutrition, age, and autoimmunity (8,9). In iodine-adequate areas, TSH physiologically increases with age, and the upper limit of TSH for the elderly ≥65 years old is 8.86 mIU/L (10). A recent study from China showed that the TSH level in adults from iodine-excessive areas is significantly higher than that in iodine-abundant areas (2.35 [1.63, 3.44 mIU/L] vs. 2.61 [1.78, 4.02 mIU/L]) (11). In addition, our previous study has also confirmed that advanced age and high urine iodine concentration (UIC) are risk factors for hypothyroidism (12).
Thyroid autoimmunity (TAI) is another risk factor for hypothyroidism in iodine-sufficient areas (13). TAI is mainly manifested by elevated levels of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) (13,14). TAI has a high incidence that increases with age (15,16). The National Health and Nutrition Examination Survey (NHANES) has reported that the incidence of TSH >4.5 in the elderly aged 70+ years of the TPOAb-positive group is much higher than that in the TPOAbnegative group (50% vs. 10%) (17). However, the association between TAI and thyroid function in the elderly is still controversial, especially in very old people. In the present study, we aimed to analyze epidemiological characteristics of thyroid hypothyroidism, including subclinical hypothyroidism (Shypo) and overt hypothyroidism (Ohypo), in those aged ≥65 years from iodine-adequate areas and reveal the correlation between TAI and hypothyroidism in the elderly of different ages.

Materials and methods Subjects
Thyroid diseases in Older Population: The Screening, Surveillance, and Intervention (TOPS) study was a crosssectional, population-based study (7). It was approved by the ethics committee of the Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine (2021-LWKYZ-054). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all subjects. From May 2021 to August 2021, a total of 2,732 subjects aged ≥ 65 years in Shunhe Town, Suyu District, Suqian City, Jiangsu Province, and Yaoji Town, Suining County, Xuzhou City, Jiangsu Province, were randomly sampled by the cluster sampling method. Excluded were those with (1) a history of thyroid diseases or previous or current use of drugs that may affect thyroid function; (2) other serious systemic diseases; or (3) incomplete clinical data. Finally, 2,443 eligible people aged ≥ 65 years were included (Figure 1), involving 1,241 men (50.80%) and 1,202 women (49.20%).

Physical examinations
The height (Ht) and body weight (Wt) of each subject were recorded to calculate the body mass index (BMI) with the formula: BMI = Wt/Ht 2 (kg/m 2 ). Digital data were recorded with two decimal places.

Thyroid ultrasound
Thyroid ultrasound was performed by experienced ultrasound physicians using a SIUI Apogee 1000 Neo ultrasound machine at 7.5-13.0 MHz. Briefly, the subject was placed in a supine position to fully expose the neck and asked to stably breathe. Ultrasonic characteristics of the thyroid were examined.

Statistical analysis
Statistical analysis was performed by SPSS 22.0. The data were expressed as mean ± standard deviation (SD). Measurement data normally distributed were compared between groups by the twosample independent t-test. Otherwise, they were compared by the Wilcoxon rank-sum test for independent samples. Enumeration data were expressed as constituent ratios. Three or more groups were compared by Chi-square test. Risk factors for Shypo and Ohypo were predicted by binary logistic regression analysis. Twosided p < 0.05 was considered statistically significant.

TAI is an independent risk factor for hypothyroidism in the elderly
The correlation between TAI and hypothyroidism is age-specific in the elderly We further explored risk factors for hypothyroidism in the elderly in different age groups. It is shown that TAI was a risk factor  Figure 2). TAI did not influence the prevalence of hypothyroidism and Shypo in those aged ≥80 years (both p > 0.05), but the increase of TC level (hypothyroidism: OR, 1.88; 95% CI, 0.99-3.57; p = 0.04; Table 4; Figure 2; Shypo: OR, 1.96; 95% CI, 1.04-3.71; p = 0.04; Table 5; Figure 2) and HDL-c level (hypothyroidism: OR, 0.24; 95% CI, 0.07-0.82; p = 0.02; Table 4; Figure 2; Shypo: OR, 0.26; 95% CI, 0.08-0.90; p = 0.03; Table 5; Figure 2) are closely related to hypothyroidism and Shypo in the elderly. In addition, the prevalence of hypothyroidism, including Ohypo and Shypo, in the elderly in different age groups was not influenced by gender and vitamin D status (all p > 0.05, Table 4).

Discussion
The high prevalence of thyroid diseases in the elderly has become widely concerning. The present cross-sectional study recruited people aged ≥60 years from two iodine-adequate areas in China, aiming to reveal epidemiological characteristics of thyroid diseases. It was found that TPOAb or TgAb positivity and Shypo were prevalent in the elderly. The overall prevalence of Ohyper in the elderly was relatively low. A previous epidemiological study from 31 provinces of China's mainland reported that the prevalence  of Shypo in the Chinese population aged ≥60 years is up to 35.22%. Moreover, the incidences of positive TPOAb and TgAb are 11.55% and 10.20% in people aged 60-69 years, and 11.41% and 9.85% in those aged ≥70 years, respectively. The prevalence of Ohyper in people aged 60-69 and ≥70 years is 0.65% and 0.47%, respectively (2). Epidemiological data from other countries and regions have revealed that the prevalence of Ohypo and Shypo in people aged >65 years ranges from 1% to 10% and 1% to 15%, respectively (21). A study from the Netherlands has demonstrated that the incidence of positive thyroid antibodies in people aged ≥85 years is about 13% (22). Consistently, our data revealed that thyroid nodules, positive thyroid antibodies, and Shypo were the most common thyroid diseases in people aged >65 years, the prevalence of which was significantly higher in women than in men. The prevalence of Ohyper and Shyper in the elderly, however, was relatively low. Age, gender, iodine intake, TAI, metabolic disorders, and vitamin D were all remarkably associated with thyroid diseases. Among them, iodine intake, age, and TAI were the most significant factors for thyroid diseases. Long-term excessive iodine intake downregulates the expression of thyrotropin receptors on the surface of thyroid cells and sodium-iodide symporter and also inhibits the activity of type II (D2) deiodinase. Eventually, thyroid function is impaired (23). In this study, interestingly, UIC was not found to be associated with the prevalence of hypothyroidism in the elderly in areas where iodine is more than adequate. Similarly, there was no significant difference in the prevalence of Shypo among the population in iodine-sufficient B A  areas. However, there was a significant positive correlation between iodine excess and Shypo, which was mainly attributed to nonautoimmune Shypo. We have demonstrated that UIC ≥700 mg/ L in iodine-sufficient areas in China is also confirmed as a risk factor for Shypo (12). UIC from spot samples has been shown to be a reliable biomarker of recent iodine intake in the population as a whole (24). However, creatinine adjustment of UIC to correct urine volume has been advocated by some authors (25).
Our results showed that age and TAI were significantly correlated with hypothyroidism in the elderly. Aging and TAI increased the risk of Shypo. The prevalence of Shypo in the elderly increased with age, reaching 11.66% in people aged ≥80 years. NHANES has proposed that the 97.5% quantile of TSH increases by 0.03 mU/L with every 1-year increase in age from 12 years (26). The French Endocrine Society consensus guidelines (2019) have consistently reported that the upper limit of the normal reference of TSH increases with age (8). The fixed reference of TSH in clinical testing may increase the detection rate of Shypo in the elderly. Our previous research has established an age-specific range of TSH levels to reduce the possibility of overdiagnosis of Shypo (8). However, according to the age-specific TSH reference range, the detection rate of Shypo was greatly reduced, and the detection rate of Ohypo was too low to be analyzed statistically. As a result, the age-specific TSH reference range was not used to define hypothyroidism in the present study.
Thyroid antibodies are important indicators for TAI and are closely linked with thyroid function. In the present study, the incidence of positive TPOAb or TgAb was 11.87%, significantly higher in women than in men. People with positive thyroid antibodies are more likely to develop thyroid dysfunction (17,27). Our results found that positive thyroid antibodies increased the risk of hypothyroidism in people aged 65-69 and 70-79 years but did not influence the prevalence of hypothyroidism in people aged ≥80 years. It is indicated that aging may weaken the influence of thyroid antibodies on thyroid function. TAI is considered a physiological condition adaptive to internal and external environmental changes. At a certain age, TAI becomes less influential on thyroid function. A study from the Netherlands involving 64 people aged 85 years has concluded that TPOAb in the elderly has a limited predictive value for thyroid function (22). However, their findings are limited by a small sample size and a short follow-up period. More efforts are required to clarify the influence of TAI on thyroid function in the elderly, especially in very old people.
Thyroid hormones regulate lipid metabolism, and Shypo can cause abnormalities in lipid metabolism. Our study also found that blood lipids are closely related to Shypo in the elderly, especially in TC and HDL-c. A study in China analyzed the relationship between Shypo and blood lipids, finding that for every 1 mIU/L increase in TSH, the TC level increased by 0.0551 mmol/L in middle-aged and elderly subjects (60-69 years old). Similarly, the LDL-c level tended to increase with age for every 1 mIU/L increase in TSH (28). In addition, the study confirmed that the TSH level was significantly higher in patients with metabolic syndrome than in healthy controls. Hypothyroidism has a significant effect on the components of the metabolic syndrome. Patients with Shypo have an increased risk of low HDL-c (28). The high prevalence of dyslipidemia in the elderly is considered a "natural condition." Both Shypo and dyslipidemia gradually increase with age, suggesting that the relationship between hypothyroidism and dyslipidemia may be affected by aging.
As a vital immunomodulatory factor, the role of vitamin D in thyroid diseases has been extensively highlighted. Mackawy et al. (28) have found an inverse correlation between 25(OH)D and TSH levels, and the prevalence of vitamin D deficiency remains high in patients with hypothyroidism. Low serum vitamin D level is independently associated with high TSH levels and the incidence of thyroid dysfunction (29,30). A recent population-based study in China has suggested that vitamin D level is significantly lower in patients with Hashimoto thyroiditis (HT) than in non-HT people. Compared with those with sufficient vitamin D levels, significantly lower FT 4 and higher TSH levels are detected in people with vitamin D insufficiency or deficiency (31). However, we did not identify a significant correlation between vitamin D levels and the prevalence of Shypo or Ohypo, suggesting the limited influence of vitamin D deficiency on thyroid function in the elderly. Some limitations should be noted. First, it was a cross-sectional study, and we were unable to assess the causal relationship between the above factors and thyroid function in the elderly. Second, we did not include information about the ultrasound aspects correlated with TAI (i.e., inhomogeneous parenchyma, presence of pseudo-nodules, thyroid volume, etc.) as a possible further tool to define the presence or absence of autoimmune thyroid disease. Third, we did not analyze the influence of sunshine exposure, diet, and vitamin D supplement on thyroid diseases in the elderly. Fourth, it is not sufficient to assess iodine status in the elderly by measuring UIC alone. Because UIC is just a reliable biomarker of recent iodine intake for the population, a creatinine adjustment of UIC to correct urine volume is required. Finally, our findings were obtained from epidemiological data in elderly Chinese; therefore, the correlation between vitamin D status and thyroid diseases in young people remains unclear.
Taken together, hypothyroidism, particularly Shypo, is common in the elderly in iodine-adequate areas. TAI is an agespecific risk factor for hypothyroidism in the elderly. A long-term follow-up is needed to further identify the influence of TAI on thyroid function in the elderly and the potential harm of Shypo on the health of old people.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed and approved by Ethics Committee of Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.