To the Editor: Thyroid carcinoma (TC) is one of the cancers with the fastest-growing morbidity globally. Studies have found that gender, genetics, selenium, and an unfavorable lifestyle are all associated with the risk of TC. However, whether vitamin D (VD) deficiency is associated with TC or not remains unclear. VD is one of the most important nutrients. VD deficiency is defined as a 25(OH)D below 20 ng/mL, and VD insufficiency as a 25(OH)D of 21–29 ng/mL.1 Some studies showed that the levels of 25(OH)D were significantly low in patients with papillary thyroid carcinoma (PTC) compared with normal controls.2 However, some other studies reported differently. To gain a better understanding of the VD and TC, we conducted this study. The protocol was registered in the International Prospective Register of Systematic Reviews with the registration number CRD42024568353 and carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Web of Science, CNKI, and SinoMed were searched from inception to May 2024. The search strategies are presented in the Supplementary Materials, https://links.lww.com/CM9/C814. The language of the article is limited to Chinese or English. Studies that met the following criteria were included: (1) study design: case-control study; (2) population: patients with benign or malignant thyroid nodules and healthy people. Studies were excluded based on the following criteria: (1) duplicate studies; (2) non-case-control studies; (3) full text not available; (4) irrelevant data; and (5) unsuitable groupings. The quality of the included studies was assessed according to the Newcastle–Ottawa Scale (NOS). A score of ≥5 was considered to be high-quality literature. Heterogeneity among the included studies was first assessed using I2 and the corresponding P value. When both P >0.100 and I2 <50% were satisfied, a fixed-effects model was used; otherwise, a random-effects model was applied. If significant heterogeneity was observed, sensitivity analysis was performed to explore potential sources of heterogeneity, and heterogeneity was recalculated after excluding studies with a large influence; if there was no heterogeneity, a fixed-effects model was used; if heterogeneity still existed, a random-effects model was used for all the included data. Subgroup analyses were performed for results with high heterogeneity. A flowchart showing the selection process for eligible studies is shown in Supplementary Figure 1, https://links.lww.com/CM9/C814. The trial selection process was summarized in Supplementary Figure 1, https://links.lww.com/CM9/C814. The basic characteristics of the studies are shown in Supplementary Table 1, https://links.lww.com/CM9/C814. The NOS scores are shown in Supplementary Table 2, https://links.lww.com/CM9/C814. Each study reported 25(OH)D levels in two groups, with statistical heterogeneity between studies (P <0.001, I2 = 93%). Patients with TC had lower 25(OH)D levels than controls. Subgroup analyses were performed using a random effects model for subgroups, with the control group including healthy controls and benign nodular disease. In both subgroups, the levels of 25(OH)D were significantly lower in the TC group compared with the control group. The pooled standardized mean difference (SMD) in the subgroup of health control was −1.32 (95% confidence interval CI: −1.85 to −0.78, P <0.001). However, the heterogeneity was high (P <0.001, I2 = 94%). The pooled SMD values were −0.46 in the subgroup of benign nodule (95% CI: −0.72 to −0.20, P <0.001), and data still had a high degree of heterogeneity (P <0.001, I2 = 84%) Supplementary Figure 2, https://links.lww.com/CM9/C814. All studies reported 25(OH)D3 levels in two groups, with statistical heterogeneity between studies (P <0.0001, I2 = 79%) Supplementary Figure 3, https://links.lww.com/CM9/C814. Subgroup analyses were performed depending on the country of the data source. The risk of TC in Chinese patients was negatively associated with 25(OH)D3 levels (weighted mean difference WMD = −0.88, 95% CI: −11.41 to −0.34), with little within-group heterogeneity (P = 0.197, I2 = 38.5%). The risk of thyroid cancer in Turkish and Korean patients was not associated with 25(OH)D3 levels (WMD = 0.06, 95%CI: –0.20 to 0.31; WMD = 0.18, 95%CI: –0.09 to 0.46), and there was moderate within-group heterogeneity (P = 0.047, I2 = 67.2%) and no heterogeneity (P = 0.577, I2 = 0.0%) Supplementary Figure 4, https://links.lww.com/CM9/C814. Two papers enrolled in gender analysis, including 1238 female and 393 male patients. There was no statistical heterogeneity between studies (P = 0.062, I2 = 0.0%), so a fixed-effects model was used to analyze the results, which showed that VD levels were significantly higher in males than females (WMD = −3.07, 95% CI: −3.88 to −2.25) Supplementary Figure 5, https://links.lww.com/CM9/C814. Three papers were enrolled in the study of lymph node metastases, which included 875 patients with positive and 3764 with negative lymph node metastases. There was a high degree of heterogeneity between studies (P <0.001, I2 = 87%), so the results were analyzed using a random effects model, which showed that VD levels were not associated with lymph node metastasis (SMD = 0.26, 95% CI: −0.09 to 0.61) Supplementary Figure 6, https://links.lww.com/CM9/C814. In these studies, the mean levels of 25(OH)D were 18.57 ng/mL for patients with TC, 23.52 ng/mL for patients with benign nodules, and 25.74 ng/mL for healthy controls. Compared to controls, VD levels in TC patients were mostly in the deficient range (<20 ng/mL). Studies were included and divided into four groups according to quartiles, with a median of 17.36 ng/mL (range: 15.12–21.13 ng/mL). The risk of TC increases progressively as 25(OH)D levels decrease (<15.12 ng/mL: odds ratio OR = 0.02, 95%CI: 0.00–8.05; ≥15.12 and <17.36 ng/mL: OR = 0.11, 95%CI: 0.04–0.30; ≥21.13 and <21.13 ng/mL: OR = 0.35, 95%CI: 0.13–0.96; ≥21.13 ng/mL: OR = 0.70, 95%CI: 0.18–2.76) Supplementary Figure 7, https://links.lww.com/CM9/C814. We analyzed the subgroups by the geographic location of the population, dividing them into four groups: East Asia, West Asia, Europe, and the Americas. In East Asians, patients with TC had significantly lower 25(OH)D levels compared to healthy controls and patients with benign nodules (SMD = –1.76, 95%CI: –2.45 to –1.07; SMD = –0.67, 95%CI: –1.09 to –0.24). In West Asia, patients with TC had lower 25(OH)D levels than healthy controls (SMD = −0.54, 95%CI: –0.90 to –0.18). In Europe, patients with TC had lower 25(OH)D levels than patients with benign nodules (SMD = −0.28, 95%CI: –0.47 to –0.09). Among the Americas, the differences were not statistically different (SMD = −0.20, 95%CI: –0.56 to 0.16) Supplementary Figures 8 and 9, https://links.lww.com/CM9/C814. There was no publication bias (Egger’s test, P = 0.976) Supplementary Figure 10, https://links.lww.com/CM9/C814. This study suggested that patients with TC had significantly lower VD levels than controls, with most being lower than 20 ng/mL (deficiency). The lower the level of 25(OH)D, the higher the risk of TC. There were significant negative correlations between VD levels and TC incidence in East Asians, West Asians, and Europeans. However, in Turkey and Korea, there was no significant association between 25(OH)D3 levels and the risk of TC. The levels of VD were significantly lower in Chinese patients with TC than those of healthy controls and benign nodules. In patients with TC, VD levels did not correlate with lymph node metastasis. However, VD levels were significantly higher in male patients with TC than in female patients, suggesting the need to consider the impact of gender factors in treatment and individualize drug administration. VD metabolites varied significantly in different ethnic groups, with whites having the highest 25(OH)D, followed by yellows, and lowest in blacks.3 The incidence of TC also varies from country to country. Lifestyle and genetic differences may explain the different results among different regions in this study. Some studies have shown a correlation between VD levels and obesity and sex hormone levels. VD deficiency is more likely to occur in obese people. The gender difference may be due to women being more focused on sunscreen use and having more fat cells. VD is a fat-soluble vitamin, which includes vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Dietary changes or oral vitamin D3 supplements can bring VD levels to recommended serum levels in patients with PTC. Some findings suggested that cancer survivors might benefit from higher VD recommendations than the general population. VD supplementation reduces all-cause mortality and overall cancer mortality in patients with differentiated TC; however, VD does not significantly improve mortality from TC because of its good prognosis and low mortality.4 VD is produced in the body by oral ingestion or exposure to sunlight. Vitamins D3 and D2 reach the liver and are respectively metabolized to 25(OH)D3 and 25(OH)D2, and 25(OH)D3 is then converted in the kidneys into the active form, 1,25(OH)2D3. 25(OH)D represents the sum of 25(OH)D2 and 25(OH)D3 and is used to evaluate the overall levels of VD in the body. 25(OH)D3 is biologically active. This study analyzed the relationship between 25(OH)D, 25(OH)D3, and TC separately. Results indicated that the risk of TC was associated with 25(OH)D levels. For 25(OH)D3, a negative association was observed in Chinese patients, whereas no significant association was found in Turkish and Korean populations, with substantial overall heterogeneity. This implies that the relationship between VD and TC may be influenced by factors beyond the biologically active 25(OH)D3, such as the contribution of 25(OH)D2 or other mechanisms related to overall VD status. The 1,25(OH)2D3 has antitumor effects via mediating apoptosis and inhibiting tumor cell proliferation. The result of this study suggests that 25(OH)D may not be associated with lymph node metastases in patients with TC. So, the levels of 1,25(OH)2D3 may be further supplemented to enrich the importance of VD levels in patients with cancer. Our study has several limitations. First, there were limited data testing the relationship between VD levels and baseline data in patients with TC, such as age. Second, there were less data on the correlation between VD levels and TC disease progression and prognosis, such as pathological staging and degree of tumor differentiation. Therefore, follow-up studies are still needed to further investigate the relationship between pathological characteristics and VD levels in patients with TC. And studies need to include more samples and more regions. In conclusion, the analysis in this study revealed that the VD levels are deficient in patients with TC, and low VD is associated with the risk of TC. In patients with TC, VD levels were significantly higher in male patients than in female patients. However, VD levels were not associated with lymph node metastasis. Conflicts of interest None. Funding The study was supported by grants from the National Natural Science Foundation of China (Nos. 82470872, and 82303031), and Shandong Provincial Natural Science Foundation of China (No. ZR2019PH025).
Lv et al. (Wed,) studied this question.