This article has an erratum available at: http://dx.doi.org/10.21037/gs-2023-04 the article has been update on 2023-08-28 at here.
Relationships between serum levels of vitamins and papillary thyroid cancer: a single center case-control study
Highlight box
Key findings
• Vitamin D deficiency may play a role in papillary thyroid cancer development.
• Vitamin A and E deficiencies tend to increase the risk of papillary thyroid cancer occurrence.
What is known and what is new?
• Vitamins are involved in various mechanisms due to their antioxidant effects and their ability to enhance the immune response.
• Deficiency of some serum vitamins can be associated with an increased risk of developing cancer, including thyroid cancer.
• This study highlights possible associations between lower serum vitamins levels and papillary thyroid cancer occurrence.
What is the implication, and what should change now?
• Vitamins deficiency can be reduced by five major interventions: dietary modification, supplementation, promotion of both public health interventions and breastfeeding.
Introduction
Epidemiological studies have indicated the role of nutrients, particularly a deficiency in their antioxidant properties, in carcinogenesis (1-3). Some nutrients are involved in DNA repair, inflammation, endogenous hormones and growth factors levels through regulation of gene expression (4,5). Vitamins are required for various functions of the body through mechanisms that include their antioxidant properties and enhancement of the immune response (6-8).
Papillary thyroid carcinoma (PTC) is an epithelial malignancy harboring follicular cell differentiation and particular nuclear features. It is the most frequent thyroid neoplasm (9). Known risk factors for PTC include radiation exposure especially childhood exposure (environmental or medical reasons), genetics, high dietary iodine intake and preexisting thyroid disease (9). Moreover, an association has been controversially suggested between inflammation in chronic lymphocytic thyroiditis (CLT) and PTC. Fiore et al. reported a higher frequency of PTC in nodular-CLT patients than in patients with non-CLT nodular goiter and a significant correlation with thyroid-stimulating hormone (TSH) levels. They hypothesized that higher TSH levels increase the probability that mutated oncogenes may cause clinically detectable cancer (10,11).
There is literature that evaluated the role of vitamin D in the development of thyroid disease (12-15), particularly of vitamin D deficiency (5,7,8,16-18) associated with thyroid cancer (TC), with one study also evaluating the serum concentrations of vitamin E, calcium, zinc which were lower in medullary TC patients than in healthy controls and that their integration can reduce the neoplastic risk (19). However, only a few studies suggested that low intake/low serum levels of vitamin D are associated with higher risk of TC (5,7,16). Knowledge gaps exist in the clinical significance of serum vitamin levels in PTC. The study of Kuang et al. (20) evaluated the impact of preoperative serum vitamin D levels and local vitamin D metabolism on PTC development and prognosis. The authors concluded that serum 25(OH)D levels may not contribute to risk assessment workup of thyroid nodules and that lower preoperative levels of vitamin D were not associated with poor prognosis of PTC. Moreover, a recent case-control study and meta-analysis found that a high level of circulating 25(OH)D was associated with a decreased TC risk (8).
Possible reasons for the inconsistencies between studies include differences in the analytical methods to measure vitamin D and its metabolites, differences in the histotypes of TC evaluated, and differences in the ethnicity and inclusion criteria of participants (7,14,16).
On the ground that certain nutrients and vitamins may be particularly associated with promoting or protecting against certain types of TC, their stratification for specific tumor characteristics is important (18,21-23).
In this study, the serum levels of various vitamins in patients with PTC and their relationships with clinical, pathological, and molecular parameters were investigated and examined. This PTC group was compared with a control group consisting of patients operated for benign nodular goiter. The aim of this paper is to highlight the association between lower serum vitamins levels and PTC occurrence. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-22-520/rc).
Methods
Study design
This was a retrospective cohort study of patients undergoing thyroid surgery. Data were progressively collected from a clinical medical record database. Quality assurance of the database was maintained by an informatics specialist.
Study setting and period
Academic Asiatic tertiary medical center for thyroid surgery. Recruitment of participants between September 2018 and October 2019. Patient recruitment was subsequently stopped due to the Covid-19 pandemic.
Ethical statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the China-Japan Union Hospital Institutional Review Board (No. JL.UNI.251), and informed consent was obtained from all individual participants. Data were collected and stored digitally. Data did not include personal identifiers and were kept confidential.
Study population
Consecutive patients with histologically diagnosed PTC who underwent thyroidectomy.
Inclusion criteria: Patients with PTC and planned surgical treatment. Euthyroidism. Age >18 years old. Exclusion criteria: Patients with tumors other than PTC. Age <18 years old. Patients with malabsorption, recurrent infections, inflammatory diseases, or patients with impaired kidney or liver function (serum creatinine >1.8 mg/dL, total bilirubin >2.5 mg/dL, alkaline phosphatase (ALP) >5 times above the interval limit reference, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times above the interval limit reference) were excluded. Patients with other TC subtypes (follicular, anaplastic, medullary, lymphoma), Graves’ disease, and/or parathyroid disease were also excluded.
Control group
Each case detected was matched to one control randomly selected from people undergoing thyroid surgery at the same center. Control subjects, that is patients without PTC, were recruited from individuals who had undergone thyroidectomy in the same time interval and whose histologic examination revealed no tumor (final diagnosis: benign multinodular goiter). The reasons for thyroidectomy are illustrated in Table 1. Patients with malabsorption, recurrent infections, inflammatory diseases, or patients with impaired renal or hepatic function were also excluded. Patients with concurrent Graves’ disease and/or parathyroid disease were excluded.
Table 1
| Mnemonic | N* |
|---|---|
| Symptoms of pressure | 29 |
| Tracheal compression^ | 16 |
| Substernal extension§ | 12 |
| Toxic multinodular goiterç | 11 |
| Suspicious cytologic findings° | 5 |
| Cosmetic deformity | 4 |
| Recent enlargement° | 3 |
*, some patients had more than one surgical indication. ^, noticeable on clinical examination, or radiological imaging. §, this includes a goiter extending 3 cm below the sternal notch or extension of the gland below the fourth thoracic vertebra. ç, patients were euthyroid at the time of surgery. °, the definitive histological examination excluded malignant pathology.
Figure 1 shows the flowchart of patient recruitment in the said two groups of patients.
Analytical tools
Serum levels of vitamins A and E were measured by high-performance liquid chromatography (HPLC). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to measure serum levels of 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3]. Serum levels of vitamin D [25(OH)D] were determined as the sum of serum levels of 25(OH)D2 and 25(OH)D3. Serum homocysteine and methylmalonic acid levels, as indicators of vitamin B12 or folate status, were measured using LC-MS/MS. Serum chemical parameters such as total protein, albumin, ALP, ALT, AST, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol were measured to assess biochemical status as well.
Definitions
Vitamin deficiencies for specific vitamins were defined as follows: vitamin A <1.05 µmol/L, vitamin E <11.6 µmol/L, vitamin B12 as a methylmalonic acid concentration >300 µmol/L or a homocysteine concentration >15 µmol/L (24). Vitamin D deficiency was defined as a serum concentration of 25(OH)D <20 ng/mL, while severe lack was defined as <10 ng/mL (20).
Measured outcomes
Vitamin deficiency was measured as the primary endpoint. Demographic and clinical characteristics such as age, body mass index (BMI), and serum biochemical test results (total protein, albumin, ALP, ALT, AST, LDL, HDL, total cholesterol) were collected from electronic medical records. In accordance with World Health Organization guidelines for the Asian population (25), the subjects were classified according to the increased risk of developing the metabolic syndrome, in particular if the BMI (kg/m2) was between 18.5 and 23 as low to moderate risk, if between 23 and 27.5 as moderate to high risk, and above 27.5 as high to very high risk. Information from surgery and pathology was stored in electronic medical records.
Statistical analysis
To estimate the number of participants necessary for this study, a sample size calculation was performed using the STATA statistical package (version 13, College Station, TX, USA). A target sample size of 47 participants per group was selected to ensure adequate power. Descriptive statistics were calculated for participant characteristics. Continuous variables were expressed as medians (interquartile ranges), means (± standard deviation) or numbers (%) and categorical variables as percentages. Differences between means and medians were assessed by t-test and Kruskal-Wallis test, respectively, while the percentages of categorical variables were evaluated by the χ2 test. Regardless of the test, a P value of <0.05 was considered statistically significant, while a P value between 0.05 and 0.10 was considered borderline significant. A normality test was used to assess the distribution of variables. Statistical analyses were performed using the SPSS® v. 22 for Windows® software package (IBM, Armonk, NY, USA).
Results
Baseline demographic and clinical characteristics of the study cohort
The general characteristics of the study participants are summarized in Table 2. This study included 51 PTC patients and 49 control subjects. Patients with TC were younger (P=0.001), had a smaller thyroid gland and nodal size (P=0.001), and had more frequently multiple nodules (χ2=9.502, P=0.0021), (Table 2). Furthermore, TC patients had a higher BMI and a lower concentration of total cholesterol than the control group (P=0.02 and P=0.03, respectively), both statistically significant (Table 2). Of the 51 PTC patients, 7 (13.7%) had microPTC (maximum diameter <10 mm), 22% had BRAF mutations, 30% had lymph node metastases, and only 2% had distant (bone) metastases (Table 3).
Table 2
| Characteristics | PTC group (n=51) | Control group (n=49) | P value |
|---|---|---|---|
| Gender | 0.49 | ||
| Female | 39 | 30 | |
| Male | 12 | 19 | |
| Age at surgery (years) | 41 [35–50] | 49 [44–55] | 0.001 |
| BMI* | 25 [21–25] | 22 [20–24] | |
| 18.5–23 | 27 (53%) | 31 (63%) | 0.02 |
| 23–27.5 | 24 (47%) | 18 (37%) | 0.03 |
| Thyroid gland volume (mL) | 29 [18–39] | 45 [39–87] | 0.001 |
| Mean dominant nodule size (mm) | 20 [7–42] | 38 [30–62] | 0.001 |
| Number of nodules | 0.0021 | ||
| Solitary | 42 (82%) | 49 (100%) | |
| Multiple | 9 (18%) | 0 | |
| Thyroid function test | |||
| TSH (μIU/mL) | 1.85±0.86 | 1.65±0.66 | 0.24 |
| Free T4 (pmol/L) | 1.20±0.43 | 1.23±0.49 | 0.28 |
| Free T3 (pmol/L) | 1.12±0.56 | 1.32±0.64 | 0.6 |
| Tg (μg/L) | 18.81±14.12 | 19.12±17.13 | 0.1 |
| Extent of Surgery | 0.21 | ||
| Total thyroidectomy | 6 (12%) | 40 (82%) | |
| Near-total thyroidectomy | 5 (10%) | 5 (10%) | |
| Subtotal thyroidectomy | – | 4 (8%) | |
| Hemithyroidectomy | – | – | |
| Total thyroidectomy + CCLND | 35 (69%) | – | |
| Total thyroidectomy + CCLND + LCLND | 5 (10%) | – | |
| Laboratory tests | |||
| Total protein (g/dL) | 7.2 [6.8–7.4] | 7.3 [6.8–7.6] | 0.91 |
| Albumin (g/dL) | 4.3 [4.1–4.3] | 4.4 [4.1–4.5] | 0.74 |
| AST (U/L) | 18 [15–23] | 16 [14–20] | 0.78 |
| ALT (U/L) | 14 [12–22] | 14 [12–18] | 0.54 |
| ALP (U/L) | 56 [45–69] | 55 [47–69] | 0.38 |
| HDL (mg/dL) | 62 [51–76] | 65 [51–73] | 0.18 |
| LDL (mg/dL) | 115 [98–140] | 109 [92–139] | 0.23 |
| Total cholesterol (mg/dL) | 178 [159–205] | 191 [175–225] | 0.002 |
| Morbidity | 0.23 | ||
| RLN palsy transient | 2 | 2 | |
| RLN palsy permanent | – | – | |
| RLN palsy all | 2 | 2 | |
| Hypocalcemia transient | 7 | 5 | |
| Hypocalcemia permanent | 1 | – | |
| Hypocalcemia all | 8 | 5 | |
| Bleeding | – | – | |
| Seroma | 1 | 1 |
Data were expressed as median [interquartile range], mean ± standard deviation, numbers (%), or numbers. P values <0.05 were considered statistically significant. *, appropriate BMI for Asian population (Lancet 2004). PTC, papillary thyroid cancer; BMI, body mass index; TSH, thyroid-stimulating hormone; Tg, thyroglobulin; CCLND, central compartment lymph nodes dissection; LCLND, lateral compartment lymph nodes dissection; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; HDL, high density lipoprotein; LDL, low density lipoprotein; RLN, recurrent laryngeal nerve.
Table 3
| PTC group | N [%] |
|---|---|
| Multifocal tumor | 11 [22] |
| Extrathyroidal extension | 6 [12] |
| Vascular invasion | 7 [14] |
| T status | |
| T1 | 17 [33] |
| T2 | 25 [49] |
| T3 | 8 [16] |
| T4 | 1 [2] |
| Positive surgical margin | 1 [2] |
| LN status | |
| NX | 11 [22] |
| N0 | 24 [47] |
| N1a | 11 [22] |
| N1b | 5 [10] |
| Mean dominant tumor size in mm [range] | 20 [7–42] |
| Tumor size <10 mm | 7 [14] |
| PTC variants (dominant tumor) | |
| Classic | 41 [80] |
| Follicular | 8 [16] |
| Tall cell | 1 [2] |
| Diffuse sclerosing | 1 [2] |
| BRAF mutations | 11 [22] |
LN, lymph node; PTC, papillary thyroid cancer.
Vitamin status
Serum levels of vitamins status in the study populations are presented in Table 4. Serum concentrations of vitamins A and E in patients with PTC were significantly lower than in controls (P<0.003). However, serum concentrations of vitamin D and methylmalonic acid were borderline significantly low (P=0.06 and P=0.055, respectively), while homocysteine was statistically similar (P=0.45) in the two groups. In detail, vitamin A deficiency was observed in 9 patients with PTC (17.6%) and in 3 patients with benign disease (6.1%) a borderline significant difference (χ2=3.14, P=0.076). Vitamin D deficiency was observed in 4 patients with PTC (7.8%) and in 3 patients with benign disease (6.1%). Vitamin B12 deficiency was observed in 2 patients with PTC (3.9%) and in 2 patients with benign thyroid disease (4%). Vitamin E deficiency was observed in 9 patients with PTC (17.6%), and in 2 patients with benign disease (4%) a significant difference (χ2=4.0, P=0.030).
Table 4
| Serum vitamin concentrations | PTC group (n=51) | Control group (n=49) | P value |
|---|---|---|---|
| Vitamin A (μmol/L) | 1.40 (1.10–1.59) | 1.78 (1.52–2.16) | <0.003 |
| Vitamin D (ng/mL) | 15.6 (9.3–22.1) | 17.9 (12.3–23.3) | 0.06 |
| Vitamin E (μmol/L) | 23.9 (20.3–32.5) | 29.1 (26.1–38.6) | <0.003 |
| Methylmalonic acid (nmol/L) | 100.3 (79.5–129.3) | 110.4 (79.5–170.1) | 0.055 |
| Homocysteine (μmol/L) | 7.8 (6.4–9.3) | 8.2 (6.8–9.6) | 0.45 |
Results are presented as median (interquartile range). P values <0.05 were considered statistically significant. PTC, papillary thyroid carcinoma.
Serum levels of vitamins were compared among subgroups of PTC patients (Table 5). The sole statistically relevant results concern the concentrations of vitamin D that were significantly lower in BRAF-positive PTC than in BRAF-negative PTC patients (P=0.021). Methylmalonic acid concentrations were only borderline significantly lower (P=0.09) in PTC patients with extrathyroidal extension compared to PTC patients without extrathyroidal extension (Table 5).
Table 5
| Vitamin A (μmol/L) | Vitamin D (ng/mL) | Vitamin E (μmol/L) | Methylmalonic Acid (μmol/L) | Homocysteine (μmol/L) | |
|---|---|---|---|---|---|
| BRAF | |||||
| Negative (n=40) | 1.44 (1.15–1.67) | 16.0 (11.1–23.8) | 26.4 (21.0–28.4) | 103.0 (82.8–161.4) | 7.9 (7.1–9.6) |
| Positive (n=11) | 1.39 (1.18–1.77) | 8.2 (7.0–15.9) | 26.7 (21.6–33.0) | 96.9 (79.0–129.5) | 8.2 (6.9–9.6) |
| P value | 0.65 | 0.021 | 0.59 | 0.65 | 0.9 |
| N status | |||||
| NX (n=11) | 1.44 (1.10–1.88) | 13.6 (8.1–21.9) | 26.2 (21.7–29.0) | 95.6 (85.0–172.4) | 8.5 (7.1–10.0) |
| N0 (n=24) | 1.44 (1.10–1.73) | 14.5 (9.7–22.0) | 26.6 (21.5–31.1) | 94.6 (74.1–125.0) | 7.6 (7.0–10.3) |
| N1a (n=11) | 1.46 (1.14–1.76) | 13.4 (8.1–22.1) | 26.1 (22.0–30.1) | 95.8 (85.0–172.1) | 8.5 (7.0–10.5) |
| N1b (n=5) | 1.44 (1.11–1.70) | 13.9 (9.6–22.1) | 27.6 (21.4–32.9) | 95.0 (74.1–120.0) | 7.5 (6.6–11.3) |
| P value | 0.81 | 0.46 | 0.60 | 0.77 | 0.81 |
| Multifocal tumor | |||||
| Positive (n=11) | 1.39 (1.10–1.71) | 15.2 (9.0–22.0) | 26.1 (21.5–32.5) | 95.4 (73.1–130.5) | 7.5 (6.3–9.0) |
| Negative (n=40) | 1.41 (1.10–1.74) | 16.1 (10.1–23.5) | 25.9 (21.1–31.0) | 97.5 (75.3–133.9) | 8.5 (7.3–10.9) |
| P value | 0.74 | 0.49 | 0.65 | 0.42 | 0.09 |
| Extrathyroidal extension | |||||
| Positive (n=6) | 1.45 (1.17–1.69) | 12.8 (9.5–22.5) | 26.0 (21.6–31.7) | 97.3 (80.1–124.4) | 7.9 (6.6–9.4) |
| Negative (n=45) | 1.30 (1.18–1.71) | 9.5 (7.2–11.3) | 25.7 (21.9–29.1) | 112.2 (109.4–177.7) | 7.5 (6.5–8.3) |
| P value | 0.6011 | 0.6 | 0.775 | 0.09 | 0.4641 |
| T status | |||||
| T1 (n=17) | 1.45 (1.19–1.68) | 15.0 (9.3–22.6) | 25.8 (21.7–31.5) | 94.3 (73.3–126.0) | 7.8 (6.7–9.3) |
| T2 (n=25) | 1.38 (1.14–1.93) | 13.4 (9.7–20.3) | 26.6 (20.5–31.7) | 108.3 (80.7–134.5) | 8.8 (6.5–10.3) |
| T3 (n=8) | 1.45 (1.19–1.68) | 15.0 (9.3–22.6) | 25.8 (21.7–31.5) | 94.3 (73.3–126.0) | 7.8 (6.7–9.3) |
| T4 (n=1) | 1.38 (1.14–1.93) | 13.4 (9.7–20.3) | 26.6 (20.5–31.7) | 108.3 (80.7–134.5) | 8.8 (6.5–10.3) |
| P value | 0.8429 | 0.6654 | 0.9139 | 0.3605 | 0.502 |
| PTC subtypes | |||||
| MicroPTC (n=7) | 1.45 (1.19–1.70) | 14.3 (9.1–21.9) | 26.0 (21.7–31.6) | 94.7 (73.0–125.7) | 7.7 (6.5–9.2) |
| MacroPTC (n=44) | 1.46 (1.14–1.73) | 16.3 (10.2–24.6) | 26.2 (20.8–31.2) | 96.4 (75.3–135.4) | 8.4 (7.2–10.2) |
| P value | 0.9357 | 0.5001 | 0.6788 | 0.8032 | 0.0946 |
| PTC variants (dominant tumor) | |||||
| Classic (n=41) | 1.44 (1.18–1.67) | 14.7 (9.0–22.3) | 25.6 (21.6–31.3) | 94.6 (73.4–127.6) | 7.8 (6.6–9.2) |
| Follicular (n=8) | 1.48 (1.28–1.86) | 16.0 (9.3–22.8) | 25.1 (21.6–30.2) | 103.3 (82.5–131.0) | 8.7 (6.8–10.2) |
| Tall cell (n=1) | 1.19 (1.04–1.89) | 14.0 (11.3–18.5) | 31.7 (22.9–35.8) | 94.3 (75.0–110.5) | 7.9 (6.5–9.6) |
| Diffuse sclerosing (n=1) | 1.17 (1.02–1.86) | 13.9 (11.1–18.3) | 30.9 (23.0–35.9) | 94.1 (74.2–111.1) | 7.8 (6.5–9.4) |
| P value | 0.5472 | 0.8976 | 0.447 | 0.6803 | 0.5515 |
P values <0.05 were considered statistically significant. PTC, papillary thyroid carcinoma.
Discussion
Serum vitamin D deficiency has been associated with an increased risk of developing chronic obstructive pulmonary disease and, most topically in an interesting meta-analysis, also with increased severity and mortality of SARS-CoV-2 infection (26,27). Vitamin D supplementation has also shown positive effects on the outcome of patients suffering from head trauma and stroke, and it is likely that it can also counteract the neurotoxicity induced by anesthetic drugs (28-30). A recent study supports the hypothesis that normal levels of vitamin D, due to its anti-inflammatory and immunomodulatory properties, reduce the risk of developing chronic inflammatory diseases and cancer of the gastrointestinal tract (31).
In a meta-analysis, it was also highlighted that this vitamin deficiency and its relative supplementation, affects with inverse associations the general neoplastic mortality but not the incidence of cancer, in particular colorectal one (32).
In an interesting Chinese case-control study, 276 subjects were recruited to investigate the association between serum vitamin D and the development of PTC (8). A meta-analysis was also performed, which included 11 articles, showed that serum vitamin D concentration was inversely associated with the risk of developing cancer. This association was independent on the BMI and physical activity performance (8).
Abuduwaili et al. evaluated retrospectively the inverse relationship between pre-operative vitamin D levels and poor prognostic factors for PTC in a large series of patients (n=1,161) and found a statistical significance concerning larger tumor diameter (P=0.049) and occurrence of lymph node metastasis (P=0.00) (33).
The literature on vitamin A and E deficiency and their interactions with the endocrine system, and in particular with the thyroid, is quite limited.
Brossaud et al. hypothesized that vitamin A (retinol), a micronutrient with known metabolic functions in the eye and brain, could play less important roles at the endocrine level, in particular adrenal and gonadal with prevailing effects on spermatogenesis (34). Regarding thyroid, authors reported that in iodine-deficient areas, vitamin A deficiency increases the TSH-stimulation and consequently the goiter size in children, and its supplementation improves the efficiency of iodine uptake reducing the risk of hypothyroidism. Previously, Zimmermann et al. had come to the same conclusions, hypothesizing a suppression of the TSH-beta pituitary gene as a possible cause (35).
Few articles on the possible effects of vitamin E deficiency on thyroid function exist, and the first study is very old (36) and the most recent concerns the risk of medullary TC (19).
Overall, a systematic review of Zhang et al. (37), evaluated the association between dietary supplements of vitamins and minerals and TC development. They found conflicting results about TC development and common antioxidants such as vitamins A, C, E and β-carotene. Moreover, dietary supplement combinations or other specific minerals and/or vitamins interventions (calcium, iodine, iron, magnesium, zinc, vitamins B and/or D) are largely inconsistent across studies. They concluded that scientific evidence about eventual protective or hazardous effect of mineral or vitamins supplementation on TC development is inconclusive and further studies are necessary to elucidate possible associations.
Despite the numerous studies that show how vitamin D has protective effects on development of cancer, the results of this study come to different conclusions.
In this study serum levels of vitamins (A, E, and D) in patients with PTC or benign thyroid disease were measured. Possible relationships between serum levels of vitamins and molecular subtypes of PTC and tumor stages were also analyzed.
This study has several strengths and limitations. First, various biases could have affected the study, mainly the retrospective nature of the study and the fact that only patients undergoing thyroid surgery were included. On the other hand, enrolling patients from a single center can ensure that patients belong to the same population with the same environmental living risk factors.
Conclusions
In conclusion, albeit with the analysis of a limited sample, it is worth noting that not only vitamin D but also vitamin A and E deficiencies tend to increase the risk of developing a PTC. Further verification of these observations on larger case series is however necessary. Vitamin deficiency can be reduced by five major interventions: supplementation, dietary modification, fortification, promotion of both public health, and breastfeeding.
Acknowledgments
Funding: The study was funded by EUROCRINE (No. 2022_01_25_05), Istituto Auxologico Italiano.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-22-520/rc
Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-22-520/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-520/coif). The authors report the funding from EUROCRINE (No. 2022_01_25_05), Istituto Auxologico Italiano. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the China-Japan Union Hospital Institutional Review Board (No. JL.UNI.251), and informed consent was obtained from all individual participants. Data were collected and stored digitally. Data did not include personal identifiers and were kept confidential.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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