The Correlation Between Serum 25-Hydroxyvitamin D and Parathyroid Hormone Levels and Orthostatic Intolerance in Children

2. Materials And Methods

2.1 Screening of OI children

We reviewed 151 children first admitted to Lanzhou University Second Hospital (LZUSH) from January 2019 to August 2020 who were discharged with a diagnosis of POTS or VVS or OH or OHT or OI or syncope. For the 151 selected children, the following inclusion conditions need to be met: (1) Conformed to the diagnostic criteria for OI in the 2018 Chinese Pediatric Cardiology Society Guideline Interpretation for Diagnosis and Treatment of syncope in children and adolescents; (2) Aged 4 to 14;(3) Serum 25(OH)D and PTH were detected at the time of initial diagnosis. (4) No previous cardiovascular disease, metabolic disease or neurological disease.

We excluded 2 children with abnormal EEG (electroencephalogram), 3 children with cardiogenic syncope, 1 child with dyskinesia and 3 children without examination of 25(OH)D or PTH by browsing the electronic records in the hospital information system (HIS). Finally, 142 children were included in this study, including 93 children with VVS, 45 children with POTS and 4 children with OHT.

2.2 Screening of healthy children

In Gansu province, vitamin D, parathyroid hormone and calcitonin are often used as a combined test to assess children's growth and development, especially bone development. Since these three tests are not expensive (157 yuan, about 24.5$), they are usually recommended for children's health checks. Based on this, we selected the medical records of children who visited the Children's Health Examination Center for physical examination within the same period of time through HIS and set the search criteria to check both plasma vitamin D and PTH for various reasons. We initially obtained 458 records and included 87 children diagnosed with healthy physical examinations after excluding 259 patients who had been tested for vitamin D for asthma, allergies, hypothyroidism, and growth retardation, and 112 patients who were taking vitamin D supplements for vitamin D deficiency.

2.3 Diagnostic criteria for POTS, VVS, OH and OHT

The diagnostic criteria for POTS, VVS and their subtypes, OH and OHT are referenced in the 2018 Chinese Pediatric Cardiology Society Guideline Interpretation for Diagnosis and Treatment of syncope in children and adolescents[11].

2.4 Statistical methods

SPSS 25.0 statistical software was used to analyze the data, the counting data was in the form of case table, the comparison between groups was in the form ofχ2 test, and the measurement data was in the form of χ2test. In the form of$\stackrel{-}{x}$± s, the measurement data in accordance with normal distribution were compared between groups by independent sample t-test or corrected t-test, and the measurement data not in accordance with normal distribution were compared between groups by independent sample nonparametric test.

Receiver operating characteristic (ROC) curve was used to analyze the predictive value of 25(OH)D in the diagnosis of OI. The area under the curve is low in the range of 0.5–0.7, medium in the range of 0.7–0.9, and high in the range of > 0.9. The 95% confidence interval of curve area does not contain 0.5 or P < 0.05, which indicates that the test indexes have predictive value for the results. P < 0.05 was statistically significant.

3. Results

3.1 Basic data analysis

A total of 142 OI patients, including 71 females and 71 males, were included in this study. The minimum age was 4 years old and the maximum age was 15 years old, with an average of 10.53 ± 2.10 years old. Eighty-seven healthy controls were included, including 52 males and 37 females. The youngest was 4 years old and the oldest was 13 years old, with an average age of 9.06 ± 2.32 years old (Table 1).

3.2 Difference of serum 25-hydroxyvitamin D and PTH between healthy control group and oi children

The level of 25(OH)D in healthy group was higher than that in OI group (P < 0.001), but there was no difference in PTH level (P = 0.064). The level of 25(OH)D in healthy group was higher than that in VVS group, POTS and OHT group (P < 0.001), but there was no significant difference in serum PTH level among the three groups (Table 1).

Table 1

Basic information of each group
Group	N(male/female)	Age (years)	25(OH)D (ng/ml)	PTH (pg/ml)
Healthy control	87(52/35)	9.06 ± 2.32	24.56 ± 13.07	31.12 ± 14.72
OI	142(71/71)	10.53 ± 2.10	12.95 ± 4.54	36.24 ± 22.92
POTS	45(26/19)	10.84 ± 1.80	12.74 ± 4.68	35.42 ± 22.19
VVS	93(43/50)	10.28 ± 2.21	13.07 ± 4.52	36.42 ± 22.26
OHT	4(2/2)	12.75 ± 0.96	12.41 ± 4.49	41.23 ± 28.74
χ2/Z/H	3.696	29.174	78.8	1.244
P	0.296	< 0.001	< 0.001	0.743

Legend: POTS: postural orthostatic tachycardia syndrome; VVS: vasovagal syncope; OHT: orthostatic hypotension

3.3 Difference of serum 25-hydroxyvitamin D and PTH in healthy children and OI children of different genders

There was no significant difference in 25(OH)D level between healthy boys and healthy girls (P = 0.684), but the PTH level of girls in healthy group was higher than that of boys (P = 0.03) (Table 2). The 25(OH)D of boys in OI group was higher than that of girls in OI group (P = 0.019), but the PTH level was significantly lower than that of girls in OI group (P < 0.001). (Table 2).

Table 2

Serum 25(OH)D and parathyroid hormone levels in healthy control group and OI group
Diagnosis group	Sex	N	25(OH)VD (ng/ml)			PTH (pg/ml)
			𝑥 ̅±𝑠	Z	P	𝑥 ̅±𝑠	Z	P
Healthy control	male	52	23.50 ± 12.26	-0.407	0.684	28.74 ± 14.48	-2.151	0.031
	female	35	26.12 ± 14.23			34.66 ± 14.54
OI	male	71	13.88 ± 4.79	2.342	0.019	29.07 ± 17.93	-4.08	< 0.001
	female	71	12.02 ± 4.10			43.41 ± 25.14
Legend: OI: orthostatic intolerance

3.4 Serum 25-hydroxyvitamin D is an important factor affecting the onset of OI, and has no significant relationship with age, PTH and gender

In binary logistic regression analysis, sex, age, 25(OH)D and PTH were taken as independent variables, and OI was taken as dependent variable. The results showed that 25(OH)D level was the only factor leading to OI among these independent variables. For each unit of 25(OH)D increase, the probability of OI decreased by 74.7% (Table 3).

Table 3

Binary logistic regression analysis of the factors affecting OI
Parameter	β	Std. Error	95% Wald CI		Hypothesis Test
Parameter	β	Std. Error	Lower	Upper	Wald Chi-Square	P
Intercept	-3.998	1.2306	-6.410	-1.586	10.555	0.001
Female	-0.395	0.3850	-1.150	0.359	1.055	0.304
Male	0
Age	-0.121	0.0895	-0.296	0.054	1.833	0.176
25(OH)D	0.253	0.0387	0.177	0.328	42.571	0.000
PTH	0.018	0.0099	-0.002	0.037	3.137	0.077
Scale	1
Legend: PTH: parathyroid hormone

The general linear model was used to evaluate the relationship between 25(OH)D and PTH, age, gender and disease status. Finally, the linear Eq. 25(OH)D= -0.087 * PTH-0.250 * Age + Male * 0.176 (male = 0,female = 1) was obtained. Although the model suggested that age and gender were two important factors affecting 25(OH)D, it could only be solved 1% of 25(OH)D level (Table 4).

Table 4

Analysis of 25(OH)D related factors by general linear model
Model	Standardized Coefficients	t	P	Collinearity Statistics
Model	β	t	P	Tolerance	VIF
(Constant)		9.814	0.000
PTH	-0.087	-0.919	0.360	0.702	1.425
Age	-0.250	-2.779	0.006	0.778	1.285
male	0.176	2.081	0.039	0.878	1.139
# Adjusted R Square: 0.112;ANOVA༚P = 0.000༛Durbin-Watson༚1.900

Legend: PTH: parathyroid hormone

3.5 Diagnostic value of serum 25-hydroxyvitamin D level in OI

The area under the ROC curve of 25(OH)D in the diagnosis of OI was 0.850 (P = 0.000); when the level of 25(OH)D was 19.50ng/ml, the sensitivity and specificity of 25(OH)D in the diagnosis of OI were 93.70% and 64.4%, respectively; the sensitivity of 25(OH)D in the diagnosis of OI was good, but the specificity was low. (Table 5, Fig. 1)

Table 5

Diagnostic value of 25(OH)D in orthostatic intolerance
Variable	Threshold (ng/ml)	Area	SE	P	95%CI
Variable	Threshold (ng/ml)	Area	SE	P	Lower	Upper
25(OH)D	19.49	0.85	0.028	0.000	0.795	0.905

4. Discussion

Vitamin D deficiency is common in healthy children, the main reasons include lack of outdoor activities, sunlight and vitamin D intake[12], and it is also related to race, season, age and body mass index[13–15]. In school students, the number of girls with vitamin D deficiency is more than that of men[16]. In winter, the 25(OH)D of black and white children decreased significantly, but the decrease of 25(OH)D of black children was smaller than that of white children, because the collagen type 1 cross-linked C-telopeptide (CTX) of black children increased significantly in winter, which could promote the vitamin D resorption rate[17]. In Danish school-age children, vitamin D level is negatively correlated with low-density lipoprotein, triglyceride and blood pressure, and this correlation has nothing to do with body fat and physical activity except blood pressure[18]. A study in China shows that the nutritional status of Nanjing Children in winter is relatively good, and the serum 25(OH)D level is 20–24 ng/ml[19]. In this study, OI children and healthy children in Lanzhou area were selected for comparison. Because of the higher dimension, vitamin D deficiency may be more common than that in Nanjing area. This study found that orthostatic intolerance was more common in school-age children, the median age was 11 years old, and the serum 25(OH)D level was significantly lower in OI children, especially in girls. Although we did not evaluate the growth environment, eating habits and daily activities of the children, but because this study is limited to Lanzhou area, there is little difference in the living environment and related eating habits of the children here, and such a large difference in vitamin D levels between healthy children and oi group can also reflect that there is a more serious vitamin D deficiency in OI children.

Vitamin D deficiency may be associated with cardiovascular disease in children [20]. Mann et al. found that low level of 25(OH)D (< 20ng/ml) can inhibit the activity of vagus nerve and increase the risk of cardiovascular disease[6]. Mustafa et al. found that the lack of 25(OH)D was significantly related to the impairment of cardiac autonomic nerve function through heart rate variability (HRV) parameter evaluation, and the cardiac autonomic nerve dysfunction was improved after 25(OH)D replacement therapy[21]. A study on cardiovascular autonomic function in patients with type 2 diabetes shows that 25(OH)D deficiency is associated with decreased parasympathetic function[22]. Vitamin D supplementation can prevent and delay the occurrence of cardiovascular autonomic dysfunction[23].

Vascular endothelial dysfunction may be another important cause of OI[1]. Vitamin D receptor (VDR) is expressed in endothelial cells, vascular smooth muscle and myocardial cells. After binding with VDR, vitamin D can stimulate the production of no by activating endothelial NO synthase (eNOS), thus mediating vasodilation[24]. In addition, cell and animal experiments in vitro also show that 25(OH)D is very important for VSMC proliferation and growth, and normal VSMC function is a necessary condition for good arterial compliance. Low 25(OH)D level inhibits the proliferation of vascular smooth muscle cells through acute calcium influx, increases the calcification of smooth muscle cells, and thus reduces arterial compliance[25, 26]. In addition, 25(OH)D is a negative endocrine regulator of RAAS system. Vitamin D can also inhibit the expression of paraglomerular cells and renin, thereby inhibiting the proliferation of VSMCs, thereby affecting blood pressure[27]. At present, studies have found that low serum 25(OH)D (≤ 25 ng/ml) level is earlier than the onset of OH, and low serum 25(OH)D can promote the onset of OH[28]. We hypothesize that vitamin D deficiency may cause or promote orthostatic intolerance related symptoms in OI children, but this needs further study.

Although there is no significant correlation between serum 25(OH)D and PTH concentration[29], most clinical studies show that serum 25(OH)D is negatively correlated with PTH. The parathyroid hormone level of children with 25(OH)D deficiency was higher than that of children without 25(OH)D deficiency[30], and this negative correlation had nothing to do with season and race[31], when the serum 25(OH)D level was lower than 30 ng/ml, PTH release was significantly promoted[15]. Amini, Z. et al. Believed that the serum 25(OH)D level of overweight or obese children would increase when it was lower than 12.4 ng/ml and 17.0 ng/ml[32]. However, Kang et al. Believe that when the25(OH)D level is less than 18.0 ng/ml, the PTH level in children's body will increase, the blood calcium level will decrease, and the possibility of hyperparathyroidism will also increase[33]. Maguire, J. L. and others believe that there is a nonlinear relationship between 25(OH)D and PTH. When 25(OH)D is 42.8ng/ml, PTH level is the lowest. When 25(OH)D is less than 42.8ng/ml, PTH will decrease significantly with the decrease of 25(OH)D. When 25(OH)D is more than 42.8ng/ml, PTH will increase slowly with the increase of 25(OH)D[34]. Some studies suggest that parathyroid hormone (PTH) supplementation can increase the expression of endothelial nitric oxide synthase (eNOS) and play a role in reducing age-related aortic endothelial dysfunction[35]. In our study, we found that the PTH level of girls was higher than that of boys in both healthy group and oi group. However, the comparison between groups found that although OI group had lower 25(OH)D level, it did not seem to change significantly in PTH level compared with normal group. Based on previous studies, we hypothesized that the PTH level of OI children would be higher than that of the normal group.

Whether vitamin D supplementation can improve the symptoms of orthostatic intolerance in children with OI needs further study.

A study in Brazil shows that 25(OH)D has a good ability to predict cardiac metabolic risk. When the concentration of 25(OH)D is higher than 32 ng/ml, the prevalence of cardiac metabolic risk in children will be reduced by 49%[36]. It has been found that increasing circulating 25(OH)D concentration can reduce the fat tissue (IMAT) between forearm muscles and increase the cross-sectional area (MCSA) of forearm and calf skeletal muscles[37], which may improve the contractility of lower limb muscles in OI children and avoid reflex hypotension due to upright. Chaudhari reported a case of 1-hydroxylase deficient POTS patients with improved palpitation symptoms after oral vitamin D treatment, suggesting that this kind of patients can be treated with calcitriol[38], but this still needs larger sample clinical trials to verify. However, in view of vitamin D deficiency in OI children, we still suggest that children should eat more foods rich in vitamin D, such as fish and dairy products, and increase light and outdoor activities. In addition, ROC curve shows that serum 25(OH)D at 19.49ng/ml has moderate sensitivity and specificity in the diagnosis of OI, which can be used for the diagnosis of OI.

5. Conclusion

This study suggested that children with OI had significant 25(OH)D deficiency. The serum 25(OH)D concentration is 19.49ng/ml as the boundary value, which can be used for the diagnosis of OI. In addition, although 25(OH)D level of OI children is decreased, the PTH level is not increased, which needs further study.

Abbreviations

OI: orthostatic intolerance; 25(OH)D: 25-hydroxyvitamin D; PTH: parathyroid hormone; VVS: vasovagal syncope; POTS: postural orthostatic tachycardia syndrome; OHT: orthostatic hypertension; 1,25 (OH) 2D3: 1,25-dihydroxyvitamin D3

Declarations

Ethics approval and consent to participate：This study is a retrospective study, in which the patients' previous examination data were involved in the use, and the disclosure of relevant private information is prohibited. This study was approved by the medical ethics committee of the second hospital of Lanzhou University [2018A-002]；

Consent for publication：Informed consent of patients has been obtained in this study, and the data in this study does not involve patient privacy；

Availability of data and materials：The datasets generated and/or analysed during the current study are not publicly available due patient privacy but are available from the corresponding author on reasonable request.；

Competing interests：The authors declare that they have no competing interests；

Funding：None；

Authors' contributions：Design and writing：Xiao Yao; Statistics and Analysis: Zhang Xiao-hua; Data collection: Wu Jin-zhi, Min Li; Review and approve publication: Dong Xiang-yu

Acknowledgements: This study thanks all -authors who have contributed to the content of this article；

Acknowledgements: Not applicable

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