The control group's mean age was 13.2 ± 2.8 years, the youngest was a boy whose debut of Graves' disease began at 2 years and 5 months, the oldest was 18 years old. Of these, there were 8 children (24.2%), 25 adolescents (75.8%), where there were 21 girls (63.6%), 12 boys (36.4%). The group with thyrotoxicosis was similar in terms of these indicators and did not have significant differences: the average age was 12.3 ± 1.6 (9–18 years old), there were 4 children (21.1%), 15 adolescents (78.9%), girls 11 (57.9%), 8 boys (42.1%).
The average height of children and adolescents with GD was 151.9 ± 2.7 cm, weight 39.4 ± 2.3 kg, body mass index (BMI) 16.6 ± 0.6, body surface area (BSA) 1.3 ± 0.05 m2. At the same time, 57.6% (19) of children in the group with thyrotoxicosis were found to be underweight, 9.1% (3) were found to be overweight and obese, these children had a history of a hypothalamic syndrome of puberty at the time of the development of Graves' disease. Anthropometric data of children and adolescents with Graves' disease by percentiles are presented in Table 1.
Table 1.Anthropometric data of children and adolescents with GD by percentiles.
Percentiles
|
Height, cm
|
Weight, kg
|
BMI, kg / m2
|
BSA, m2
|
Percentile 3
|
123,8
|
20,0
|
12,0
|
0,8
|
Percentile 5
|
124,6
|
20,6
|
12,2
|
0,9
|
Percentile 10
|
133,2
|
22,4
|
13,1
|
1,0
|
Percentile 25
|
142,0
|
27,0
|
13,9
|
1,0
|
Median 50
|
157,0
|
40,0
|
16,3
|
1,3
|
Percentile 75
|
163,0
|
52,0
|
19,2
|
1,5
|
Percentile 90
|
168,8
|
55,6
|
20,5
|
1,6
|
Percentile 93.5
|
173,6
|
56,0
|
21,2
|
1,7
|
Percentile 95
|
174,4
|
56,8
|
21,3
|
1,7
|
Percentile 97
|
175,1
|
58,0
|
21,7
|
1,7
|
Indicators of children's thyroid status with Graves' disease indicate thyrotoxicosis and a significant difference compared to the control group (Table 2).
Table 2.Thyroid status of the examined children and adolescents
Indicators
|
GD, М±SD
|
Control group, М±SD
|
р
|
TSH (0.28–4.3 mIU/ml)
|
0,007 ± 0,001
|
2,5 ± 0,8
|
р<0,001
|
fT3 (2.5–4.3 ng/dl)
|
24,5 ± 1,5
|
3,8 ± 0,8
|
р<0,001
|
fT4 (1.1–1.8 ng/dl)
|
6,4 ± 0,2
|
1,5 ± 0,3
|
р<0,001
|
TPOAb (up to 34 IU/ml)
|
387 ± 30,6
|
17,8 ± 8,3
|
р<0,001
|
TSHRAb (up to 1.75 IU/l)
|
24,3 ± 1,2
|
1,0 ± 0,4
|
р<0,001
|
(p < 0.05, p < 0.01 - in relation to the control group) |
In 15.2% (5) adolescents with Graves' disease, the highest threshold for determining the level of antibodies to TSH receptors was revealed, indicating pronounced immune aggression of thyrotoxicosis. The median thyroid status in the group of children and adolescents with thyrotoxicosis is presented in Table 3.
Table 3.Thyroid status of children and adolescents with GD by percentiles
Percentiles
|
TSH, mIU/ml
|
fT3, ng/dl
|
fT4, ng/dl
|
TPOAb, IU/ml
|
TSHRAb, IU/l
|
Percentile 3
|
0,001
|
6,9
|
3,9
|
85,5
|
9,7
|
Percentile 5
|
0,001
|
8,0
|
4,3
|
93,7
|
10,2
|
Percentile 10
|
0,001
|
11,7
|
4,7
|
117,8
|
10,5
|
Percentile 25
|
0,001
|
20,0
|
5,3
|
263,7
|
14,2
|
Median 50
|
0,005
|
25,9
|
6,5
|
441,5
|
25,0
|
Percentile 75
|
0,01
|
30,7
|
7,6
|
514,0
|
32,4
|
Percentile 90
|
0,012
|
32,4
|
7,8
|
584,0
|
40,0
|
Percentile 93.5
|
0,015
|
32,5
|
7,8
|
584,0
|
40,0
|
Percentile 95
|
0,017
|
33,2
|
7,8
|
593,1
|
40,0
|
Percentile 97
|
0,019
|
34,4
|
7,8
|
607,7
|
40,0
|
In the study of bone metabolism indicators, it was revealed that the average value of the vitamin D level in the control group was 20.4 ± 6.2 ng/ml. The median baseline calcidiol level in the analysed group was 21.1 ng/ml. The worst provision with vitamin D was demonstrated by children: the concentration of 25(OH)D in them was 18.5 ± 5.4 ng/ml, in adolescents, the average level of vitamin D was higher and amounted to 21.8 ± 7.0 ng/ml, but the difference was insignificant. The analysis demonstrates that only 2 (8.7%) children of the control group had optimal values of 25(OH)D concentration (Fig. 1).
In the group with thyrotoxicosis, the average vitamin D level was 9.8 ± 1.1 ng/ml. The median baseline calcidiol level in the analysed group was 9.5 ng/ml. In this group, on the contrary, adolescents showed the worst provision with vitamin D: the concentration of 25(OH)D in them was 11.4 ± 1.3 ng/ml, in children with GD, the average level of vitamin D was higher and amounted to 15.5 ± 5, 4 ng/ml, p > 0.05 compared between children and adolescents. None of the patients had an optimal concentration of 25(OH)D (Fig. 1).
The results obtained indicate that even considering sufficient insolation in the Republic of Uzbekistan, 43.4% of children and adolescents without endocrine pathology revealed a vitamin D deficiency. At the same time, vitamin D deficiency was 2 times more frequent in the group with thyrotoxicosis (87.8% (29)), and its failure was observed in 12.2% (4) of pediatric patients.
The analysis of the parameters of parathyroid hormone (PTH) in the children and adolescents under study showed no less exciting patterns that, undoubtedly, not only affect the current processes of phosphorus-calcium metabolism but, apparently, have a severe impact on the processes of bone mineralisation in children and adolescents. The average level of parathyroid hormone in the control group was 49.2 ± 4.3 ng/ml. In this group, the average PTH values in the blood serum in children were 1.5 times less than in adolescents and amounted to 38.6 ± 2.2 ng/ml and 57.4 ± 5.7 ng/ml, respectively. Of these, 1 (4.3%) was diagnosed with a decrease in the PTH level of less than 15 ng/ml, 6 (26.1%) had an increased PTH level. In the group with thyrotoxicosis, the average parathyroid hormone level was significantly lower than in the control group and amounted to 45.1 ± 4.9 ng/ml, p < 0.05.
On the contrary, in this group, the mean values of PTH in the blood serum in children were 1.2 times higher than in adolescents and amounted to 51.8 ± 2.3 ng/ml and 43.4 ± 3.1 ng/ml, respectively, but the difference was not reliable. In the group with thyrotoxicosis, hypoparathyroidism was 6.3 times more common than among healthy children (27.3% (9)). Simultaneously, 8 (24.2%) showed an increase in more than 65 ng/ml PTH levels.
Table 4.DXA indicators in the studied children and adolescents.
Group
|
BMD femoral neck, g/cm2 (M ± SDS)
|
Femur Z-score
|
BMD of the spine L1-L4, g/cm2 (M ± SDS)
|
Z-score L1-L4
|
BMD total, g/cm2 (M ± SDS)
|
Total Z-score
|
|
right
|
left
|
right
|
left
|
Control, n = 23
|
0,804 ± 0,16
|
0,801 ± 0,18
|
0,3
|
0,4
|
0,776 ± 0,19
|
0,5
|
0,718 ± 0,14
|
-0,3
|
Thyrotoxicosis, n = 19
|
0,863 ± 0,18
|
0,878 ± 0,2
|
-0,8*
|
-0,9*
|
0,798 ± 0,28
|
-0,6*
|
0,770 ± 0,15
|
-0,7*
|
* - p ≤ 0.05 in comparison with the control group |
The medians of the Z-scores of the FN on the right and left, the lumbar vertebrae L1-L5 and the body as a whole in the group of children and adolescents with thyrotoxicosis were significantly lower than the control values. They testified to osteoporosis in this group, where p ≤ 0.01 in all indicators compared with the control group (Fig. 2).
Thus, the results obtained indicate the presence of vitamin D deficiency in 87.8% of children and adolescents with thyrotoxicosis, and 12.2% were found to be deficient in this hormone. It is possible that vitamin D deficiency, which has an immunosuppressive effect, is also a provoking factor in the development of thyrotoxicosis caused by Graves' disease [18, 19, 20].
When determining the relationship between vitamin D concentration and the level of antibodies to TSHR, we established a significant association between the content of 25(OH)D and the value of TSHRAb in the group of patients with GD. The correlation analysis results indicate GD patients' meaningful feedback between the vitamin D content and the level of TSHRAb (r=-0.38; p < 0.05). Our results suggest an association between vitamin D deficiency and autoimmune-induced thyroid dysfunction. Low vitamin D levels are possibly the primary factor involved in the pathogenesis of the disease.
In a study by Ahn HwaYoung et al. (2017) evaluated the correlation between serum 25(OH)D2 levels and thyroid-stimulating antibodies (TSAb) in 143 adult GD patients. Regression analysis of the risk ratio (RR) and the confidence interval (CI) revealed that high levels of bT4 (> 1.4ng/dL; RR 3.252; 95% CI 1.022–10.347) correlated with low levels of 25(OH)D2 (≤ 14, 23 ng/ml), and, accordingly, with a higher likelihood of developing /recurrent GD (RR, 3.016; 95% CI, 1.163–7.819). Thus, the authors concluded that the level of 25(OH)D2 in serum may be an independent risk factor in predicting Graves' disease's development and recurrence [19].
There is no consensus about the change in the level of PTH in the blood during thyrotoxicosis. According to the literature data, thyrotoxicosis is accompanied by an increase in PTH concentration, normalising during successful therapy [21]. Although there are opposite works, indicating hypoparathyroidism in Graves' disease [22]. According to our results, in the group with thyrotoxicosis, hypoparathyroidism occurred 4.9 times more often than among healthy children (24.2%).
Formation of peak bone mass is a crucial stage in age-related development of the skeleton and a critical physiological moment that determines bone strength throughout the entire subsequent life of a person [5, 23]. In adults, thyrotoxicosis causes severe osteoporosis and increases the risk of fractures, but when compensation is quickly achieved, a significant BMD decrease is not observed. Subclinical hyperthyroidism is also associated with low BMD and an increased risk of fractures [24]. However, there are practically no data on children. According to the DXA results obtained by us at the time of the study in children and adolescents with thyrotoxicosis, the Z-scores of the femoral neck on the right and left, lumbar vertebrae and the common body were significantly lower than the control, in 63.6% osteoporosis was diagnosed, in 24.2% - osteopenia. However, at the moment, we cannot determine whether osteoporosis is secondary as a complication of thyrotoxicosis, or it is of mixed aetiology, also associated with vitamin D deficiency.