In the present study, we observed high serum level of FGF23, 1,25OH2D and high normal PTH level in normo-parathyroid controls. We also detect strong positive correlation between 1,25(OH)2D3, FGF23 and ferritin level in control group. Expectedly in this study, low serum calcium in association with low serum PTH in patients with hypoparathyroidism were detected. In contrast, high normal serum calcium and PTH in control group was observed. That suggested other factors might be involved in the stimulation of parathyroid secretion. It seems that high ferritin levels in patients with thalassemia might have had possible stimulatory effect on PTH secretion in intact parathyroid function, resulting in high normal serum PTH and calcium.
Pawlotsky et al. revealed a positive correlation between serum ferritin and high Serum PTH in patients with iron overload syndrome (19). Kurtoglu et al. showed a high PTH level in major thalassemia patients more in first two decades (2). Also, another study on 90 patients with thalassemia showed that more than 25% of them had high normal levels of PTH and calcium. They also found a significant correlation between ferritin and PTH in these patients (20). On the other hand, some patients with thalassemia may develop parathyroid dysfunction at older age because of iron overload and iron deposition on parathyroid glands (2). The underlying mechanism might be that iron overload could induce lysosomal and sarcolemmal membrane damage through free radical formation and lipid peroxidation and causes the destruction of parathyroid glands (21). And, cell surface transferrin receptors could able to play a role in protecting parathyroid glands against inorganic iron (22).
In present study we have showed that both case and controls had insufficient 25(OH)D serum level. Napoli et al. reported that serum 25(OH)D deficiency in adult patients with beta thalassemia (23). In this study, we observed a high normal 1,25(OH)2D3 serum level, in spite of 25(OH)D deficiency in the control group. High normal serum PTH might be a potent factor to enhance alfa-1-hydroxilase activity in these patients. Also this study showed a strong positive correlation between 1,25(OH)2D3 and ferritin level in the control group, which was not observed in patients with hypoparathyroidism. Therefore, it is possible that in state of intact parathyroid function, high ferritin level might enhance 1,25OH2D production through direct stimulation of alfa-1-hydroxilase or indirectly through parathyroid hormone action. Some previous reports showed a significant low level of vitamin D in patients with thalassemia, but few of them evaluated serum 1,25(OH)2D3 in patients with thalassemia (1,23). Wood et al. showed high serum level of 1,25(OH)2D3 in patients with thalassemia. He suggested that it could occur even through primary hyperparathyroidism or upregulation of extra-renal alfa-1 hydroxylase activity (24).
This study revealed a normal serum phosphate level, in spite of high FGF23 and high urinary phosphate loss in the control group. It was suggested that high serum level of 1,25(OH)2D3 in patients with thalassemia could enhance intestinal phosphate absorption, which leads to a normal serum phosphate even with high urinary phosphate loss (25). Another finding of the present study was high level of serum FGF23 in patients with thalassemia. Two mechanisms could be put forward to explain the increase of serum FGF23 in these patients. The first is the stimulatory effect of PTH or 1,25(OH)2D3 on FGF23 production (26,27). Also, Moshayoff et al. showed that serum FGF23 levels were increased by PTH administration in both in vivo and in vitro (28). In additional, one study revealed that PTH has direct and indirect effect through 1,25(OH)2D3 on FGF23 secretion (29). The second mechanism of FGF23 increasing, might be due to ferritin. There are controversies about the effects of iron deficiency or iron overload on serum level of FGF23. Recent studies have shown that iron deﬁciency could increases FGF23 degradation and administration of parenteral iron products, such as ferric carboxymaltose increases FGF23 level (15,16,18). On the other hand, some studies have shown the association between Iron deficiencies with increase serum FGF23 and conversely iron transfusion resulted in decline FGF23 level (17). However, the effect of ferritin on FGF23 has not been studied in patients with thalassemia. As result of strong positive correlation between ferritin and FGF23 in our patients with thalassemia, it is possible that there is a direct stimulatory effect of ferritin on FGF23 secretion, which should be more investigated in future studies.
Another finding of the present study is that, in our patients with thalassemia affected by hypoparathyroidism and hyperphosphatemia, in spite of increase in FGF23 serum level, there was no rise in urinary phosphate excretion. Recently, limited numbers of studies were performed to evaluate the effect of PTH on FGF23 function in phosphate homeostasis (30). Yamashita et al. showed that FGF23 was increased in hypoparathyroidism and hyperphosphatemia, which was normalized along with serum phosphate normalization after parathyroid function improvement (31). The present study might suggest that FGF23 was not able to exert its full function in reducing serum phosphate in the absence of PTH. This could be due to PTH role in regulating FGF23 function.
In spite many interesting finding in this study we have some limitations, the first one was that the present study is a descriptive with small number of patient and not a clinical trial. Future clinical trials is suggested in patients with hypoparathyroidism after PTH treatment to investigate the FGF23 functions more accurately. Also, investigating FGF23 and PTH gene expression could lead to having more detailed about the physiology, cause and effects. Further studies are suggested to evaluate the role of ferritin on PTH, FGF23 in normal population with and without hypoparathyroidism.