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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2498
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4211-4215
Copyright © 2005 by The Endocrine Society

Fibroblast Growth Factor-23 in Patients with Graves’ Disease before and after Antithyroid Therapy: Its Important Role in Serum Phosphate Regulation

Hiroyuki Yamashita, Yuji Yamazaki, Hisashi Hasegawa, Takeyoshi Yamashita, Seiji Fukumoto, Takashi Shigematsu, Junichiro James Kazama, Masafumi Fukagawa and Shiro Noguchi

Noguchi Thyroid Clinic and Hospital Foundation (H.Y., S.N.), Oita 874-0932, Japan; Pharmaceutical Research Labs (Y.Y., H.H., T.Y.), KIRIN Brewery Co. Ltd., Takasaki 370-1295, Japan; Division of Nephrology and Endocrinology (S.F.), Department of Internal Medicine, Tokyo University Hospital, Tokyo 113-8655, Japan; Division of Nephrology (T.S.), Tokyo-Jikeikai Medical School Aoto Hospital, Katsushika 125-8506, Japan; Division of Clinical Nephrology and Rheumatology (J.J.K.), Niigata University Graduate School of Medicine and Dental Research, Niigata 951-8510, Japan; and Division of Nephrology and Dialysis Center (M.F.), Kobe University School of Medicine, Kobe 650-0017, Japan

Address all correspondence and requests for reprints to: Hiroyuki Yamashita, M.D., Ph.D., Noguchi Thyroid Clinic and Hospital Foundation, 6-33 Noguchi-Nakamachi, Beppu Oita 874-0932, Japan. E-mail: yama{at}noguchi-med.or.jp.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Hyperthyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of fibroblast growth factor (FGF)-23 in serum phosphate homeostasis in patients with Graves’ disease during the course of treatment for hyperthyroidism.

Context: The study group comprised 56 patients (45 for a cross-sectional study and 11 for a longitudinal study) with Graves’ disease. For the cross-sectional study, patients were assigned, on the basis of their serum phosphate level, to a hypophosphatemia group (n = 14), a normophosphatemia group (n = 16), or a hyperphosphatemia group (n = 15). Serum FGF-23, calcium, phosphate, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were compared between the three groups. For the longitudinal study, we assessed changes in these biochemical indices before and after antithyroid treatment.

Results: In the cross-sectional study, the serum FGF-23 level was significantly higher (P < 0.05) in the hyperphosphatemia group than in the other groups (61 ± 36 ng/liter vs. 31 ± 22 ng/liter and 30 ± 9 ng/liter). In the longitudinal study, serum levels of FGF-23 decreased significantly (P < 0.05) from a high of 54 ± 12 ng/liter before treatment to 29 ± 14 ng/liter after treatment. In contrast, the serum 1,25(OH)2D level increased significantly (P < 0.005) from 55 ± 22 pmol/liter before treatment to 185 ± 76 pmol/liter 3 months after treatment. Serum FGF-23 levels were positively correlated with serum phosphate levels (P < 0.0001) and negatively correlated with serum 1,25(OH)2D levels (P < 0.0001).

Conclusions: The significant positive correlation between serum levels of phosphate and FGF-23 indicates that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PTH AND THE vitamin D-endocrine system play key roles in the regulation of serum phosphate levels by their action in the kidney and intestine. However, PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] act predominantly to control calcium homeostasis, and phosphate homeostasis often undergoes changes as a result. Therefore, maintaining phosphate homeostasis is abandoned in favor of maintaining calcium homeostasis in some clinical settings. Phosphatonins, a new class of factors that regulate phosphate homeostasis, have been discovered through studies of phosphate-wasting disorders such as X-linked hypophosphatemia (1, 2), autosomal dominant hypophosphatemic rickets (3), and tumor-induced osteomalacia (4, 5, 6, 7). Fibroblast growth factor (FGF)-23 is a possible phosphatonin in that it regulates phosphate homeostasis via a PTH-independent mechanism (8).

Hyperphosphatemia and hypercalcemia occur in a significant proportion of patients with hyperthyroidism, and both conditions tend to resolve after antithyroid drug treatment (9). Patients treated for hyperthyroidism with antithyroid drugs also show a significant increase in bone mineral density (10). Formation of bone requires calcium and phosphorus as substrates and is regulated by complex interactions of PTH, 1,25(OH)2D, and thyroid hormones. Several studies have examined the effects of antithyroid drug treatment on bone turnover, phosphate, and calcium in patients with Graves’ disease (11, 12, 13, 14, 15); however, FGF-23 has not been studied in hyperthyroid patients.

The aim of the present study was to determine the serum FGF-23 levels during treatment for hyperthyroidism in patients with Graves’ disease to clarify the physiological role of FGF-23 in serum phosphate homeostasis.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Graves’ disease was diagnosed in 568 patients at the Noguchi Thyroid Clinic and Hospital Foundation in 2002. The 568 patients were classified on the basis of their serum phosphate levels into a hypophosphatemia group (phosphate level < 0.81 mmol/liter; n = 54), a normophosphatemia group (phosphate level between 0.81 and 1.45 mmol/liter; n = 271), and a hyperphosphatemia group (phosphate level > 1.45 mmol/liter; n = 229). Twenty patients from each group (60 in total) were selected at random. Written informed consent for measurement of FGF-23 in frozen serum samples collected on the first visit to our clinic was obtained from 45 of these 60 patients. These 45 patients became subjects of a cross-sectional study. Twenty-five had already received antithyroid drug treatment (methimazole, in the majority of cases) from their referring doctors. For the longitudinal study, 11 patients were selected from new patients who visited our clinic between March and May in 2003. These 11 patients had not been treated previously by antithyroid drugs, and they had hyperphosphatemia before treatment. They gave informed consent to participate in a prospective study of sequential changes in serum FGF-23 in the hyperthyroid state and during antithyroid drug treatment. Thus, the overall study group comprised a total of 56 patients with Graves’ disease. The patients’ renal function was normal according to serum creatinine and urea assays, and none of the patients had received any drug known to interfere with vitamin D or calcium levels. Diagnosis of Graves’ disease was made on the basis of clinical findings, elevated serum levels of free T3 (FT3) and free T4 (FT4) with an undetectable TSH concentration, positive immunoreactivity for an anti-TSH receptor antibody, and an elevated rate of 131I uptake. The study protocol was approved by the Noguchi Thyroid Clinic Ethical Committee.

Laboratory tests

Blood samples were collected under fasting conditions on the first visit to our clinic from patients in the cross-sectional study and from patients in the longitudinal study before treatment and 3 wk, 2 months, and 3 months after antithyroid treatment (methimazole, in all cases). Serum levels of alkaline phosphatase, total calcium, albumin, and inorganic phosphate, creatinine, and blood urea nitrogen were measured by routine automated procedures. FT3 (normal range, 3.4–6.6 pmol/liter), FT4 (12–22 nmol/liter), and TSH (0.30–3.50 µU/liter) levels were determined with a commercially available chemiluminescence immunoassay (Ciba Corning Diagnostics Corp., Medfield, MA). TSH-binding inhibitory Ig (normal range, –15 to 8%) levels were measured with a TSH-receptor antibody assay kit (INCSTAR Corp., Stillwater, MN). Serum intact PTH was measured by the ECLusys 2010 (Roche Diagnostics, Mannheim, Germany). Serum 1,25(OH)2D levels were measured by receptor-binding assay with bovine mammary gland receptor (16); intra- and interassay coefficients of variation were 8.1 and 8.3%, respectively. Serum FGF-23 levels (reference range, 10–50 ng/liter) were determined by sandwich ELISA for human FGF-23 (Kainos, Inc., Tokyo, Japan) that uses two monoclonal antibodies to FGF-23 to measure biologically active full-length FGF-23; intra- and interassay coefficients of variation for this assay series were less than 5.0% (17). The serum FGF-23 level in 104 healthy control subjects ranged from 8.2–54.3 ng/liter (mean ± SD; 28.9 ± 11.2 ng/liter) (17).

Statistical analysis

Data are expressed as mean ± SD unless otherwise indicated. Differences in biochemical indices before and after treatment were analyzed using the paired Student’s t test. Comparison between groups was performed using ANOVA with Tukey-Kramer post hoc testing when appropriate. Correlation was tested by Spearman’s correlation coefficient. P < 0.05 was considered significant. Statistical analyses were performed with SAS-JMP, version 4.0.2 (SAS Institute, Inc., Cary, NC).


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The clinical and biochemical characteristics of the 45 patients in the cross-sectional study are summarized in Table 1Go. The serum levels of FT3 and FT4 were significantly higher in the hyperphosphatemia group than in the other two groups (P < 0.05). The serum FGF-23 level was also significantly higher in the hyperphosphatemia group than in the normophosphatemia group or the hypophosphatemia group; however, there was no significant difference in the serum FGF-23 level between the normophosphatemia group and the hypophosphatemia group (Fig. 1Go). There were 10 patients (22%) with an FGF-23 level above the reference range: nine (60%) in the hyperphosphatemia group, one (6%) in the normophosphatemia group, and none in the hypophosphatemia group.


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  		TABLE 1. Clinical and biochemical data for study groups

 


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  		FIG. 1. Comparison of serum FGF-23 between three groups classified by serum phosphate levels: the hypophosphatemia group (Hypo-Pi; n = 14), normophosphatemia group (Normo-Pi; n = 16), and hyperphosphatemia group (Hyper-Pi; n = 15).

 
The mean age of the 11 patients in the longitudinal study was 50 yr, and all were women. Serial changes in biochemical data after antithyroid drug treatment are shown in Table 2Go and Fig. 2Go. As expected, the levels of thyroid hormones and calcium were high before treatment and gradually decreased after the treatment (Table 2Go). Serum levels of FGF-23 and phosphate were also high before treatment, and they decreased significantly as early as 3 wk after the start of treatment (Fig. 2Go, A and B). In contrast, the serum 1,25(OH)2D level was low before treatment, and it increased significantly during the course of treatment (Fig. 2CGo). Serum FGF-23 levels were positively correlated with serum phosphate levels (r = 0.599; P < 0.0001) and negatively correlated with serum 1,25(OH)2D levels (r = –0.681; P < 0.0001).


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  		TABLE 2. Serial changes in biochemical data after antithyroid drug treatment

 


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  		FIG. 2. Serum levels of phosphate (A), FGF-23 (B), and 1,25(OH)2D (C) before and 3 wk (3 W), 2 months (2 M), and 3 months (3 M) after antithyroid drug treatment.

 

   Discussion
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
We reported serum levels of FGF-23 in patients with primary hyperparathyroidism (pHPT), which is generally associated with hypercalcemia and hypophosphatemia, and concluded that FGF-23 may not play a significant role in regulating phosphate in patients with pHPT, especially in those with normal renal function (18). In the present study, we investigated the role of FGF-23 in patients with Graves’ disease who sometimes showed hyperphosphatemia and hypercalcemia. The concurrence of hypercalcemia and hyperphosphatemia is interesting because it suggests the presence of a phosphatonin. Suppressed PTH under hypercalcemic conditions can induce hyperphosphatemia; therefore, a phosphatonin may play a role in the regulation of serum phosphate homeostasis.

Elevation of serum phosphate in hyperthyroidism is caused by increased bone resorption, enhanced renal tubular reabsorption of phosphate by direct action of the thyroid hormone (19, 20), and PTH suppression induced by hypercalcemia (21). In the present study, we confirmed the presence of hypercalcemia and hyperphosphatemia with a suppressed serum PTH concentration in some patients in the hyperthyroid state. We also observed decreased serum levels of 1,25(OH)2D in the hyperthyroid state, which could result from direct inhibition of vitamin D hydroxylases by thyroid hormone (22), represent hypoparathyroidism secondary to hypercalcemia, or result from the action of FGF-23.

In the present study of the physiological role of FGF-23, interpretation of the results was inevitably confounded by the fact that changes in calcium and PTH levels were accompanied by changes in serum phosphate and FGF-23 levels. Therefore, it is necessary to compare the status of FGF-23 in this study with that in other phosphate disorders to clarify the role of FGF-23 in maintaining phosphate homeostasis. Gupta et al. (23) reported elevated FGF-23 levels in patients with hypoparathyroidism. In the other part of the study, we examined sequential changes in serum phosphate and FGF-23 levels in patients with transient hyperparathyroidism after total thyroidectomy for thyroid cancer. These patients had hyperphosphatemia with increased levels of FGF-23. We observed that the peak level of phosphate always preceded that of FGF-23, suggesting phosphate elevation is a primary factor in the FGF-23 increase (data not shown), although it cannot be entirely ruled out that thyroid hormone directly influenced FGF-23 levels in our patients. An increased level of FGF-23 in patients with hyperphosphatemia associated with either hypercalcemia (hyperthyroidism state) or hypocalcemia (hypoparathyroid state) suggests that serum calcium is not a significant regulator of FGF-23. Hyperphosphatemia is also frequently associated with renal failure, and several investigators have reported elevated levels of FGF-23 in patients with end-stage renal failure (24, 25, 26, 27). Imanishi et al. (25) suggested that serum phosphate may be a regulator of the plasma FGF-23 level; this was on the basis of a positive correlation between serum phosphate and plasma FGF-23 levels in patients with end-stage renal failure. Shigematsu et al. (26) reported the same finding in patients with chronic kidney disease. They also suggested that PTH might be responsible for elevation of serum FGF-23 through a mechanism that is still unclear (26). At least in patients with normal renal function, it appears that FGF-23 production may not be regulated by PTH because in cases of hypoparathyroidism, FGF-23 levels increase despite low or undetectable levels of PTH. We reported that serum FGF-23 levels did not change after parathyroidectomy despite the normalization of calcium and PTH levels in patients with pHPT (18). These lines of evidence and the positive correlation between serum phosphate and FGF-23 levels in this study strongly suggest that FGF-23 production is up-regulated by hyperphosphatemia.

Serum FGF-23 levels changed after antithyroid drug therapy according to the changes in serum phosphate levels. We did not find any difference in serum FGF-23 levels between the normophosphatemia group and the hypophosphatemia group. In our previous study, FGF-23 was not suppressed in patients with pHPT who had a low or low-normal serum phosphate level caused by an elevated PTH level. These results suggest that serum FGF-23 may not play a significant role in the regulation of serum phosphate in hypophosphatemia. However, there is a possibility that the present assay for FGF-23 may not be sensitive enough at the low end to really look at hypophosphatemia.

The physiological role of elevated serum FGF-23 levels in patients with hyperphosphatemia should be considered. FGF-23 is known to decrease renal phosphate reabsorption (28) and inhibit the synthesis of 1,25(OH)2D, which is thought to increase both renal phosphate reabsorption and intestinal phosphate absorption (29). These findings suggest that the serum FGF-23 level increases to maintain a normal serum phosphate concentration by increasing fractional phosphate excretion and inhibiting the synthesis of 1,25(OH)2D when hyperphosphatemia is induced. In the present study, we observed PTH suppression in the presence of hyperphosphatemia, which essentially increases the serum PTH level, especially in patients with renal failure. This indicates that hyperphosphatemia is not corrected but rather is exacerbated by PTH suppression in the presence of hypercalcemia in patients with hyperthyroidism. PTH suppression may be beneficial because osteoporosis caused by hyperthyroidism is accelerated if hypersecretion of PTH occurs; therefore, FGF-23 plays an important role in phosphate homeostasis that is independent of PTH in patients with hyperthyroidism. We think that FGF-23 cannot overcome the effect of hyperphosphatemia by the actions of excess thyroid hormone. Additional studies are warranted to determine why the degree of FGF-23 elevation is insufficient to normalize the serum phosphate level.

Serum FGF-23 was increased in hyperphosphatemia in patients with Graves’ disease in the hyperthyroid state and normalized in accordance with normalized phosphate levels after antithyroid drug treatment. There was a significant positive correlation between the serum phosphate and FGF-23 levels, suggesting a possible feedback mechanism involving FGF-23 for maintenance of serum phosphate homeostasis.


   Footnotes
 
First Published Online April 12, 2005

Abbreviations: FGF, Fibroblast growth factor; FT3, free T3; 1,25(OH)2D, 1,25-dihydroxyvitamin D; pHPT, primary hyperparathyroidism.

Received December 20, 2004.

Accepted March 31, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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