The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3979-3982
Copyright © 2004 by The Endocrine Society
Venous Sampling for Fibroblast Growth Factor-23 Confirms Preoperative Diagnosis of Tumor-Induced Osteomalacia
Yasuhiro Takeuchi,
Hisanori Suzuki,
Sayoko Ogura,
Rie Imai,
Yuji Yamazaki,
Takeyoshi Yamashita,
Yoshinari Miyamoto,
Hiroshi Okazaki,
Kozo Nakamura,
Kazuhiko Nakahara,
Seiji Fukumoto and
Toshiro Fujita
Division of Endocrinology and Nephrology, Department of Medicine, University of Tokyo School of Medicine (Y.T., H.S., S.O., T.F.); Pharmaceutical Research Laboratories, KIRIN Brewery Co. Ltd. (R.I., Y.Y., T.Y.); Department of Orthopedics, University of Tokyo School of Medicine (Y.M., H.O., Ko.N.); and Department of Laboratory Medicine, University of Tokyo (Ka.N., S.F.), Tokyo 113-8655, Japan
Address all correspondence and requests for reprints to: Dr. Yasuhiro Takeuchi, Division of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon Minato-ku, Tokyo 105-8470, Japan. E-mail: takeuchi-tky{at}umin.ac.jp. Or to: Dr. Seiji Fukumoto, Department of Laboratory Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: fukumoto-tky{at}umin.ac.jp.
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Abstract
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Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder characterized by hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for hypophosphatemia, and skeletal undermineralization. Patients with TIO suffer from severe muscle weakness and pain. Because surgical removal of the responsible tumors is the only satisfactory treatment for TIO, identification of the tumors is clinically essential. However, because they are predominantly slow-growing neoplasms of benign mesenchymal origin, localization of the responsible tumors is often very difficult. Moreover, even if a tumor is found in a patient with hypophosphatemic osteomalacia, we have had no way to know that the tumor is actually causing the disease. Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal phosphate wasting. We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor. For the first time, we describe a patient with adult-onset hypophosphatemic osteomalacia in whom a clinical diagnosis of TIO was confirmed before surgical removal of the tumor by localizing the responsible tumor using venous sampling for FGF-23 together with magnetic resonance imaging. This combinatorial procedure would be clinically useful for sporadic cases of hypophosphatemic rickets/osteomalacia.
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Introduction
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TUMOR-INDUCED OSTEOMALACIA (TIO), which is also known as oncogenic osteomalacia, is a paraneoplastic disorder characterized by hypophosphatemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D [1,25(OH)2D] for hypophosphatemia, and skeletal undermineralization. (1) Patients with TIO suffer from significant morbidity and sometimes become completely bedridden. These patients show clinical characteristics similar to those of either X-linked hypophosphatemic rickets/osteomalacia (XLH) (2) or autosomal dominant hypophosphatemic rickets/osteomalacia (3). Fibroblast growth factor-23 (FGF-23) was recently identified as a causative factor for TIO and was shown to induce renal tubular phosphate wasting (4), although other factors, such as matrix extracellular phosphoglycoprotein and secreted frizzled-related protein 4, may also be involved in the pathogenesis of TIO (5). Actually, surgical removal of the tumor secreting FGF-23 completely cures TIO (6, 7). Therefore, identification of tumors causing TIO is clinically essential. However, because tumors causing TIO are predominantly slow-growing neoplasms of benign mesenchymal origin (8) and sometimes very small, localization of the responsible tumors is often very difficult (6, 9). We have recently shown that the circulatory FGF-23 level was high in a patient with TIO and rapidly decreased after removal of the responsible tumor (7). A high circulating FGF-23 level alone, however, is not diagnostic for TIO, because serum levels of FGF-23 are high in most patients with XLH as well as TIO (7), and it has been reported that there are some patients who first manifest symptoms in adulthood, but have a missense mutation in the PHEX gene that is responsible for XLH (10). Furthermore, even if tumors are found in patients with high FGF-23 levels, there has been no preoperative way to diagnose whether these tumors are actually producing FGF-23 and causing TIO. We here describe a patient with adult-onset hypophosphatemic osteomalacia in whom clinical diagnosis of TIO was confirmed before surgical removal of the tumor by venous sampling for FGF-23 together with magnetic resonance imaging (MRI).
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Subject and Methods
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A 37-yr-old man presented with chronic pain of the spine, ribs, femurs, and hip joints and progressive muscle weakness for 2 yr. The clinical examination was otherwise normal, except for an abnormal mass, 2 cm in diameter, in the right inguinal region that had been recognized by the patient 17 yr previously. There was no family history of metabolic bone diseases.
The clinical evaluation revealed low serum phosphate levels with low maximum transport of phosphate in renal proximal tubules (TmP/GFR) and elevated serum bone-type alkaline phosphatase levels (Table 1
). The serum levels of calcium, 25-hydroxyvitamin D, and PTH were normal, and the serum 1,25(OH)2D level was inappropriately low. A bone survey showed radiolucent lines in the left femur and pelvic bone, suggesting pseudofractures typically found in patients with osteomalacia. Oral supplementation with phosphate and 1
-hydroxyvitamin D3 increased serum phosphate level only slightly, but did not improve urinary phosphate wasting.
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TABLE 1. Laboratory data in a patient with hypophosphatemic osteomalacia before and after surgical removal of the tumor
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Assays
Serum, plasma, and urinary constituents were measured by standard techniques. Serum intact PTH levels were measured using a commercially available assay kit. Assays of serum 25-hydroxyvitamin D and 1,25(OH)2D were performed by HPLC (11). TmP/GFR values were derived from the nomogram provided by Walton and Bijvoet (12).
The clinical procedures used in this study were approved by the institutional review board. After written informed consent was obtained, systemic venous sampling was performed, and serum FGF-23 concentrations were measured by the sandwich ELISA method (7).
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Results
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Clinical features strongly suggested TIO in this subject. Serum levels of FGF-23 in samples obtained from peripheral blood were about 1.5-fold higher than the upper limit of the reference range (Table 1
) (7). Although an abnormal mass was detected in right inguinal region, we were not sure whether this was the cause of TIO in this patient, because it had been recognized 15 yr before the symptoms appeared. Therefore, to determine the region where FGF-23 was produced in this patient, venous sampling was conducted. Blood samples were collected from all major veins through a catheter inserted in the left femoral vein, and FGF-23 levels in these samples were analyzed. There was a 3-fold step-up of the serum FGF-23 level between the right femoral vein and the right common iliac vein, a 25% step-down after the merge of both common iliac veins, and a further decrease after the junction of both renal veins (Fig. 1A). There was no difference in serum FGF-23 levels in the left common iliac, bilateral femoral, subclavicular, and common jugular veins or inferior and superior vena cavae from those of peripheral circulating levels. MRI revealed a right inguinal sc mass of 3 x 3 x 2.5 cm that was rich in vasculature with cystic components (Fig. 1B). We found no abnormal mass in the pelvic region by MRI. These observations strongly suggested the right inguinal tumor as causative of the hypophosphatemic osteomalacia in this case.
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FIG. 1. Systemic survey of serum FGF-23 levels with venous sampling (A) and MRI of the right inguinal tumor (B). A, Serum FGF-23 levels with venous sampling at right (a) and left (b) common jugular veins, right (c) and left (d) subclavicular veins, superior vena cava distal (e), proximal (f) to the juncture of azygous vein, inferior vena cava proximal (g) and distal (h) to the junction of renal veins, right (i) and left (j) common iliac veins, and right (k and m) and left (l) femoral veins. Blood sampling was performed near the tumor (k) and distal to the tumor (m). B, MRI in horizontal sections (top and middle) and a sagittal section (bottom) reveals a tumor with heterogeneous contrast enhancement in the right inguinal sc region (arrows). R, Right; L, left; V, ventral; D, dorsal.
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After removal of the tumor, serum levels of FGF-23 rapidly decreased to undetectable range (<8 pg/ml) within 3 h, and the phosphate level gradually returned toward normal without supplementation of oral phosphate and active vitamin D3 (Fig. 2A). The half-life of circulating FGF-23 was calculated to be 21.5 min (Fig. 2B). Serum 1,25(OH)2D levels increased after the decrease in serum FGF-23 concentration and exceeded the upper limit of reference range when serum FGF-23 was undetectable; the serum phosphate level increased to within the normal range (Table 1 and Fig. 2C). The serum PTH level slightly increased, possibly in response to a slight decrease in the serum calcium level.
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FIG. 2. Biochemical parameters for phosphate metabolism, including FGF-23 after surgical removal of the tumor (A), disappearance of FGF-23 from the circulation as a function of time (B), and time courses of serum phosphate, maximum TmP/GFR, and FGF-23 before and after surgery (C). The reference range of values for serum phosphate (2.5–4.5 mg/dl) is indicated by the hatched area. The reference range of serum FGF-23 levels (10–50 pg/ml) is indicated by the dotted area. The correlation between FGF-23 levels before and after the surgery and the time of blood collection indicated the following formula: y = 99.145 x e–0.0318 x T, where T indicates the time after surgery (minutes), and y is a percentage of the FGF-23 value if the preoperative value is 100%. The half-life of serum FGF-23 was calculated as T when y is 50%. To convert values for phosphate to millimoles per liter, multiply by 0.323. To convert values for calcium to millimoles per liter, multiply by 0.25. To convert values for magnesium to millimoles per liter, multiply by 0.411. To convert values for creatinine to micromoles per liter, multiply by 88.4. To convert values for PTH to picomoles per liter, multiply by 0.106. To convert values for 1,25(OH)2D to picomoles per liter, multiply by 2.6. To convert values for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.
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The pathological diagnosis of the tumor was hemangiopericytoma.
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Discussion
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It is often difficult to find a definitive cause of adult-onset hypophosphatemic osteomalacia in sporadic cases. TIO is probably the commonest among them; however, there has been no preoperative diagnostic means to identify tumors responsible for TIO. To avoid unnecessary surgical procedures, preoperative identification of tumors responsible for TIO is important, because the tumor found in a typical and expected location was not always responsible for hypophosphatemic osteomalacia, as previously reported (13). Although some reports suggest that scintigraphic studies using radioactive octreotide are useful to reveal the tumor involved in TIO (6, 14, 15, 16), the positive scan does not necessarily indicate that the detected tumor is involved in TIO. Furthermore, this procedure cannot be used in some countries, including Japan. FGF-23, identified as a causative factor for TIO (4), is commonly involved in the pathogenesis of TIO (7, 17). However, because serum levels of FGF-23 in XLH patients are often higher than the reference range (7), elevated circulating levels of FGF-23 cannot discriminate patients with TIO from those with XLH, particularly in sporadic cases. We assumed that venous sampling for systemic survey of regional serum FGF-23 levels would be useful for the diagnosis of TIO and localization of the responsible tumor. Although collecting blood samples from many veins may seem difficult, it is actually a very simple procedure for radiologists, because we collected blood from only major veins, without inserting and wedging catheters into small ones. The half-life of FGF-23 (21.5 min) found in this study is close to that of aldosterone, so that it is short enough to identify the FGF-23-producing tumor with a venous sampling procedure (18). In addition, after removal of the tumor, serum levels of FGF-23 were undetectable for about 10 d, then returned to the reference range. This observation indicates that persistent hypophosphatemia or some other metabolic changes in patients with TIO suppressed the secretion of FGF-23 from tissues that physiologically synthesize FGF-23, and that the responsible tumor was the only source of circulatory FGF-23 in this case. The serum FGF-23 level returned to the peripheral level after successive merge with left iliac vein and bilateral renal veins in the present case. Therefore, it certainly depends on the location of the tumor and the secretion rate of FGF-23 from the tumor how selectively blood samples are to be collected, and the systemic venous sampling procedure may not always localize the responsible tumor. Nevertheless, clearly high levels of FGF-23 in serum from a specific vein strongly suggest the presence of an FGF-23-producing tumor in the region distal to the sampling point and virtually establish the diagnosis of TIO. This information should be clinically useful for further meticulous search and identification of the tumor responsible for TIO even in cases whose tumor cannot be detected by routine examination, although such an exploration may not always succeed in identifying the tumor.
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Footnotes
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This work was supported in part by grants from Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Ministry of Health, Labor, and Welfare of Japan; the National Dairy Promotion; the Research Society for Metabolic Bone Diseases, and the Yamaguchi Endocrine Research Association.
Abbreviations: FGF-23, Fibroblast growth factor-23; 1,25(OH)2D, 1,25-dihydroxyvitamin D; MRI, magnetic resonance imaging; TIO, tumor-induced osteomalacia; TmP/GFR, maximum transport of phosphate in renal proximal tubules; XLH, X-linked hypophosphatemic rickets/osteomalacia.
Received February 29, 2004.
Accepted May 17, 2004.
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Abstract
Introduction
