Severe Hypophosphatemia in a79-Year-Old Man
Qing H.Meng1*and Elizabeth A.Wagar1
CASE DESCRIPTION
A79-year-old white man with a history of progressive
bone pain was admitted for evaluation3years ago.The
patient reported that the pain began in both feet and
gradually spread to the rest of the body over a2-year
period.Further assessment revealed multiple stress
fractures in the feet.Bone mineral density test
indicated osteopenia.Serial bone mineral density tests
during the2years showed that his osteopenia was pro-
gressing.Results of several serum protein electro-
phoreses were essentially normal.His medical history,
which included surgical removal of a cerebral aneu-rysm near the sella turcica and bacterial meningitis, suggested no pertinent etiologic factors.Physical ex-amination revealed no clinically significant findings except unsteady gait.His serum phosphate concentra-tions declined from2.5to1.8mg/dL over the2years before admission.Laboratory test results at the time of admission are summarized in Table1.The patient’s phosphate concentration reached a nadir of1.2mg/dL at admission.His serum alkaline phosphatase was in-creased.Other notable abnormalities included low normal calcium,normal to borderline high parathy-roid hormone(PTH),2and increased24-h urine phosphate and calcium excretion.Other routine biochemical parameters[including ionized calcium, thyroid-stimulating hormone,and free thyroxine(T4)] were normal.The patient underwent a whole-body scan showing multiple bone lesions.Diagnostic imag-ing studies including x-ray,a computer axial tomogra-phy(CAT),and MRI of the lungs,abdomen,and pelvis were reported to be normal at admission.
Based on the above findings,the patient was diag-nosed with osteomalacia secondary to hypophos-p
hatemia.He was then treated with several medica-tions,including bisphosphonates,calcitriol,vitamin D,and calcium and phosphorus supplements.Vitamin D was given because his initial calcium and phosphate concentrations were low,and it was discontinued later following improvement of serum calcium con-centrations.Despite substantial phosphorus re-placement(250mg phosphorus per tablet,2tablets3 times a day),the hypophosphatemia continued, along with bone fragility and muscle weakness over the next3years,and his height decreased from173to 163cm.
DISCUSSION
The patient was evaluated further by several physicians from different disciplines3years after the first admis-sion.This evaluation revealed extensive bone lesions and multiple rib fractures consistent with osteomala-cia.In addition,he was found to have a soft tissue mass on the left posterior10th rib,and computed tomogra-phy(CT)scan revealed cortical destruction of this rib. Follow-up MRI showed a mass suggesting expansile hemangiopericytoma of the left posterior thorax.CT-guided fine-needle aspiration biopsy and histologic evaluation of the sample confirmed hemangiopericy-toma.His plasma concentration of fibroblast growth factor23(FGF23)was increased(292RU/mL;refer-ence intervalՅ180RU/mL).A diagnosis of hemangio-pericytoma with secondary tumor-induced osteomala-cia and hypophosphatemia was made based on the above findings.The patient underwent resection,
hdtune2.52
and a mass of approximately8ϫ4cm involving predomi-nantly the left10th rib,with extension into the9–10 interspace and into the posterior paraspinal muscula-ture,was removed.Immunohistochemical staining re-vealed that FGF23was highly overexpressed in the tu-mor tissue.Since excision of the tumor,the patient has
1Department of Laboratory Medicine,The University of Texas MD Anderson Cancer Center,Houston,TX.
*Address correspondence to this author at:Department of Laboratory Medicine,The University of Texas MD Anderson Cancer Center,1515Holcombe Blvd,Unit37, Houston,TX77030-4009.Fax713-792-4793;e-mail qhmeng@mdanderson. org.
Received May29,2013;accepted August20,2013.
DOI:10.1373/clinchem.2013.210534
©2013American Association for Clinical Chemistry
2Nonstandard abbreviations:PTH,parathyroid hormone;CAT,computer axial tomography;FGF23,fibroblast growth factor23.
Clinical Chemistry60:7
928–932(2014)
Clinical Case Study 928
had complete reversal of his metabolic abnormalities in 2months.His phosphate and calcium concentrations normalized;he no longer requires any calcium,vita-min D,or phosphorus supplementation;and his motor strength is improving.His overall well-being has im-proved greatly.His bone density is improving.These improvements are consistent with the literature indi-cating that serum phosphate returns to normal by post-operative day5but some patients may take as long as10 days.Most patients feel better within days to weeks of tumor removal.Bone healing starts immediatel
皮鞋很忙y,but it may take up to a year or more for clinically significant clinical improvement(1).
Phosphate is an important element for cellular functions,bone development,and mineralization. Hypophosphatemia is defined as a serum phosphate concentrationϽ2.5mg/dL.A serum phosphate con-centrationϽ1.5mg/dL is considered severe hypophos-phatemia and typically results in clinical signs and symptoms(2).Chronic hypophosphatemia can be in-duced by decreased phosphate intake;increased renal phosphate wasting due to primary or secondary hyper-parathyroidism or a renal tubular defect causing de-creased renal phosphate absorption and increased ex-cretion;unusual loss from the gastrointestinal tract caused by diarrhea,malabsorption,or vitamin D defi-ciency;and tumor(2).
Diet is the primary source of phosphate,but inad-equate phosphate intake alone is not a common cause of hypophosphatemia.It is generally recognized that PTH and vitamin D are the key regulators of phos-phate metabolism.However,several novel regula-tors of phosphate homeostasis have been identified as being associated with hypophosphatemia of various types,such as tumor-induced osteomalacia,several he-reditary forms of hypophosphatemic rickets,X-linked hy-pophosphatemia,and autosomal dominant hypophos-phatemia(1,3).Oncogenic hypophosphatemia is a rare cause of severe hypophosphatemia.
Tumor-induced osteomalacia,also known as oncogenic hypophosphatemic osteomalacia or on-cogenic osteomalacia,is a paraneoplastic syndrome that presents with muscle weakness,bone pain,and osteomalacia in association with specific tumors and overexpression of FGF23(3,4).Tumor-induced os-teomalacia is rare,but when it occurs is most com-monly caused by benign phosphaturic mesenchymal tumors among which hemangiopericytoma is the primary one(5).It can also be induced by other types of tumors such as carcinomas,sarcomas,neu-rofibromatosis,bone neoplasms,and pseudotumors (4,6).Most of these tumors are benign,but they have malignant potential.Tumor-induced osteoma-lacia has revealed novel aspects of endocrine inter-actions among the skeleton,the kidney,and the parathyroid glands.Clinical signs in adults include worsening myalgias,bone pain,and fatigue;as the condition progresses,recurrent fractures are com-mon.Children present with difficulty in walking, stunted growth,and rickets(3).
Because most of the tumors are benign and grow slowly,and the symptoms are nonspecific,identifica-tion and localization of the tumor is difficult.The typ-ical time from the onset of symptoms to a presumptive diagnosis of tumor-induced osteomalacia often ex-ceeds2.5years,and the mean time from then until the responsible tumor is identified is approximately5years (3).In our case,several factors may have caused the delay of the diagnosis.For example,the early diagnostic i
maging studies including x-ray,CAT scan,and MRI of the lungs,abdomen,and pelvis were reported to be normal at admission.Initial bone osteomalacia was di-agnosed and treated,but no definitive cause was iden-tified.A diagnosis of lymphoma made the doctors sus-pect that the patient’s hypophosphatemic osteomalacia was likely due to Fanconi syndrome caused by the lym-phoma.However,no improvement was achieved in his symptoms and clinical findings after chemotherapy and complete remission of lymphoma.
The mechanism of tumor-induced osteomalacia is thought to be related to increased secretion of FGF23. The FGF23gene is expressed at very low concentrations in normal tissue but at very high concentrations in tu-mors associated with osteomalacia(3,7).FGF23is a
Clinical Case Study Clinical Chemistry60:7(2014)929
secretory product of tumors associated with oncogenic osteomalacia(8).It inhibits the expression of type IIa and IIC sodium phosphate cotransporters on the apical membrane of proximal tubular cells,thus blocking tu-bular phosphate reabsorption.It also inhibits1-␣hy-droxylase activity and stimulates the alternative24-hydroxylase activity,leading to the suppression of renal conversion of25-hydroxyvitamin-D to1,25-dihydroxyvitamin D(2,3,8,9).Evidence suggests that increased FGF23concentrations occur even in early stages of chronic kidney disease(2)and may contrib-ute to tissue damage in individuals with chronic renal failure.The characteristic biochemical phenotype is hypophosphatemia,hyperphosphaturia,normal or low serum calcium,increased serum alkaline phospha-tase,normal or increased serum PTH,normal serum 25-hydroxyvitamin-D,and low or normal serum1,25-dihydroxyvitamin-D(9,10).In our case,we did not see very low serum1,25-dihydroxyvitamin D results. First,the patient had been given vitamin D,which may raise1,25-dihydroxyvitamin D to some extent.Second, FGF23was not very high,which may compromise the inhibitory potential.Third,1,25-dihydroxyvitamin D is also regulated by PTH and the PTH concentration was relatively high in our case.Fourth,in comparison to the results after surgical removal of the tumor,se-rum1,25-dihydroxyvitamin D concentration was lower before surgery(42vs56
pg/mL),suggesting that there was an inhibition of1,25-dihydroxyvitamin D to some extent.Our1,25-dihydroxyvitamin D results are consistent with those from other case studies(7–10). Besides the causes of hypophosphatemia already out-lined,other clinical entities that result in progressive weakness,bone and muscle pain,and fractures should be included in the differential diagnosis.X-linked hy-pophosphatemia and autosomal dominant hypophos-phatemia are biochemically indistinguishable from tumor-induced osteomalacia;genetic testing for the PHEX(phosphate-regulating gene with homologies to endopeptidase on the X-chromosome)and FGF23 genes will identify patients with X-linked hypophos-phatemia and autosomal dominant hypophos-phatemia,respectively(1,3,9,10).
In conclusion,tumor-induced osteomalacia is a
rare pathologic disorder that presents with muscle weakness,bone pain,hypophosphatemia,and osteo-malacia.Tumor-induced osteomalacia is usually caused by a benign mesenchymal tumor,and complete remission can be achieved by tumor resection.In addi-tion to other biochemical measurements including se-rum phosphate,alkaline phosphatase,PTH,and vita-min D and urine phosphate,earlier ordering of serum FGF23would reduce the delay and contribute to less morbidity for patients with this disease.Author Contributions:All authors confirmed they have contributed to the
intellectual content of this paper and have met the following3re-quirements:(a)significant contributions to the conception and design, acquisition of data,or analysis and interpretation of data;(b)drafting or revising the article for intellectual content;and(c)final approval of the published article.
Authors’Disclosures or Potential Conflicts of Interest:Upon man-uscript submission,all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:
钱学森 气功Employment or Leadership:E.A.Wagar,University of Texas M.D. Anderson Cancer Center.
Clinical Case Study 930Clinical Chemistry60:7(2014)
Consultant or Advisory Role:None declared.
Stock Ownership:None declared.
Honoraria:None declared.
Research Funding:None declared.
Expert Testimony:None declared.
Patents:None declared.
Role of Sponsor:The funding organizations played no role in the design of study,choice of enrolled patients,review and interpretation of data,or preparation or approval of manuscript.
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英国专场1.Chong WH,Molinolo AA,Chen CC,Collins MT.Tumor-induced osteomalacia.
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3.Jan de Beur SM.Tumor-induced osteomalacia.JAMA2005;294:1260–7.
4.Lewiecki EM,Urig EJ Jr,Williams RC Jr.Tumor-induced osteomalacia:lessons
learned.Arthritis Rheum2008;58:773–7.
5.Clifton-Bligh RJ,Hofman MS,Duncan E,Sim IeW,Darnell D,Clarkson A,
et al.Improving diagnosis of tumor-induced osteomalacia with Gallium-68 DOTATATE PET/CT.J Clin Endocrinol Metab2013;98:687–94.
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6.Komı´nek P,Sta´rek I,Geierova´M,Matousˇek P,Zelenı´k K.Phosphaturic
mesenchymal tumour of the sinonasal area:case report and review of the literature.Head Neck Oncol2011;3:16.
7.Takeuchi Y,Suzuki H,Ogura S,Imai R,Yamazaki Y,Yamashita T,et al.
Venous sampling for fibroblast growth factor-23confirms preoperative di-agnosis of tumor-induced osteomalacia.J Clin Endocrinol Metab2004;89: 3979–82.
8.Carpenter TO.Oncogenic osteomalacia:a complex dance of factors.N Engl
J Med2003;348:1705–8.fgf
9.Jonsson KB,Zahradnik R,Larsson T,White KE,Sugimoto T,Imanishi Y,et al.
Fibroblast growth factor23in oncogenic osteomalacia and X-linked hy-pophosphatemia.N Engl J Med2003;348:1656–63.
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Commentary Shikha Khosla1*
Tumor-induced osteomalacia(TIO)2is a rare condi-tion,well described in the literature.It is typically caused by tumors of mesenchymal origin that overex-press the phosphatonin fibroblast growth factor
23 (FGF-23).Patients present with bone pain,muscle weakness,and recurrent fractures.TIO has an insidi-ous onset,and patients may have significant bone demineralization when they seek care.Hypophos-phatemia is the hallmark of the disease.Laboratory data also show normal serum calcium and PTH,low or normal25-hydroxyvitamin D,and low1,25-dihydroxyvitamin D concentrations.Serum alkaline phosphate is high.Urine calcium is low but urine phos-phate is high.Renal phosphate wasting can be assessed by calculating a random percent tubular reabsorption of phosphate or a fasting tubular maximum for phos-phate corrected for glomerular filtration rate(1).In-appropriately normal or increased plasma FGF-23 concentrations are present.Genetic causes of hy-pophosphatemia(X-linked,autosomal dominant, and autosomal recessive hypophosphatemic rickets) have similar biochemical profiles.These causes can be distinguished from TIO by detailed history in-cluding age of onset,physical findings(such as changes in dentition),and genetic testing.Acquired causes such as heavy metal poisoning or acquired Fanconi syndrome will have findings of renal tubu-lar damage(1,2).
These tumors may be small,in obscure places,and difficult to localize.Patients should undergo a com-plete physical examination and extensive head-to-toe radiologic evaluation to locate these tumors.Func-tional studies include indium-111–labeled octreotide scan and fluorodeoxyglucose positr
on emission to-mography(FDG-PET)(1,3).Coregistered computed tomography(CT)with PET or octreotide scan greatly improves localization success rates.Whereas CT scans and MRI may be helpful,dual-energy x-ray absorpti-ometry(DXA)and bone scans usually are not.Selective venous sampling is sometimes used to identify the of-fending lesion in patients with multiple tumoral growths or intracranial lesions(1,4).
Medical management includes replacement of phosphate and calcitriol.Octreotide therapy may mit-igate symptoms(5).Resection of tumor is curative. Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following3re-quirements:(a)significant contributions to the conception and design, acquisition of data,or analysis and interpretation of data;(b)drafting or revising the article for intellectual content;and(c)final approval of the published article.
Authors’Disclosures or Potential Conflicts of Interest:No authors declared any potential conflicts of interest.
Department of Endocrinology,Metabolism and Diabetes,Veterans Affairs Med-
ical Center,Washington,DC.
*Address correspondence to this author at:50Irving St NW,Room GE246,
Washington,DC20422.Fax202-745-8302;e-mail shikha.v.
Received January3,2014;accepted January23,2014.
DOI:10.1373/clinchem.2013.217034
©2014American Association for Clinical Chemistry
2Nonstandard abbreviations:TIO,tumor-induced osteomalacia;FGF-23,fibro-
blast growth factor23;FDG-PET,fluorodeoxyglucose positron emission tomog-
raphy;CT,computed tomography;DXA,dual-energy x-ray absorptiometry.
Clinical Case Study
Clinical Chemistry60:7(2014)931
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