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 asssment 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 veral rum protein electro-
phores were esntially normal.His medical history,美国留学存款证明
which included surgical removal of a cerebral aneu-rysm near the lla turcica and bacterial meningitis, suggested no pertinent etiologic factors.Physical ex-amination revealed no clinically significant findings except unsteady gait.His rum 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 rum alkaline phosphata was in-cread.Other notable abnormalities included low normal calcium,normal to borderline high parathy-roid hormone(PTH),2and incread24-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.
Bad on the above findings,the patient was diag-nod with osteomalacia condary to hypophos-
phatemia.He was then treated with veral medica-tions,including bisphosphonates,calcitriol,vitamin D,and calcium and phosphorus supplements.Vitamin D was given becau his initial calcium and phosphate concentrations were low,and it was discontinued later following improvement of rum 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 decread from173to 163cm.
DISCUSSION
columbus dayThe patient was evaluated further by veral 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 incread(292RU/mL;refer-ence intervalՅ180RU/mL).A diagnosis of hemangio-pericytoma with condary tumor-induced osteomala-cia and hypophosphatemia was made bad on the above findings.The patient underwent rection,
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 overexpresd 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
easton2Nonstandard abbreviations:PTH,parathyroid hormone;CAT,computer axial tomography;FGF23,fibroblast growth factor23.
Clinical Chemistry60:7
928–932(2014)
Clinical Ca 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.The improvements are consistent with the literature indi-cating that rum 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
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 rum phosphate concentrationϽ2.5mg/dL.A rum phosphate con-centrationϽ1.5mg/dL is considered vere hypophos-phatemia and typically results in clinical signs and symptoms(2).Chronic hypophosphatemia can be in-duced by decread phosphate intake;incread renal phosphate wasting due to primary or condary hyper-parathyroidism or a renal tubular defect causing de-cread renal phosphate absorption and incread ex-cretion;unusual loss from the gastrointestinal tract caud 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 cau of hypophosphatemia.It is generally recognized that PTH and vitamin D are the key regulators of phos-phate metabolism.However,veral novel regula-tors of phosphate homeostasis have been identified as being associated with hypophosphatemia of various types,such as tumor-induced osteomalacia,veral he-reditary forms of hypophosphatemic rickets,X-linked hy-pophosphatemia,and autosomal dominant hypophos-phatemia(1,3).Oncogenic hypophosphatemia is a rare cau of vere hypophosphatemia.
Tumor-induced osteomalacia,also known as oncogenic hypophosphatemic osteomalacia or on-cogenic osteomalacia,is a paraneoplastic syndrome that prents 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 caud by benign phosphaturic menchymal 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 pudotumors (4,6).Most of the 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 worning myalgias,bone pain,and fatigue;as the condition progress,recurrent fractures are com-mon.Children prent with difficulty in walking, stunted growth,and rickets(3).
Becau 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 ont 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 ca,veral factors may have caud 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-agnod and treated,but no definitive cau was iden-tified.A diagnosis of lymphoma made the doctors sus-pect that the patient’s hypophosphatemic osteomalacia was likely due to Fanconi syndrome caud 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 incread cretion of FGF23. The FGF23gene is expresd at very low concentrations in normal tissue but at very high concentrations in tu-mors associated with osteomalacia(3,7).FGF23is a
Clinical Ca Study Clinical Chemistry60:7(2014)929
cretory 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-droxyla activity and stimulates the alternative24-hydroxyla activity,leading to the suppression of renal conversion of25-hydroxyvitamin-D to1,25-dihydroxyvitamin D(2,3,8,9).Evidence suggests that incread FGF23concentrations occur even in early stages of chronic kidney dia(2)and may contrib-ute to tissue damage in individuals with chronic renal failure.The characteristic biochemical phenotype is hypophosphatemia,hyperphosphaturia,normal or low rum calcium,incread rum alkaline phospha-ta,normal or incread rum PTH,normal rum 25-hydroxyvitamin-D,and low or normal rum1,25-dihydroxyvitamin-D(9,10).In our ca,we did not e very low rum1,25-dihydroxyvitamin D results. First,the patient had been given vitamin D,which may rai1,25-dihydroxyvitamin D to some extent.Second, FGF23was not very high,which may compromi the inhibitory potential.Third,1,25-dihydroxyvitamin D is also regulated by PTH and the PTH concentration was relatively high in our ca.Fourth,in comparison to the results after surgical removal of the tumor,-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 tho from other ca studies(7–10). Besides the caus 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 endopeptida 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 prents with muscle weakness,bone pain,hypophosphatemia,and osteo-malacia.Tumor-induced osteomalacia is usually caud by a benign menchymal tumor,and complete remission can be achieved by tumor rection.In addi-tion to other biochemical measurements including -rum phosphate,alkaline phosphata,PTH,and vita-min D and urine phosphate,earlier ordering of rum FGF23would reduce the delay and contribute to less morbidity for patients with this dia.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:
Employment or Leadership:E.A.Wagar,University of Texas M.D. Anderson Cancer Center.
绯闻女孩 第三季
Clinical Ca Study 930Clinical Chemistry60:7(2014)
Consultant or Advisory Role:None declared.
Stock Ownership:None declared.
Honoraria:None declared.
Rearch 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.
References
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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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节拍练习8.Carpenter TO.Oncogenic osteomalacia:a complex dance of factors.N Engl
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Commentary Shikha Khosla1*
Tumor-induced osteomalacia(TIO)2is a rare condi-tion,well described in the literature.It is typically caud by tumors of menchymal origin that overex-press the phosphatonin fibroblast growth factor
23 (FGF-23).Patients prent with bone pain,muscle weakness,and recurrent fractures.TIO has an insidi-ous ont,and patients may have significant bone demineralization when they ek care.Hypophos-phatemia is the hallmark of the dia.Laboratory data also show normal rum 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 assd 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 incread plasma FGF-23 concentrations are prent.Genetic caus of hy-pophosphatemia(X-linked,autosomal dominant, and autosomal recessive hypophosphatemic rickets) have similar biochemical profiles.The caus can be distinguished from TIO by detailed history in-cluding age of ont,physical findings(such as changes in dentition),and genetic testing.Acquired caus such as heavy metal poisoning or acquired Fanconi syndrome will have findings of renal tubu-lar damage(1,2).
The 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 the tumors.Func-tional studies include indium-111–labeled octreotide scan and fluorodeoxygluco posit
ron 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 ud 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).Rection 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奥运会足球比赛赛程
©2014American Association for Clinical Chemistry
硕士学位英文
2Nonstandard abbreviations:TIO,tumor-induced osteomalacia;FGF-23,fibro-
blast growth factor23;FDG-PET,fluorodeoxygluco positron emission tomog-
raphy;CT,computed tomography;DXA,dual-energy x-ray absorptiometry.
Clinical Ca Study
Clinical Chemistry60:7(2014)931
