Journal Article
Erik A. Imel,
1Departments of Medicine (E.A.I., M.J.E.), Indianapolis, Indiana 46202
2Pediatrics (E.A.I.), Indianapolis, Indiana 46202
Search for other works by this author on:
Michael J. Econs1Departments of Medicine (E.A.I., M.J.E.), Indianapolis, Indiana 46202
3Medical and Molecular Genetics (M.J.E.), Indiana University School of Medicine, Indianapolis, Indiana 46202
*Address all correspondence and requests for reprints to: Michael J. Econs, M.D., F.A.C.P., F.A.C.E., Division of Endocrinology and Metabolism, Indiana University School of Medicine, 541 North Clinical Drive, CL 459, Indianapolis, Indiana 46202.
Search for other works by this author on:
Accepted:
02 November 2011
-
- Split View
-
- Article contents
- Figures & tables
- Video
- Audio
- Supplementary Data
Cite
Cite
Erik A. Imel, Michael J. Econs, Approach to the Hypophosphatemic Patient, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 3, 1 March 2012, Pages 696–706, //doi.org/10.1210/jc.2011-1319
Close
-
- More
Close
Navbar Search Filter Microsite Search Term Search
Hypophosphatemia is commonly missed due to nonspecific signs and symptoms, but it causes considerable morbidity and in some cases contributes to mortality. Three primary mechanisms of
hypophosphatemia exist: increased renal excretion, decreased intestinal absorption, and shifts from the extracellular to intracellular compartments. Renal hypophosphatemia can be further divided into fibroblast growth factor 23-mediated or non-fibroblast growth factor 23-mediated causes. Proper diagnosis requires a thorough medication history, family history, physical examination, and assessment of renal tubular phosphate handling to identify the cause. During the past decade, our understanding
of phosphate metabolism has grown greatly through the study of rare disorders of phosphate homeostasis. Treatment of hypophosphatemia depends on the underlying disorder and requires close biochemical monitoring. This article illustrates an approach to the hypophosphatemic patient and discusses normal phosphate metabolism.
Case
A 65-yr-old man developed right medial knee pain while golfing. A tibial stress fracture was identified. He then developed a contralateral stress fracture and generalized pain and weakness in his legs and back. He had no previous history of fracture or childhood rickets. He has type 2 diabetes, hypercholesterolemia, and hypertension, treated with glipizide, quinapril, rosiglitazone, and atorvastatin. He was taking hydrocodone/acetaminophen, rofecoxib, and tramadol for pain, plus 1000 mg of calcium and 600 units of vitamin D daily. Family history was unremarkable.
On examination, he was hypertensive (147/81 mm Hg), weight was 99.2 kg, and height was 182 cm. He had normal dentition, without intraoral masses. He had a cataract in his left eye. He had no palpable masses in his neck or extremities. Examination of lungs, heart, and abdomen was normal, except for a systolic murmur. He required a walker to ambulate, used his arms to rise from a chair, but could do a sit-up. Laboratory testing revealed calcium of 8.9 mg/dl, creatinine of 0.8 mg/dl, 25-hydroxyvitamin D (25OHD) of 26 ng/ml, 1,25-dihydroxyvitamin D (1,25OHD) of 25 pg/ml, alkaline phosphatase that had risen from 66 to 171 U/liter, and serum phosphate ranging from 1.1 to 1.7 mg/dl.
Accreditation and Credit Designation Statements
The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation.
The Endocrine Society designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Learning Objectives
Upon completion of this educational activity, participants should be able to:
- •.
Explain the basic physiology and pathophysiology of phosphates.
- •.
Recognize the causes and symptoms of hypophosphatemia and select appropriate diagnostic testing.
- •.
Apply strategies to diagnose and manageacute and chronic hypohosphatemia.
Target Audience
This Journal-based CME activity should be of substantial interest to endocrinologists.
Disclosure Policy
Authors, editors, and Endocrine Society staff involved in planning this CME activity are required to disclose to learners any relevant financial relationship(s) that have occurred within the last 12 months with any commercial interest(s) whose products or services are discussed in the CME content. The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable.
Disclosures for JCEM Editors are found at //www.endo-society.org/journals/Other/faculty_jcem.cfm.
The following individuals reported relevant financial relationships:
Michael J. Econs, M.D., is a consultant to and receives royalties from, Kyowa Hakko Kirin Pharma, Inc.
Eric Imel, M.D., is an investigator for Kyowa Hakko Kirin Pharma, Inc.
Editor-in-Chief, Leonard Wartofsky, M.D., reported no relevant financial relationships.
Endocrine Society staff associated with the development of content for this activity reported no relevant financial relationships.
Acknowledgement of Commercial Support
This activity is not supported by grants, other funds, or in-kind contributions from commercial supporters.
Privacy and Confidentiality Statement
The Endocrine Society will record learner's personal information as provided on CME evaluations to allow for issuance and tracking of CME certificates. No individual performance data or any other personal information collected from evaluations will be shared with third parties.
Method of Participation
This Journal-based CME activity is available in print and online as full text HTML and as a PDF that can be viewed and/or printed using Adobe Acrobat Reader. To receive CME credit, participants should review the learning objectives and disclosure information; read the article and reflect on its content; then go to //jcem.endojournals.org and find the article, click on CME for Readers, and follow the instructions to access and complete the post-activity test questions and evaluation.
To complete this activity, participants must:
- •.
Have access to a computer with an internet connection.
- •.
Use a major web browser, such as Internet Explorer 7+, Firefox 2+, Safari, Opera, or Google Chrome; in addition, cookies and Javascript must be enabled in the browser's options.
The estimated time to complete this activity, including review of material, is 1 hour. If you have questions about this CME activity, please direct them to .
Activity release date: March 2012
Activity expiration date: March 2013
Background
Phosphate is involved in a variety of processes including acid-base buffering, postreceptor signaling, energy transfer, and information storage and translation in DNA and RNA. The primary repository (85%) of phosphate is in the bone, where calcium and phosphate (in hydroxyapatite) provide skeletal strength and rigidity (1). Outside of bone, most phosphate is intracellular.
Phosphate is abundantly present in many foods. Isolated dietary phosphate deficiency is uncommon, and deficiency usually occurs with generalized malnutrition. Intestinal phosphate absorption is up-regulated by 1,25OHD. In equilibrium, about 300 mg of phosphate moves into and out of bone daily in adults. Phosphate is freely filtered at the glomerulus and then reabsorbed, but proximal tubular reabsorption is inhibited by both PTH and fibroblast growth factor 23 (FGF23).
For adults, hypophosphatemia is generally defined by serum phosphate concentration below 2.5 mg/dl (0.8 millimolar). However, infants have higher normal phosphate ranges than adults, and these values gradually decline throughout childhood and adolescence to adult levels (2, 3). Young children also have higher renal phosphate thresholds than adults (tubular maximum reabsorption of phosphate per unit of glomerular filtrate, TmP/GFR) (2). This is likely an accommodation to an increased need for phosphate to adequately mineralize the growing skeleton because phosphate concentrations within the adult normal range cause rickets in infancy. Many clinical laboratories do not report age-appropriate normal ranges for phosphate, resulting in missed or delayed diagnoses of hypophosphatemia in children.
Clinical Presentation
Symptoms are nonspecific and are more common with severe and acute hypophosphatemia. Many patients with mild hypophosphatemia are asymptomatic, and hypophosphatemia may be an incidental finding. Generalized muscle weakness is the most common symptom of hypophosphatemia, and weakness and fatigue are frequent symptoms with acquired hypophosphatemia. However, weakness is infrequent in patients with congenital forms, such as X-linked hypophosphatemia (XLH). Other neurological symptoms (including paresthesias, dysarthria, altered mental status, seizures, and neuropathy) are reported with severe hypophosphatemia, but these are rare presenting symptoms for hypophosphatemia in general (4–7). Acute severe hypophosphatemia can be life-threatening and is associated with mortality and impaired cardiac and respiratory function among hospitalized patients (8).
Myalgia may accompany weakness in some patients, but severe acute muscle pain may indicate rhabdomyolysis resulting from hypophosphatemia. Hypophosphatemia may also cause intravascular hemolysis. During cell lysis, intracellular phosphate and proteins such as myoglobin are released, which can cause renal damage and hyperphosphatemia, obscuring previous hypophosphatemia.
Patients with chronic hypophosphatemia develop osteomalacia and resultant bone pain. Pain may occur with or without pseudofractures. However, osteomalacia requires time to develop and is not present during acute hypophosphatemia. Growing children with prolonged hypophosphatemia from any etiology develop rachitic features, including genu valgum or varum, frontal bossing, widening of the ends of long bones, and short stature.
A careful history of both prescription and nonprescription medications may identify the cause of hypophosphatemia (Table 1). In addition, family history may reveal a heritable disorder, although some patients with inherited hypophosphatemia may be unaware of their family diagnosis (9).
Table 1.
Differential diagnosis of hypophosphatemia
| XLH (PHEX) | Hyperparathyroidism | Impaired dietary intake | Refeeding syndrome | Mannitol |
| ADHR (FGF23) | HHRH | Phosphate binders | Glucose infusion | Bisphosphonates |
| ARHR (DMP1, ENPP1) | Diuretics: acetazolamide, thiazides, loop diuretics | Sevelamer | Insulin infusion | |
| TIO | Antacids containing calcium, magnesium, aluminum | Salicylate poisoning | ||
| FD | Fanconi syndrome | Hyperventilation | ||
| Linear sebaceous nevus syndrome | Genetic causes: Dent's disease, cystinosis, NaPi2a mutations, others | Alcoholism | Respiratory alkalosis | |
| Postrenal transplantation hypophosphatemia | Drug induced: toluene, streptozocin, ifosfamide, cisplatin, tetracyclines, aminoglycosides, antiretrovirals (tenofovir, adefovir), and imatinib | Premature infants | Catecholamines | |
| Iron polymaltose infusions | Malabsorption | |||
| Vitamin D deficiency | ||||
| Vitamin D metabolism defects | ||||
| 1α-hydroxylase deficiency | ||||
| Vitamin D receptor mutation |
| XLH (PHEX) | Hyperparathyroidism | Impaired dietary intake | Refeeding syndrome | Mannitol |
| ADHR (FGF23) | HHRH | Phosphate binders | Glucose infusion | Bisphosphonates |
| ARHR (DMP1, ENPP1) | Diuretics: acetazolamide, thiazides, loop diuretics | Sevelamer | Insulin infusion | |
| TIO | Antacids containing calcium, magnesium, aluminum | Salicylate poisoning | ||
| FD | Fanconi syndrome | Hyperventilation | ||
| Linear sebaceous nevus syndrome | Genetic causes: Dent's disease, cystinosis, NaPi2a mutations, others | Alcoholism | Respiratory alkalosis | |
| Postrenal transplantation hypophosphatemia | Drug induced: toluene, streptozocin, ifosfamide, cisplatin, tetracyclines, aminoglycosides, antiretrovirals (tenofovir, adefovir), and imatinib | Premature infants | Catecholamines | |
| Iron polymaltose infusions | Malabsorption | |||
| Vitamin D deficiency | ||||
| Vitamin D metabolism defects | ||||
| 1α-hydroxylase deficiency | ||||
| Vitamin D receptor mutation |
See Refs. 1, 7, 14, 18–21, 23, 26, 27, 30–36, 39, 40, 43–46, 53, 70, 78–81.
Table 1.
Differential diagnosis of hypophosphatemia
| XLH (PHEX) | Hyperparathyroidism | Impaired dietary intake | Refeeding syndrome | Mannitol |
| ADHR (FGF23) | HHRH | Phosphate binders | Glucose infusion | Bisphosphonates |
| ARHR (DMP1, ENPP1) | Diuretics: acetazolamide, thiazides, loop diuretics | Sevelamer | Insulin infusion | |
| TIO | Antacids containing calcium, magnesium, aluminum | Salicylate poisoning | ||
| FD | Fanconi syndrome | Hyperventilation | ||
| Linear sebaceous nevus syndrome | Genetic causes: Dent's disease, cystinosis, NaPi2a mutations, others | Alcoholism | Respiratory alkalosis | |
| Postrenal transplantation hypophosphatemia | Drug induced: toluene, streptozocin, ifosfamide, cisplatin, tetracyclines, aminoglycosides, antiretrovirals (tenofovir, adefovir), and imatinib | Premature infants | Catecholamines | |
| Iron polymaltose infusions | Malabsorption | |||
| Vitamin D deficiency | ||||
| Vitamin D metabolism defects | ||||
| 1α-hydroxylase deficiency | ||||
| Vitamin D receptor mutation |
| XLH (PHEX) | Hyperparathyroidism | Impaired dietary intake | Refeeding syndrome | Mannitol |
| ADHR (FGF23) | HHRH | Phosphate binders | Glucose infusion | Bisphosphonates |
| ARHR (DMP1, ENPP1) | Diuretics: acetazolamide, thiazides, loop diuretics | Sevelamer | Insulin infusion | |
| TIO | Antacids containing calcium, magnesium, aluminum | Salicylate poisoning | ||
| FD | Fanconi syndrome | Hyperventilation | ||
| Linear sebaceous nevus syndrome | Genetic causes: Dent's disease, cystinosis, NaPi2a mutations, others | Alcoholism | Respiratory alkalosis | |
| Postrenal transplantation hypophosphatemia | Drug induced: toluene, streptozocin, ifosfamide, cisplatin, tetracyclines, aminoglycosides, antiretrovirals (tenofovir, adefovir), and imatinib | Premature infants | Catecholamines | |
| Iron polymaltose infusions | Malabsorption | |||
| Vitamin D deficiency | ||||
| Vitamin D metabolism defects | ||||
| 1α-hydroxylase deficiency | ||||
| Vitamin D receptor mutation |
See Refs. 1, 7, 14, 18–21, 23, 26, 27, 30–36, 39, 40, 43–46, 53, 70, 78–81.
Diseases of Hypophosphatemia
Three primary mechanisms of hypophosphatemia exist: increased renal excretion, decreased intestinal absorption, and movement of phosphate from the extracellular to intracellular compartments. The initial step in diagnosis involves determining whether hypophosphatemia is renal or nonrenal. Renal hypophosphatemia can be FGF23-mediated or non-FGF23-mediated. Some renal or gastrointestinal mechanisms for hypophosphatemia may cause either acute or chronic hypophosphatemia. Movement of phosphate into cells can cause acute hypophosphatemia, usually following a period of phosphate depletion. Multiple mechanisms may coincide in some patients.
Renal
The classic, and most common, inherited renal phosphate wasting disorder is XLH. XLH usually presents with typical signs of rickets in young children, accompanied by hypophosphatemia, inappropriately low or normal 1,25OHD, and low TmP/GFR. The inheritance pattern is X-linked dominant. Consequently, both males and females are affected, and there is no male-to-male transmission of the disease. However, severity of disease varies widely, even within a kindred (10). Poor linear growth is common, often despite adequate medical treatment. Some data suggest that earlier diagnosis and treatment improve height outcomes (11). However, patients often still require orthopedic surgical procedures (such as femoral or tibial osteotomies) to modulate the progression of lower extremity deformities. Additional features of XLH include frequent dental abscesses and the development of enthesopathy (calcification of tendons and ligaments). Enthesopathy frequently causes joint stiffness and can be the most limiting feature of the disease in adulthood. Adults commonly have significant osteoarthritis with resulting joint pain (12).
XLH is caused by inactivating mutations in PHEX (13), which lead to increased bone expression of the phosphate-regulating hormone FGF23 (14). FGF23 enters the circulation and acts primarily at renal tubular FGF receptors, in conjunction with the coreceptor klotho (15), decreasing proximal renal tubular phosphate reabsorption and 1,25OHD production, and also increasing vitamin D degradation (16). Although these effects on phosphate transport and 1,25OHD metabolism occur in the proximal tubule, FGF23 signaling appears to start in the distal tubule (17). Mechanisms translating the initial distal tubule signal to proximal tubule effect have not been determined. Nevertheless, FGF23 excess causes the biochemical phenotype of XLH. Less common autosomal recessive forms of hypophosphatemic rickets are caused by inactivating mutations in both dentin matrix protein 1 (DMP1) and in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), both with hypophosphatemia due to excess FGF23 (18–20).
Mutations in FGF23 resulting in impaired cleavage cause FGF23 excess in autosomal dominant hypophosphatemic rickets (ADHR) (21–23). These patients have an interesting clinical phenotype characterized by variability in age of clinically evident disease and incomplete penetrance (24). Hypophosphatemic rickets may develop during childhood, like XLH patients. However, a significant number of subjects from the same kindreds had a delayed onset of phenotype, with normophosphatemia and normal growth without rickets during childhood, to be followed by onset of hypophosphatemic osteomalacia in adolescence or adulthood. Most ADHR patients with delayed onset have been women (23–25). Furthermore, some subjects have later normalized their serum phosphate and stopped therapy. These changes over time are due to alterations in FGF23 (23) concentrations, suggesting that ADHR patients are intermittently regulating FGF23 and phosphate normally.
FGF23-mediated hypophosphatemia also occurs associated with focal sites of abnormal FGF23 production, including fibrous dysplasia (FD) of bone, linear sebaceous nevus syndrome, and tumor-induced osteomalacia (TIO). FD can be associated with café au lait macules and precocious puberty or other endocrine hyperfunction in McCune-Albright syndrome. Consequently, patients with FD should be tested for additional endocrine abnormalities. Phosphate wasting and FGF23 concentration correlates with the total amount of FD lesions (26). Linear sebaceous nevus syndrome is a neuroectodermal disorder associated with seizures, developmental defects, and cutaneous lesions producing FGF23 (27).
Acquired chronic renal phosphate wasting should prompt consideration of TIO, although ADHR, FD, and some types of Fanconi syndrome may also present after childhood. The biochemical phenotype of TIO is identical to that of XLH, but may be more severe. Many tumor types have been reported, including some malignant tumors, but in general these tumors are small, benign, and can be located anywhere in the body. The majority of tumors are classified as phosphaturic mesenchymal tumors of a mixed connective tissue type (28). Multiple phosphatonins have been implicated in TIO, but FGF23 is the most consistent and well-characterized (29–32). If measurement can be made, elevated circulating FGF23 concentration is a sensitive indicator of TIO (30). However, it is not specific because many other disorders involve high FGF23 concentrations.
Hypophosphatemia occurring after renal transplant is caused by prolonged excess FGF23 production acquired during chronic kidney disease (33). Excess FGF23 production gradually resolves over time but may require treatment with phosphate and calcitriol with gradual tapering of doses until the elevated FGF23 resolves.
Some renal disorders associated with phosphate wasting are not FGF23-mediated, but are due to direct tubular abnormalities. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is due to mutations in NaPi2c, a sodium-dependent phosphate cotransporter in the renal proximal tubule (34). Contrary to XLH patients, those with HHRH develop an appropriate increase in 1,25OHD and resultant hyperabsorption of calcium, hypercalciuria, and a propensity to nephrolithiasis. Fanconi syndrome is due to a variety of drugs, toxins, or genetic causes, resulting in variable renal losses of phosphate, calcium, and other ions; glucosuria; and aminoaciduria. Some genetic causes of hypophosphatemia due to Fanconi syndrome include mutations in chloride channel 5 (Dent's disease), sodium phosphate cotransporter 2a (NaPi2a), and cystinosin (CTNS, causing nephropathic cystinosis) (35–37).
Posthepatic resection hypophosphatemia is common and can last several days, but the cause is unclear. Although renal phosphate losses occur, this transient hypophosphatemia does not appear to be mediated by either FGF23 or PTH (38).
Nonrenal
Impaired phosphate intake or gastrointestinal absorption causes acute or chronic hypophosphatemia, but shifts from the extracellular compartment to the intracellular compartment cause acute hypophosphatemia. Frequently acute hypophosphatemia is nonrenal in origin, but it often involves a combination of factors.
Dietary phosphate deficiency is not usually an isolated deficiency, but is usually combined with vitamin D and other nutritional deficiencies. Premature infants require higher mineral intake than older infants for skeletal mineralization and thus require additional mineral supplementation, especially if fed with human milk (39). Acutely or chronically ill patients often have impaired nutritional intake or gastrointestinal absorption predisposing to hypophosphatemia. Antacids or other phosphate-binding agents impair absorption, causing acute or chronic hypophosphatemia (1). Parenteral nutrition may contribute to hypophosphatemia if insufficient phosphate is provided.
Any conditions resulting in poor overall nutrition, such as alcoholism, anorexia, severe malabsorption, and starvation, can cause phosphate depletion. Sometimes serum phosphate is normal, despite overall depletion before nutritional intervention. During refeeding, phosphate is shifted into cells for glucose utilization, resulting in hypophosphatemia. Patients with refeeding syndrome are also at risk for hypokalemia and hypomagnesemia. Likewise, phosphate depletion results from hyperglycemia-induced osmotic diuresis in the diabetic ketoacidosis patient. Once insulin administration begins, glucose utilization and cellular phosphate uptake increase and hypophosphatemia develops (1).
Similarly, during salicylate poisoning or rapid mechanical ventilation, phosphate moves into cells due to respiratory alkalosis (5, 40). Anxiety-induced hyperventilation may likewise cause transient hypophosphatemia (41). These acute forms of hypophosphatemia quickly improve with resolution of respiratory alkalosis.
Multiple drugs and toxins induce acute or chronic hypophosphatemia through a variety of mechanisms: isolated phosphaturia, Fanconi syndrome, intestinal phosphate binding, or intracellular uptake of phosphate (Table 1). In one study, 82% of inpatient acute hypophosphatemia were attributed to medications (42). Some forms of iv iron cause hypophosphatemia and osteomalacia due to increased FGF23 concentrations (43–45). Increased urinary excretion of phosphate may complicate diuretic and corticosteroid use. Mannitol can cause a pseudohypophosphatemia due to an assay artifact, but it may also have a mild phosphaturic effect (1). Although phosphate concentrations increase during advanced chronic kidney disease, daily or continuous hemodialysis and phosphate binders can sometimes induce hypophosphatemia (46).
Evaluation
Physical examination
A comprehensive physical examination should identify consequences of hypophosphatemia and clues to an underlying cause. Special focus should be on the musculoskeletal exam, looking for signs of weakness, pathological fractures or pseudofractures, and skeletal deformities. Bone pain may be present, but severe muscle pain may indicate rhabdomyolysis. In children, rachitic features should be noted, and in adults rachitic features suggest chronic hypophosphatemia since childhood. Short stature with increased upper to lower segment ratio also suggests previous childhood rickets, even without leg deformities. Decreased range of motion at the spine, hips, and other large joints can indicate calcified entheses, a common feature in adults with XLH. Facial asymmetry or deformation of long bones may be signs of underlying FD. Maxillary bones are common sites of FD, whereas the sinuses are a common location for tumors causing TIO. If TIO is suspected, a thorough examination for palpable soft tissue masses should be performed. Hepatomegaly may suggest either an underlying tumor or chronic alcoholism. Skin findings such as café au lait macules (FD and McCune Albright syndrome) and linear sebaceous nevi should be noted.
Laboratory assessment
Laboratory assessment should establish the underlying cause of hypophosphatemia (Table 2). During treatment of diabetic ketoacidosis, or refeeding, or after known medications, the cause of hypophosphatemia is usually clear. Otherwise, the first step is to determine whether hypophosphatemia is renal or nonrenal in origin. This requires assessment of the TmP/GFR (Fig. 1) (47). Simultaneous collection of fasting second morning void urine and blood is usually sufficient; if the results are unclear, however, a specific fasting 2-h morning urine collection should be performed, with blood sampling halfway through the collection. The tubular reabsorption of phosphate is calculated and is used with serum phosphate to determine the TmP/GFR from a nomogram (Fig. 1). The TmP/GFR normal range approximates the same numerical range as the age-appropriate serum phosphate concentration in milligrams per deciliter. If both serum phosphate and TmP/GFR are low, this indicates inappropriate renal phosphate wasting. A normal (or high) TmP/GFR indicates renal conservation of phosphate, and hence a nonrenal cause of hypophosphatemia.
Table 2.
Expected laboratory values in the untreated state for selected causes of hypophosphatemia
| Renal hypophosphatemia (TmP/GFR low) | |||||||||
| FGF23-mediated | |||||||||
| XLH, ADHR, ARHR, TIO, FD, postrenal transplant | ↓ | ⇆ | ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↑ | ↓ | ⇆, ↓ |
| Non-FGF23-mediated | |||||||||
| Hyperparathyroidism | ↓ | ↑ | ⇆, ↑ | ↑ | ⇆ | ↑ | ⇆, ↑ | ↓ | ↓, ⇆, ↑a |
| HHRH (NPT2c) | ↓ | ⇆b | ↑ | ↓, ⇆ | ⇆ | ↑ | ↓ | ↓ | ↑ |
| Posthepatic resection hypophosphatemia | ↓ | ⇆ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Diuretics (acetazolamide, thiazides, loop diuretics) | ↓ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Fanconi syndromec | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↓ | ↓ | ↑ |
| Nonrenal hypophosphatemia(TmP/GFR normal or high) | |||||||||
| Impaired intestinal absorption or intake | |||||||||
| Impaired dietary intake or malabsorptiond | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Phosphate bindersd,e | ↓ | ⇆, ↑ | ⇄, ↑ | ⇆ | ⇆ | ↑ | ↓ | ↑ | ↓ |
| Intracellular uptake | |||||||||
| Refeeding syndrome | ↓ | ⇆ | ⇆ | ⇆ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Renal hypophosphatemia (TmP/GFR low) | |||||||||
| FGF23-mediated | |||||||||
| XLH, ADHR, ARHR, TIO, FD, postrenal transplant | ↓ | ⇆ | ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↑ | ↓ | ⇆, ↓ |
| Non-FGF23-mediated | |||||||||
| Hyperparathyroidism | ↓ | ↑ | ⇆, ↑ | ↑ | ⇆ | ↑ | ⇆, ↑ | ↓ | ↓, ⇆, ↑a |
| HHRH (NPT2c) | ↓ | ⇆b | ↑ | ↓, ⇆ | ⇆ | ↑ | ↓ | ↓ | ↑ |
| Posthepatic resection hypophosphatemia | ↓ | ⇆ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Diuretics (acetazolamide, thiazides, loop diuretics) | ↓ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Fanconi syndromec | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↓ | ↓ | ↑ |
| Nonrenal hypophosphatemia(TmP/GFR normal or high) | |||||||||
| Impaired intestinal absorption or intake | |||||||||
| Impaired dietary intake or malabsorptiond | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Phosphate bindersd,e | ↓ | ⇆, ↑ | ⇄, ↑ | ⇆ | ⇆ | ↑ | ↓ | ↑ | ↓ |
| Intracellular uptake | |||||||||
| Refeeding syndrome | ↓ | ⇆ | ⇆ | ⇆ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
ALP, Alkaline phosphatase; ↓, below normal range; ⇆, within normal range; ↑, above normal range.
a
Urine calcium depends on severity of hyperparathyroidism.
b
In HHRH, serum calcium may be high normal, and PTH may be low.
c
Urinary wasting of other electrolytes, glucose, and amino acids.
d
Serum and urine calcium, and serum PTH may be variable. In isolated dietary phosphate deficiency or isolated phosphate malabsorption (most commonly with phosphate binders) 1,25OHD may be up-regulated, leading to increased calcium absorption and potentially hypercalciuria and hypercalcemia.
e
In chronic kidney disease (often treated with phosphate binders), calcium and alkaline phosphatase may be low, and phosphorus, FGF23, and PTH are usually high.
Table 2.
Expected laboratory values in the untreated state for selected causes of hypophosphatemia
| Renal hypophosphatemia (TmP/GFR low) | |||||||||
| FGF23-mediated | |||||||||
| XLH, ADHR, ARHR, TIO, FD, postrenal transplant | ↓ | ⇆ | ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↑ | ↓ | ⇆, ↓ |
| Non-FGF23-mediated | |||||||||
| Hyperparathyroidism | ↓ | ↑ | ⇆, ↑ | ↑ | ⇆ | ↑ | ⇆, ↑ | ↓ | ↓, ⇆, ↑a |
| HHRH (NPT2c) | ↓ | ⇆b | ↑ | ↓, ⇆ | ⇆ | ↑ | ↓ | ↓ | ↑ |
| Posthepatic resection hypophosphatemia | ↓ | ⇆ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Diuretics (acetazolamide, thiazides, loop diuretics) | ↓ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Fanconi syndromec | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↓ | ↓ | ↑ |
| Nonrenal hypophosphatemia(TmP/GFR normal or high) | |||||||||
| Impaired intestinal absorption or intake | |||||||||
| Impaired dietary intake or malabsorptiond | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Phosphate bindersd,e | ↓ | ⇆, ↑ | ⇄, ↑ | ⇆ | ⇆ | ↑ | ↓ | ↑ | ↓ |
| Intracellular uptake | |||||||||
| Refeeding syndrome | ↓ | ⇆ | ⇆ | ⇆ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Renal hypophosphatemia (TmP/GFR low) | |||||||||
| FGF23-mediated | |||||||||
| XLH, ADHR, ARHR, TIO, FD, postrenal transplant | ↓ | ⇆ | ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↑ | ↓ | ⇆, ↓ |
| Non-FGF23-mediated | |||||||||
| Hyperparathyroidism | ↓ | ↑ | ⇆, ↑ | ↑ | ⇆ | ↑ | ⇆, ↑ | ↓ | ↓, ⇆, ↑a |
| HHRH (NPT2c) | ↓ | ⇆b | ↑ | ↓, ⇆ | ⇆ | ↑ | ↓ | ↓ | ↑ |
| Posthepatic resection hypophosphatemia | ↓ | ⇆ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Diuretics (acetazolamide, thiazides, loop diuretics) | ↓ | ⇆, ↑ | ⇆ | ⇆ | ⇆ | ⇆ | ↓ | ↓ | ⇆ |
| Fanconi syndromec | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆ | ⇆, ↓ | ↓ | ↓ | ↑ |
| Nonrenal hypophosphatemia(TmP/GFR normal or high) | |||||||||
| Impaired intestinal absorption or intake | |||||||||
| Impaired dietary intake or malabsorptiond | ↓ | ⇆, ↓ | ⇆, ↑ | ⇆, ↑ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
| Phosphate bindersd,e | ↓ | ⇆, ↑ | ⇄, ↑ | ⇆ | ⇆ | ↑ | ↓ | ↑ | ↓ |
| Intracellular uptake | |||||||||
| Refeeding syndrome | ↓ | ⇆ | ⇆ | ⇆ | ⇆, ↓ | ↓, ⇆, ↑ | ↓ | ↑ | ↓ |
ALP, Alkaline phosphatase; ↓, below normal range; ⇆, within normal range; ↑, above normal range.
a
Urine calcium depends on severity of hyperparathyroidism.
b
In HHRH, serum calcium may be high normal, and PTH may be low.
c
Urinary wasting of other electrolytes, glucose, and amino acids.
d
Serum and urine calcium, and serum PTH may be variable. In isolated dietary phosphate deficiency or isolated phosphate malabsorption (most commonly with phosphate binders) 1,25OHD may be up-regulated, leading to increased calcium absorption and potentially hypercalciuria and hypercalcemia.
e
In chronic kidney disease (often treated with phosphate binders), calcium and alkaline phosphatase may be low, and phosphorus, FGF23, and PTH are usually high.
Fig. 1.
Nomogram for determining TmP/GFR. The tubular reabsorption of phosphate (TRP) is calculated using the formula: 1 − [(urine phosphate * serum creatinine)/(serum phosphate * urine creatinine)]. Left axis, PO4 indicates phosphate in mg/dl to the outside of the axis and mmol/l to the inside of the axis. Right axis, TmPO4/GFR is the renal threshold phosphate concentration in mg/dl to the outside of the axis and in mmol/l to the inside of the axis. CPO4 is the clearance of phosphate. Ccreat is the clearance of creatinine. [Reprinted from R. J. Walton and O. L. Bijvoet: Nomogram for derivation of renal threshold phosphate concentration. Lancet 306:309–310, 1975 (47), with permission. © Elsevier.]
In chronic hypophosphatemia, osteomalacia develops and the total (or bone-specific) alkaline phosphatase is usually in the high or high-normal range. Concomitant hypercalcemia during hypophosphatemia suggests hyperparathyroidism, whereas hypocalcemia suggests vitamin D deficiency or other abnormality in vitamin D metabolism. 25OHD should be measured because vitamin D deficiency may accompany poor nutrition and phosphate deficiency. In FGF23-mediated disorders, 1,25OHD will be inappropriately low or normal during hypophosphatemia, but in other disorders, the physiological response to hypophosphatemia results in elevated 1,25OHD concentrations. Measuring PTH allows for determination of hyperparathyroidism, although patients with FGF23-mediated disorders may also develop hyperparathyroidism (48, 49). FGF23 measurement is not yet routinely available in clinical practice but is potentially useful in evaluating chronic hypophosphatemia (29).
Assessing urine calcium and creatinine in either a fasting or 24-h specimen allows for detection of hypercalciuria that can be seen in Fanconi syndrome, hypercalcemic hyperparathyroidism, and some inherited forms of hypophosphatemia. Aminoaciduria, proteinuria, microglobulinuria, and glucosuria are also indicators of Fanconi syndrome.
Imaging
For most acute hypophosphatemia, imaging is not necessary unless required to evaluate neurological, cardiac, or respiratory complications. For chronic hypophosphatemia, imaging is performed to evaluate both causes and consequences of hypophosphatemia.
Plain radiographs of areas of deformity noted on physical examination or of specific sites of pain should be performed to detect signs of rickets, FD, or pseudofractures. With severe osteomalacia, 99technetium bone scintigraphy may demonstrate increased uptake at multiple areas, including ribs and pseudofractures. FD lesions may also be detected by bone scintigraphy (26). Computed tomography or magnetic resonance imaging is used to more fully characterize craniofacial or spinal FD lesions and evaluate possible neurovascular impingement.
When TIO is suspected, imaging should be directed by thorough physical examination because tumors may be palpable. Tumors causing TIO are often difficult to find. A wide variety of imaging techniques have been used to detect causative tumors, including plain radiographs, computed tomography, magnetic resonance imaging, octreotide scanning, and combined positron emission tomography/computed tomography (50–56). Whole body imaging techniques may offer an advantage. However, there appears to be a reporting bias for positive detection of tumors with various modalities. In our experience, sensitivity of each method is limited. A tumor is probably located only about half the time, despite multiple imaging techniques (30, 31). Furthermore, sometimes an identified lesion represents false positivity and is not causative of hypophosphatemia. Sometimes after multiple negative imaging studies, tumors are subsequently identified when tests are repeated after a few years.
Selective venous sampling for FGF23 concentrations has identified 18 tumors in five different reports (57–61). An estimated sensitivity of 87% and specificity of 71% were reported for a minimum intact FGF23 ratio of 1.6 between the maximum FGF23 concentration and the mean of the other sites sampled (61). However, false-positive results were noted, and venous sampling was nondiagnostic for six patients without otherwise identifiable lesions on comprehensive imaging (1, 61). Although this technique has potential, we recommend that it be considered experimental.
Hypophosphatemic osteomalacia is sometimes discovered as low bone density on dual-energy x-ray absorptiometry scanning. This is more common with acquired hypophosphatemia, and treatment rapidly improves bone density. However, although the mechanism is uncertain, patients with XLH often have mildly increased bone density, despite active osteomalacia (62).
Bone biopsy for osteomalacia is not typically needed but shows increased unmineralized osteoid and delayed mineralization rate. Biopsy of patients with XLH shows periosteocytic halos that are not present in TIO patients (55).
Management
Treatment will alter some diagnostic tests, so it is useful to obtain the proper biochemical testing to identify renal or nonrenal hypophosphatemia before initiating treatment. Treatment should address the underlying cause when possible, removing causative drugs or addressing dietary deficiencies. Acute severe hypophosphatemia in hospitalized patients may contribute to respiratory or hemodynamic instability, and a 2- to 4-fold increase in mortality is reported in prospective and retrospective studies (63, 64), while repletion can improve hemodynamic or respiratory instability.
When treating acute hypophosphatemia, the underlying cause must be addressed when possible. Intravenous phosphate is appropriate in the acute setting: when critically ill, when enteral intake is impaired, or when oral phosphate is not tolerated, especially when serum phosphate is less than 1.5 mg/dl. When hypophosphatemia is an expected complication of medical treatment, such as in refeeding syndrome, chronic alcoholic patients, or diabetic ketoacidosis, phosphate is added to maintenance iv fluids to prevent or treat hypophosphatemia, usually in the form of potassium phosphate.
Intravenous phosphate should be used cautiously. Treatment of severe acute hypophosphatemia is based on small uncontrolled adult studies with only 10 to 16 patients with serum phosphate below 1.5 mg/dl per study (65–68). Varying regimens are published (Table 3), which are not validated in children. However, the response to iv phosphate is highly variable and not easily predicted by initial levels. When providing iv phosphate, serum calcium, phosphate, potassium, magnesium, and creatinine should be closely monitored (at least every 6 h), and telemetry is recommended. The most significant risks of iv phosphate are acute severe life-threatening hypocalcemia, with tetany, seizures, electrocardiogram changes and shock, and overtreatment resulting in hyperphosphatemia and hyperkalemia (because of potassium phosphate formulations). Ectopic mineralization may occur with aggressive repletion. Intravenous phosphate should not be given to hypocalcemic patients. Concomitant low calcium and phosphate suggests vitamin D deficiency, and such patients should be managed with repletion of vitamin D or calcitriol. Patients with renal failure are also at higher risk of complications from iv phosphate. In general, oral phosphate is safer and is the preferred route in the stable patient with acute or chronic hypophosphatemia. However, hypocalcemia may still occur during aggressive oral phosphate repletion.
Table 3.
Treatment of hypophosphatemia
| Acute hypophosphatemia iv phosphate regimens (serum phosphate <1.5 mg/dl)a,b,c | Rosen et al. (68) | 15 mmol (464 mg) in 100 ml 0.9% saline over 2-h bolus, repeated after 6 h if needed [maximum 45 mmol (1393 mg) in 24 h] | Calcium, phosphate, potassium, magnesium, creatinine every 6 h; electrocardiogram monitoring/telemetry |
| Vannatta et al. (67) | 0.32 mmol/kg (9.9 mg/kg) infused over 12 h and repeated every 12 h until serum phosphate was >2 mg/dl | ||
| Clark et al. (66) | 0.64 mmol/kg (19.8 mg/kg) over 8–12 h | ||
| Taylor et al. (adapted) (65) | If phosphate 1.0–1.7 mg/dl, give 0.4 mmol/kg (12.4 mg/kg) over 6 h, maximum dose 40 mmol (1238 mg). If phosphate <1 mg/dl, give 0.5 mmol/kg (15.5 mg/kg) over 6 h, maximum dose 50 mmol (1548 mg) | ||
| Oral phosphate saltsb,c | Shiber et al. (4), Miller et al. (82) | 30–40 mg/kg per day in four or five divided doses | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Vitamin D | 800 to 1000 units daily (may require more if deficient) | ||
| Refeeding syndromeb,c | Stanga et al. (83) | 0.5–0.8 mmol/kg per day (15–25 mg/kg per day) in iv fluids | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Chronic hypophosphatemia (especially renal phosphate wasting)d | |||
| Phosphate saltsc | Carpenter et al. (70) | 20–40 mg/kg per day divided into four doses | Calcium, phosphate, potassium, creatinine monthly until stable, then every 3 months with alkaline phosphatase, PTH every 6 to 12 months, renal ultrasound every 1–2 yr |
| Calcitriole | Carpenter et al. (70) | 20–30 ng/kg per day divided into two doses |
| Acute hypophosphatemia iv phosphate regimens (serum phosphate <1.5 mg/dl)a,b,c | Rosen et al. (68) | 15 mmol (464 mg) in 100 ml 0.9% saline over 2-h bolus, repeated after 6 h if needed [maximum 45 mmol (1393 mg) in 24 h] | Calcium, phosphate, potassium, magnesium, creatinine every 6 h; electrocardiogram monitoring/telemetry |
| Vannatta et al. (67) | 0.32 mmol/kg (9.9 mg/kg) infused over 12 h and repeated every 12 h until serum phosphate was >2 mg/dl | ||
| Clark et al. (66) | 0.64 mmol/kg (19.8 mg/kg) over 8–12 h | ||
| Taylor et al. (adapted) (65) | If phosphate 1.0–1.7 mg/dl, give 0.4 mmol/kg (12.4 mg/kg) over 6 h, maximum dose 40 mmol (1238 mg). If phosphate <1 mg/dl, give 0.5 mmol/kg (15.5 mg/kg) over 6 h, maximum dose 50 mmol (1548 mg) | ||
| Oral phosphate saltsb,c | Shiber et al. (4), Miller et al. (82) | 30–40 mg/kg per day in four or five divided doses | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Vitamin D | 800 to 1000 units daily (may require more if deficient) | ||
| Refeeding syndromeb,c | Stanga et al. (83) | 0.5–0.8 mmol/kg per day (15–25 mg/kg per day) in iv fluids | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Chronic hypophosphatemia (especially renal phosphate wasting)d | |||
| Phosphate saltsc | Carpenter et al. (70) | 20–40 mg/kg per day divided into four doses | Calcium, phosphate, potassium, creatinine monthly until stable, then every 3 months with alkaline phosphatase, PTH every 6 to 12 months, renal ultrasound every 1–2 yr |
| Calcitriole | Carpenter et al. (70) | 20–30 ng/kg per day divided into two doses |
a
Intravenous regimens are listed from four adult studies; caution should be used if applying to children. Intravenous phosphate should be avoided in hypocalcemic or hypercalcemic patients. Intravenous doses of phosphate over 30 mmol should be given in a central venous catheter.
b
Severe hypocalcemia may result from aggressive iv or oral phosphate repletion. Impaired kidney function may increase the risk of hypocalcemia.
c
Potassium phosphate salts should not be used if the patient is hyperkalemic or has impaired kidney function.
d
Primary renal phosphate wasting disorders, especially FGF23-mediated disorders such as XLH, usually require treatment with both calcitriol and phosphate. Phosphate is not used alone (without calcitriol) in XLH or when PTH is elevated because this can cause or worsen hyperparathyroidism.
e
If hypercalciuria is present at diagnosis, this should be confirmed, and if persistent, calcitriol should be avoided because calcitriol treatment will increase calciuria. Hypercalciuria in a previously untreated patient may indicate a different type of phosphate wasting disorder, such as HHRH, which is not treated with calcitriol.
Table 3.
Treatment of hypophosphatemia
| Acute hypophosphatemia iv phosphate regimens (serum phosphate <1.5 mg/dl)a,b,c | Rosen et al. (68) | 15 mmol (464 mg) in 100 ml 0.9% saline over 2-h bolus, repeated after 6 h if needed [maximum 45 mmol (1393 mg) in 24 h] | Calcium, phosphate, potassium, magnesium, creatinine every 6 h; electrocardiogram monitoring/telemetry |
| Vannatta et al. (67) | 0.32 mmol/kg (9.9 mg/kg) infused over 12 h and repeated every 12 h until serum phosphate was >2 mg/dl | ||
| Clark et al. (66) | 0.64 mmol/kg (19.8 mg/kg) over 8–12 h | ||
| Taylor et al. (adapted) (65) | If phosphate 1.0–1.7 mg/dl, give 0.4 mmol/kg (12.4 mg/kg) over 6 h, maximum dose 40 mmol (1238 mg). If phosphate <1 mg/dl, give 0.5 mmol/kg (15.5 mg/kg) over 6 h, maximum dose 50 mmol (1548 mg) | ||
| Oral phosphate saltsb,c | Shiber et al. (4), Miller et al. (82) | 30–40 mg/kg per day in four or five divided doses | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Vitamin D | 800 to 1000 units daily (may require more if deficient) | ||
| Refeeding syndromeb,c | Stanga et al. (83) | 0.5–0.8 mmol/kg per day (15–25 mg/kg per day) in iv fluids | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Chronic hypophosphatemia (especially renal phosphate wasting)d | |||
| Phosphate saltsc | Carpenter et al. (70) | 20–40 mg/kg per day divided into four doses | Calcium, phosphate, potassium, creatinine monthly until stable, then every 3 months with alkaline phosphatase, PTH every 6 to 12 months, renal ultrasound every 1–2 yr |
| Calcitriole | Carpenter et al. (70) | 20–30 ng/kg per day divided into two doses |
| Acute hypophosphatemia iv phosphate regimens (serum phosphate <1.5 mg/dl)a,b,c | Rosen et al. (68) | 15 mmol (464 mg) in 100 ml 0.9% saline over 2-h bolus, repeated after 6 h if needed [maximum 45 mmol (1393 mg) in 24 h] | Calcium, phosphate, potassium, magnesium, creatinine every 6 h; electrocardiogram monitoring/telemetry |
| Vannatta et al. (67) | 0.32 mmol/kg (9.9 mg/kg) infused over 12 h and repeated every 12 h until serum phosphate was >2 mg/dl | ||
| Clark et al. (66) | 0.64 mmol/kg (19.8 mg/kg) over 8–12 h | ||
| Taylor et al. (adapted) (65) | If phosphate 1.0–1.7 mg/dl, give 0.4 mmol/kg (12.4 mg/kg) over 6 h, maximum dose 40 mmol (1238 mg). If phosphate <1 mg/dl, give 0.5 mmol/kg (15.5 mg/kg) over 6 h, maximum dose 50 mmol (1548 mg) | ||
| Oral phosphate saltsb,c | Shiber et al. (4), Miller et al. (82) | 30–40 mg/kg per day in four or five divided doses | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Vitamin D | 800 to 1000 units daily (may require more if deficient) | ||
| Refeeding syndromeb,c | Stanga et al. (83) | 0.5–0.8 mmol/kg per day (15–25 mg/kg per day) in iv fluids | Calcium, phosphate, potassium, magnesium, creatinine every 12–24 h |
| Chronic hypophosphatemia (especially renal phosphate wasting)d | |||
| Phosphate saltsc | Carpenter et al. (70) | 20–40 mg/kg per day divided into four doses | Calcium, phosphate, potassium, creatinine monthly until stable, then every 3 months with alkaline phosphatase, PTH every 6 to 12 months, renal ultrasound every 1–2 yr |
| Calcitriole | Carpenter et al. (70) | 20–30 ng/kg per day divided into two doses |
a
Intravenous regimens are listed from four adult studies; caution should be used if applying to children. Intravenous phosphate should be avoided in hypocalcemic or hypercalcemic patients. Intravenous doses of phosphate over 30 mmol should be given in a central venous catheter.
b
Severe hypocalcemia may result from aggressive iv or oral phosphate repletion. Impaired kidney function may increase the risk of hypocalcemia.
c
Potassium phosphate salts should not be used if the patient is hyperkalemic or has impaired kidney function.
d
Primary renal phosphate wasting disorders, especially FGF23-mediated disorders such as XLH, usually require treatment with both calcitriol and phosphate. Phosphate is not used alone (without calcitriol) in XLH or when PTH is elevated because this can cause or worsen hyperparathyroidism.
e
If hypercalciuria is present at diagnosis, this should be confirmed, and if persistent, calcitriol should be avoided because calcitriol treatment will increase calciuria. Hypercalciuria in a previously untreated patient may indicate a different type of phosphate wasting disorder, such as HHRH, which is not treated with calcitriol.
Management of chronic hypophosphatemia depends on the underlying cause. Avoidance of phosphate binders or other causative medications and specific treatment of the underlying cause is appropriate. In Fanconi syndrome, careful replacement with phosphate and calcium may be required. HHRH is typically treated with phosphate, but not calcitriol, because 1,25OHD is appropriately elevated in these patients, resulting in hypercalciuria.
The standard medical treatment of FGF23-mediated disorders (XLH, FD, TIO, ADHR, etc.) is based on current knowledge for treating XLH with calcitriol and phosphate. More thorough discussions of which patients should be treated are available elsewhere (69, 70). Almost all children with XLH require therapy, although many still require surgery to correct lower extremity deformities. Decisions about treating adults with XLH are much more complex, but patients with stress fractures and bone pain should be considered for therapy after full discussion of risks. Joint problems in XLH are not improved by current therapy (69).
Current medical therapy for FGF23-mediated disorders consists of attempting to replete the consequences of FGF23 excess. No current treatment alters the effect of FGF23 on the kidney. Because FGF23 excess inhibits both 1,25OHD production and phosphate reabsorption, patients typically receive relatively high doses of phosphate and calcitriol. This standard of care has been demonstrated to improve osteomalacia in XLH (71, 72), but it is based largely on uncontrolled retrospective studies (70). Few studies had any controls (73), and some included historical controls (74, 75).
Potassium- and sodium-phosphate salts are given in doses of elemental phosphorus ranging from 20–40 mg/kg per day in four divided doses (70). Side effects commonly include gastrointestinal distress and diarrhea, which can sometimes be limited by starting at a low dose and titrating up to the target dose. In excessive doses, oral or iv phosphate can cause an acute phosphate nephropathy and renal failure. Calcitriol dosing is usually 20–30 ng/kg per day, although transiently higher doses may be used for several months to speed healing of osteomalacia, followed by decreasing to the above maintenance dose.
This therapy requires close monitoring of serum and urine calcium, phosphate, and creatinine, with careful dose adjustment. Because treatment with phosphate and calcitriol increases the daily urine calcium and phosphate excreted, we do not target consistently normal serum phosphate concentrations. In fact, persistent normal serum phosphate concentrations may be an indication for decreasing the doses. After initial healing of osteomalacia, skeletal calcium uptake decreases and hypercalciuria or hypercalcemia indicates the calcitriol dose should be decreased. Likewise, if serum phosphate becomes elevated, the phosphate and/or the calcitriol dose should be decreased. Although not always elevated (especially in adults with XLH), the alkaline phosphatase will generally decrease during treatment.
Nephrocalcinosis, renal insufficiency, and secondary (sometimes tertiary) hyperparathyroidism can be complications of this therapy (49, 76). Consequently, we recommend monitoring of PTH at least once or twice yearly and renal ultrasounds every 1 or 2 yr in patients being treated with calcitriol and phosphate. Of note, current treatment with calcitriol and phosphate also tends to increase FGF23 concentrations (77).
In TIO, the goal of treatment should be complete resection of the tumor for surgical cure when possible. These tumors also occasionally metastasize, and recurrences may develop years after initial surgical cure. Long-term monitoring of phosphate and alkaline phosphatase is recommended to detect recurrences. If a causative tumor cannot be found and completely resected, TIO patients generally respond dramatically to medical treatment with phosphate and calcitriol as the osteomalacia heals, with resolution of weakness and bone pain, and return to full ambulation.
Back to the Patient
TmP/GFR was low (1.2 mg/dl), indicating renal phosphate wasting. There was no aminoaciduria. PTH was 45 pg/ml. Dual-energy x-ray absorptiometry revealed a T-score of −2.2 at the femoral neck. Intact FGF23 concentration was 97 pg/ml (normal, <70 pg/ml). Treatment with calcitriol and phosphate improved the patient's pain and corrected his alkaline phosphatase. His stress fractures resolved, and he returned to free ambulation. Initial imaging studies failed to reveal a likely source for TIO. Eventually, a positron emission tomography/computed tomography identified a 1.3-cm cortical lesion in the left iliac bone. Resection revealed a spindle cell neoplasm with features consistent with phosphaturic mesenchymal tumor, mixed connective tissue type. He quickly tapered off of calcitriol and phosphate salts; 3 wk after surgery, serum phosphate was 3.9 mg/dl.
Conclusion
Hypophosphatemia is commonly missed due to nonspecific signs and symptoms, but it causes considerable morbidity and can contribute to mortality. Proper diagnosis requires a thorough medication history, family history, examination, and assessment of renal tubular phosphate handling to identify the cause. Imaging studies should be directed at determining complications of hypophosphatemia and identifying potential causes such as TIO or FD. Treatment of hypophosphatemia is determined by the underlying cause. Medical treatment of renal phosphate wasting disorders can dramatically improve weakness and osteomalacia.
Acknowledgments
The authors' work is supported by National Institutes of Health Grants R01 AR042228 (to M.J.E.) and K23 AR057096 (to E.A.I.) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Disclosure Summary: M.J.E. receives royalties from, and is a consultant to, Kyowa Hakko Kirin Pharma, Inc., and E.A.I. participates in a clinical trial with Kyowa Hakko Kirin Pharma, Inc.
Abbreviations
ADHR
Autosomal dominant hypophosphatemic rickets
FD
FGF23
fibroblast growth factor 23
HHRH
hereditary hypophosphatemic rickets with hypercalciuria
1,25OHD
25OHD
TIO
tumor-induced osteomalacia
TmP/GFR
tubular maximum reabsorption of phosphate per unit of glomerular filtrate
XLH
X-linked hypophosphatemia.
References
1.
Liamis
G
,Milionis
HJ
,Elisaf
M
2010
Medication-induced hypophosphatemia: a review.
QJM
103
:
449
–
459
2.
Kruse
K
,Kracht
U
,Göpfert
G
1982
Renal threshold phosphate concentration (TmPO4/GFR).
Arch Dis Child
57
:
217
–
223
3.
Soldin
SJ
,Hunt
C
,Hicks
JM
1999
Pediatric reference ranges for phosphorus on the Vitros 500 Analyzer.
Clin Chem
45
:
A22
(abstract)
4.
Shiber
JR
,Mattu
A
2002
Serum phosphate abnormalities in the emergency department.
J Emerg Med
23
:
395
–
400
5.
Laaban
JP
,Marsal
L
,Waked
M
,Vuong
TK
,Rochemaure
J
1990
Seizures related to severe hypophosphataemia induced by mechanical ventilation.
Intensive Care Med
16
:
135
–
136
6.
Silvis
SE
,DiBartolomeo
AG
,Aaker
HM
1980
Hypophosphatemia and neurological changes secondary to oral caloric intake: a variant of hyperalimentation syndrome.
Am J Gastroenterol
73
:
215
–
222
7.
Silvis
SE
,Paragas
PD
1972
Paresthesias, weakness, seizures, and hypophosphatemia in patients receiving hyperalimentation.
Gastroenterology
62
:
513
–
520
8.
Brunelli
SM
,Goldfarb
S
2007
Hypophosphatemia: clinical consequences and management.
J Am Soc Nephrol
18
:
1999
–
2003
9.
Econs
MJ
,Samsa
GP
,Monger
M
,Drezner
MK
,Feussner
JR
1994
X-linked hypophosphatemic rickets: a disease often unknown to affected patients.
Bone Miner
24
:
17
–
24
10.
Econs
MJ
,Feussner
JR
,Samsa
GP
,Effman
EL
,Vogler
JB
,Martinez
S
,Friedman
NE
,Quarles
LD
,Drezner
MK
1991
X-linked hypophosphatemic rickets without “rickets.”
Skeletal Radiol
20
:
109
–
114
11.
Mäkitie
O
,Doria
A
,Kooh
SW
,Cole
WG
,Daneman
A
,Sochett
E
2003
Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets.
J Clin Endocrinol Metab
88
:
3591
–
3597
12.
Reid
IR
,Hardy
DC
,Murphy
WA
,Teitelbaum
SL
,Bergfeld
MA
,Whyte
MP
1989
X-linked hypophosphatemia: a clinical, biochemical, and histopathologic assessment of morbidity in adults.
Medicine (Baltimore)
68
:
336
–
352
13.
Hyp_Consortium
1995
A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium.
Nat Genet
11
:
130
–
136
14.
Liu
S
,Guo
R
,Simpson
LG
,Xiao
ZS
,Burnham
CE
,Quarles
LD
2003
Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX.
J Biol Chem
278
:
37419
–
37426
15.
Urakawa
I
,Yamazaki
Y
,Shimada
T
,Iijima
K
,Hasegawa
H
,Okawa
K
,Fujita
T
,Fukumoto
S
,Yamashita
T
2006
Klotho converts canonical FGF receptor into a specific receptor for FGF23.
Nature
444
:
770
–
774
16.
Shimada
T
,Hasegawa
H
,Yamazaki
Y
,Muto
T
,Hino
R
,Takeuchi
Y
,Fujita
T
,Nakahara
K
,Fukumoto
S
,Yamashita
T
2004
FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
J Bone Miner Res
19
:
429
–
435
17.
Farrow
EG
,Davis
SI
,Summers
LJ
,White
KE
2009
Initial FGF23-mediated signaling occurs in the distal convoluted tubule.
J Am Soc Nephrol
20
:
955
–
960
18.
Feng
JQ
,Ward
LM
,Liu
S
,Lu
Y
,Xie
Y
,Yuan
B
,Yu
X
,Rauch
F
,Davis
SI
,Zhang
S
,Rios
H
,Drezner
MK
,Quarles
LD
,Bonewald
LF
,White
KE
2006
Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.
Nat Genet
38
:
1310
–
1315
19.
Levy-Litan
V
,Hershkovitz
E
,Avizov
L
,Leventhal
N
,Bercovich
D
,Chalifa-Caspi
V
,Manor
E
,Buriakovsky
S
,Hadad
Y
,Goding
J
,Parvari
R
2010
Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene.
Am J Hum Genet
86
:
273
–
278
20.
Lorenz-Depiereux
B
,Schnabel
D
,Tiosano
D
,Häusler
G
,Strom
TM
2010
Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets.
Am J Hum Genet
86
:
267
–
272
21.
ADHR Consortium
2000
Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23.
Nat Genet
26
:
345
–
348
22.
Bai
XY
,Miao
D
,Goltzman
D
,Karaplis
AC
2003
The autosomal dominant hypophosphatemic rickets R176Q mutation in fibroblast growth factor 23 resists proteolytic cleavage and enhances in vivo biological potency.
J Biol Chem
278
:
9843
–
9849
23.
Imel
EA
,Hui
SL
,Econs
MJ
2007
FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets.
J Bone Miner Res
22
:
520
–
526
24.
Econs
MJ
,McEnery
PT
1997
Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder.
J Clin Endocrinol Metab
82
:
674
–
681
25.
Gribaa
M
,Younes
M
,Bouyacoub
Y
,Korbaa
W
,Ben Charfeddine
I
,Touzi
M
,Adala
L
,Mamay
O
,Bergaoui
N
,Saad
A
2010
An autosomal dominant hypophosphatemic rickets phenotype in a Tunisian family caused by a new FGF23 missense mutation.
J Bone Miner Metab
28
:
111
–
115
26.
Riminucci
M
,Collins
MT
,Fedarko
NS
,Cherman
N
,Corsi
A
,White
KE
,Waguespack
S
,Gupta
A
,Hannon
T
,Econs
MJ
,Bianco
P
,Gehron Robey
P
2003
FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting.
J Clin Invest
112
:
683
–
692
27.
Hoffman
WH
,Jueppner
HW
,Deyoung
BR
,O'dorisio
MS
,Given
KS
2005
Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome.
Am J Med Genet A
134
:
233
–
236
28.
Folpe
AL
,Fanburg-Smith
JC
,Billings
SD
,Bisceglia
M
,Bertoni
F
,Cho
JY
,Econs
MJ
,Inwards
CY
,Jan de Beur
SM
,Mentzel
T
,Montgomery
E
,Michal
M
,Miettinen
M
,Mills
SE
,Reith
JD
,O'Connell
JX
,Rosenberg
AE
,Rubin
BP
,Sweet
DE
,Vinh
TN
,Wold
LE
,Wehrli
BM
,White
KE
,Zaino
RJ
,Weiss
SW
2004
Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.
Am J Surg Pathol
28
:
1
–
30
29.
Endo
I
,Fukumoto
S
,Ozono
K
,Namba
N
,Tanaka
H
,Inoue
D
,Minagawa
M
,Sugimoto
T
,Yamauchi
M
,Michigami
T
,Matsumoto
T
2008
Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients. Proposal of diagnostic criteria using FGF23 measurement.
Bone
42
:
1235
–
1239
30.
Imel
EA
,Peacock
M
,Pitukcheewanont
P
,Heller
HJ
,Ward
LM
,Shulman
D
,Kassem
M
,Rackoff
P
,Zimering
M
,Dalkin
A
,Drobny
E
,Colussi
G
,Shaker
JL
,Hoogendoorn
EH
,Hui
SL
,Econs
MJ
2006
Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia.
J Clin Endocrinol Metab
91
:
2055
–
2061
31.
Jonsson
KB
,Zahradnik
R
,Larsson
T
,White
KE
,Sugimoto
T
,Imanishi
Y
,Yamamoto
T
,Hampson
G
,Koshiyama
H
,Ljunggren
O
,Oba
K
,Yang
IM
,Miyauchi
A
,Econs
MJ
,Lavigne
J
,Jüppner
H
2003
Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
N Engl J Med
348
:
1656
–
1663
32.
Yamazaki
Y
,Okazaki
R
,Shibata
M
,Hasegawa
Y
,Satoh
K
,Tajima
T
,Takeuchi
Y
,Fujita
T
,Nakahara
K
,Yamashita
T
,Fukumoto
S
2002
Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia.
J Clin Endocrinol Metab
87
:
4957
–
4960
33.
Bhan
I
,Shah
A
,Holmes
J
,Isakova
T
,Gutierrez
O
,Burnett
SM
,Jüppner
H
,Wolf
M
2006
Post-transplant hypophosphatemia: tertiary ‘hyper-phosphatoninism?’
Kidney Int
70
:
1486
–
1494
34.
Bergwitz
C
,Roslin
NM
,Tieder
M
,Loredo-Osti
JC
,Bastepe
M
,Abu-Zahra
H
,Frappier
D
,Burkett
K
,Carpenter
TO
,Anderson
D
,Garabedian
M
,Sermet
I
,Fujiwara
TM
,Morgan
K
,Tenenhouse
HS
,Juppner
H
2006
SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.
Am J Hum Genet
78
:
179
–
192
35.
Hoopes
RR
,Raja
KM
,Koich
A
,Hueber
P
,Reid
R
,Knohl
SJ
,Scheinman
SJ
2004
Evidence for genetic heterogeneity in Dent's disease.
Kidney Int
65
:
1615
–
1620
36.
Nesterova
G
,Gahl
WA
1993
Cystinosis
. In: ,
Pagon
R
,Bird
T
,Dolan
C
,Stephens
K
, eds.GeneReviews
.
Seattle
:
University of Washington
.
37.
Magen
D
,Berger
L
,Coady
MJ
,Ilivitzki
A
,Militianu
D
,Tieder
M
,Selig
S
,Lapointe
JY
,Zelikovic
I
,Skorecki
K
2010
A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome.
N Engl J Med
362
:
1102
–
1109
38.
Nafidi
O
,Lapointe
RW
,Lepage
R
,Kumar
R
,D'Amour
P
2009
Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia.
Ann Surg
249
:
824
–
827
39.
Mayne
PD
,Kovar
IZ
1991
Calcium and phosphorus metabolism in the premature infant.
Ann Clin Biochem
28
:
131
–
142
40.
Laaban
JP
,Grateau
G
,Psychoyos
I
,Laromiguière
M
,Vuong
TK
,Rochemaure
J
1989
Hypophosphatemia induced by mechanical ventilation in patients with chronic obstructive pulmonary disease.
Crit Care Med
17
:
1115
–
1120
41.
Roestel
C
,Hoeping
W
,Deckert
J
2004
Hypophosphatemia in panic disorder.
Am J Psychiatry
161
:
1499
–
1500
42.
Halevy
J
,Bulvik
S
1988
Severe hypophosphatemia in hospitalized patients.
Arch Intern Med
148
:
153
–
155
43.
Schouten
BJ
,Doogue
MP
,Soule
SG
,Hunt
PJ
2009
Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia.
Ann Clin Biochem
46
:
167
–
169
44.
Schouten
BJ
,Hunt
PJ
,Livesey
JH
,Frampton
CM
,Soule
SG
2009
FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study.
J Clin Endocrinol Metab
94
:
2332
–
2337
45.
Shimizu
Y
,Tada
Y
,Yamauchi
M
,Okamoto
T
,Suzuki
H
,Ito
N
,Fukumoto
S
,Sugimoto
T
,Fujita
T
2009
Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia.
Bone
45
:
814
–
816
46.
Hothi
DK
,Harvey
E
,Piva
E
,Keating
L
,Secker
D
,Geary
DF
2006
Calcium and phosphate balance in adolescents on home nocturnal haemodialysis.
Pediatr Nephrol
21
:
835
–
841
47.
Walton
RJ
,Bijvoet
OLM
1975
Nomogram for derivation of renal threshold phosphate concentration.
Lancet
306
:
309
–
310
48.
Carpenter
TO
,Mitnick
MA
,Ellison
A
,Smith
C
,Insogna
KL
1994
Nocturnal hyperparathyroidism: a frequent feature of X-linked hypophosphatemia.
J Clin Endocrinol Metab
78
:
1378
–
1383
49.
Rivkees
SA
,el-Hajj-Fuleihan
G
,Brown
EM
,Crawford
JD
1992
Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets.
J Clin Endocrinol Metab
75
:
1514
–
1518
50.
Woo
VL
,Landesberg
R
,Imel
EA
,Singer
SR
,Folpe
AL
,Econs
MJ
,Kim
T
,Harik
LR
,Jacobs
TP
2009
Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: report of a case and review of the literature.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
108
:
925
–
932
51.
Moran
M
,Paul
A
2002
Octreotide scanning in the detection of a mesenchymal tumour in the pubic symphysis causing hypophosphataemic osteomalacia.
Int Orthop
26
:
61
–
62
52.
Dupond
JL
,Mahammedi
H
,Prié
D
,Collin
F
,Gil
H
,Blagosklonov
O
,Ricbourg
B
,Meaux-Ruault
N
,Kantelip
B
2005
Oncogenic osteomalacia: diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case.
Bone
36
:
375
–
378
53.
Hesse
E
,Moessinger
E
,Rosenthal
H
,Laenger
F
,Brabant
G
,Petrich
T
,Gratz
KF
,Bastian
L
2007
Oncogenic osteomalacia: exact tumor localization by co-registration of positron emission and computed tomography.
J Bone Miner Res
22
:
158
–
162
54.
Shulman
DI
,Hahn
G
,Benator
R
,Washington
K
,White
KE
,Farber
J
,Econs
MJ
2004
Tumor-induced rickets: usefulness of MR gradient echo recall imaging for tumor localization.
J Pediatr
144
:
381
–
385
55.
Ward
LM
,Rauch
F
,White
KE
,Filler
G
,Matzinger
MA
,Letts
M
,Travers
R
,Econs
MJ
,Glorieux
FH
2004
Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna.
Bone
34
:
905
–
911
56.
David
K
,Revesz
T
,Kratimenos
G
,Krausz
T
,Crockard
HA
1996
Oncogenic osteomalacia associated with a meningeal phosphaturic mesenchymal tumor. Case report.
J Neurosurg
84
:
288
–
292
57.
Nasu
T
,Kurisu
S
,Matsuno
S
,Tatsumi
K
,Kakimoto
T
,Kobayashi
M
,Nakano
Y
,Wakasaki
H
,Furuta
H
,Nishi
M
,Sasaki
H
,Suzuki
H
,Ito
N
,Fukumoto
S
,Nanjo
K
2008
Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23.
Intern Med
47
:
957
–
961
58.
Westerberg
PA
,Olauson
H
,Toss
G
,Wikström
B
,Morales
O
,Linde
T
,Jonsson
K
,Ljunggren
O
,Larsson
TE
2008
Preoperative tumor localization by means of venous sampling for fibroblast growth factor-23 in a patient with tumor-induced osteomalacia.
Endocr Pract
14
:
362
–
367
59.
Ito
N
,Shimizu
Y
,Suzuki
H
,Saito
T
,Okamoto
T
,Hori
M
,Akahane
M
Fukumoto
S
,Fujita
T
2010
Clinical utility of systemic venous sampling of FGF23 for identifying tumours responsible for tumour-induced osteomalacia.
J Intern Med
268
:
390
–
394
60.
Takeuchi
Y
,Suzuki
H
,Ogura
S
,Imai
R
,Yamazaki
Y
,Yamashita
T
,Miyamoto
Y
,Okazaki
H
,Nakamura
K
,Nakahara
K
,Fukumoto
S
,Fujita
T
2004
Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia.
J Clin Endocrinol Metab
89
:
3979
–
3982
61.
Andreopoulou
P
,Dumitrescu
CE
,Kelly
MH
,Brillante
BA
,Cutler Peck
CM
,Wodajo
FM
,Chang
R
,Collins
MT
2011
Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.
J Bone Miner Res
26
:
1295
–
1302
62.
Reid
IR
,Murphy
WA
,Hardy
DC
,Teitelbaum
SL
,Bergfeld
MA
,Whyte
MP
1991
X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry.
Am J Med
90
:
63
–
69
63.
Camp
MA
,Allon
M
1990
Severe hypophosphatemia in hospitalized patients.
Miner Electrolyte Metab
16
:
365
–
368
64.
Zazzo
JF
,Troché
G
,Ruel
P
,Maintenant
J
1995
High incidence of hypophosphatemia in surgical intensive care patients: efficacy of phosphorus therapy on myocardial function.
Intensive Care Med
21
:
826
–
831
65.
Taylor
BE
,Huey
WY
,Buchman
TG
,Boyle
WA
,Coopersmith
CM
2004
Treatment of hypophosphatemia using a protocol based on patient weight and serum phosphorus level in a surgical intensive care unit.
J Am Coll Surg
198
:
198
–
204
66.
Clark
CL
,Sacks
GS
,Dickerson
RN
,Kudsk
KA
,Brown
RO
1995
Treatment of hypophosphatemia in patients receiving specialized nutrition support using a graduated dosing scheme: results from a prospective clinical trial.
Crit Care Med
23
:
1504
–
1511
67.
Vannatta
JB
,Andress
DL
,Whang
R
,Papper
S
1983
High-dose intravenous phosphorus therapy for severe complicated hypophosphatemia.
South Med J
76
:
1424
–
1426
68.
Rosen
GH
,Boullata
JI
,O'Rangers
EA
,Enow
NB
,Shin
B
1995
Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia.
Crit Care Med
23
:
1204
–
1210
69.
Tenenhouse
HS
,Econs
MJ
2001
Mendelian hypophosphatemias
. In: ,
Scriver
CR
,Beaudet
AL
,Valle
D
,Sly
WS
,Vogelstein
B
,Childs
B
,Kinzler
KW
, eds.The metabolic and molecular bases of inherited disease
.
New York
:
McGraw-Hill Professional
;
5039
–
5067
70.
Carpenter
TO
,Imel
EA
,Holm
IA
,Jan de Beur
SM
,Insogna
KL
2011
A clinician's guide to X-linked hypophosphatemia.
J Bone Miner Res
26
:
1381
–
1388
71.
Harrell
RM
,Lyles
KW
,Harrelson
JM
,Friedman
NE
,Drezner
MK
1985
Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.
J Clin Invest
75
:
1858
–
1868
72.
Glorieux
FH
,Marie
PJ
,Pettifor
JM
,Delvin
EE
1980
Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets.
N Engl J Med
303
:
1023
–
1031
73.
Lyles
KW
,Harrelson
JM
,Drezner
MK
1982
The efficacy of vitamin D2 and oral phosphorus therapy in X-linked hypophosphatemic rickets and osteomalacia.
J Clin Endocrinol Metab
54
:
307
–
315
74.
Balsan
S
,Tieder
M
1990
Linear growth in patients with hypophosphatemic vitamin D-resistant rickets: influence of treatment regimen and parental height.
J Pediatr
116
:
365
–
371
75.
Verge
CF
,Lam
A
,Simpson
JM
,Cowell
CT
,Howard
NJ
,Silink
M
1991
Effects of therapy in X-linked hypophosphatemic rickets.
N Engl J Med
325
:
1843
–
1848
76.
Taylor
A
,Sherman
NH
,Norman
ME
1995
Nephrocalcinosis in X-linked hypophosphatemia: effect of treatment versus disease.
Pediatr Nephrol
9
:
173
–
175
77.
Imel
EA
,DiMeglio
LA
,Hui
SL
,Carpenter
TO
,Econs
MJ
2010
Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations.
J Clin Endocrinol Metab
95
:
1846
–
1850
78.
Girgis
CM
,Wong
T
,Ngu
MC
,Emmett
L
,Archer
KA
,Chen
RC
,Seibel
MJ
2011
Hypophosphataemic osteomalacia in patients on adefovir dipivoxil.
J Clin Gastroenterol
45
:
468
–
473
79.
François
H
,Coppo
P
,Hayman
JP
,Fouqueray
B
,Mougenot
B
,Ronco
P
2008
Partial Fanconi syndrome induced by imatinib therapy: a novel cause of urinary phosphate loss.
Am J Kidney Dis
51
:
298
–
301
80.
Saidenberg-Kermanac'h
N
,Souabni
L
,Prendki
V
,Prie
D
,Boissier
MC
2011
Normal plasma FGF23 levels kinetic in tenofovir-related hypophosphatemic osteomalacia in an HIV-infected patient with von Recklinghausen disease.
Joint Bone Spine
78
:
306
–
308
81.
Bellini
E
,Pia
A
,Brizzi
MP
,Tampellini
M
,Torta
M
,Terzolo
M
,Dogliotti
L
,Berruti
A
2011
Sorafenib may induce hypophosphatemia through a fibroblast growth factor-23 (FGF23)-independent mechanism.
Ann Oncol
22
:
988
–
990
82.
Miller
DW
,Slovis
CM
2000
Hypophosphatemia in the emergency department therapeutics.
Am J Emerg Med
18
:
457
–
461
83.
Stanga
Z
,Brunner
A
,Leuenberger
M
,Grimble
RF
,Shenkin
A
,Allison
SP
,Lobo
DN
2008
Nutrition in clinical practice—the refeeding syndrome: illustrative cases and guidelines for prevention and treatment.
Eur J Clin Nutr
62
:
687
–
694
Copyright © 2012 by The Endocrine Society
Copyright © 2012 by The Endocrine Society
Citations
Views
Altmetric
Email alerts
Related articles in PubMed
Citing articles via
Latest
Most Read
Most Cited
More from Oxford Academic