Approach to patients with hypophosphataemia

Review

Approach to patients with hypophosphataemia Pablo Florenzano, Cristiana Cipriani, Kelly L Roszko, Seiji Fukumoto, Michael T Collins, Salvatore Minisola, Jessica Pepe

Phosphate metabolism is an evolving area of basic and clinical research. In the past 15 years, knowledge on disturbances of phosphate homoeostasis has expanded, as has the discovery of new targeted therapies. Hypophosphataemia might be the biochemical finding in several diseases, and its clinical evaluation should initially focus on the assessment of pathophysiological mechanisms leading to low serum phosphate concentrations. Clinical consequences of hypophosphataemia can involve multiple organ systems and vary depending on several factors, the most important being the underlying disorder. This Review focuses on the approach to patients with hypo­ phosphataemia and how underlying pathophysiological mechanisms should be understood in the evaluation of differential diagnosis. We define an algorithm for the assessment of hypophosphataemia and review the most up-todate literature on specific therapies. Continuous research in this area will result in a better understanding and management of patients with hypophosphataemia.

Introduction Hypophosphataemia is a common disorder of mineral metabolism, and its clinical consequences can be observed in several organs and systems. Clinical presentation of a patient with hypophosphataemia can vary depending on its severity, onset (acute vs chronic), and patient age. Besides the skeleton, the haemopoietic system can be affected by hypophosphataemia, and also the skeletal muscle, myocardium, respiratory system, CNS, and sensory organs. Evaluation and management of patients with hypophosphataemia is therefore of the utmost importance, particularly considering the possibility of new targeted therapies. Clinical assessment should primarily focus on identifying mechanisms of hypophosphataemia. Phosphate is involved in different physiological pathways and the maintenance of phosphate homoeostasis requires actions from several organs. Identification of the causes of reduced serum phosphate concentrations is therefore essential in the approach to the patient and for establishing the treatment of choice. This Review focuses on the assessment of patients with hypophosphataemia by defining the causes and mechanisms of low serum phosphate concentrations and related genetic and acquired disorders. We also provide an algorithm for the approach to a patient with hypophosphataemia and an up-to-date review on specific therapies.

Definition and epidemiology Phosphate is a fundamental element involved in a number of physiological pathways,1–4 such as skeletal development5 and mineralisation, membrane com­position,6 nucleotide structure,7 cellular signalling,8 energy storage and transfer, and maintenance of acid–base equilibrium.9,10 Normal concentration of serum phosphate in adults is between 0·8 mmol/L and 1·45 mmol/L (2·5–4·5 mg/dL; obtained by dividing mmol/L values by 0·3229). Neonates, infants, and children have higher reference values. This point, and the stage of pubertal development, should be taken into account for proper interpretation of the results in these age ranges (table 1).11 Preanalytical factors can influence phosphate concentrations, such as the method of sampling, delayed analysis, the acid–base balance status,

and concomitant diseases.12 For example, pseudo­ hypophosphataemia has been described in multiple myeloma with or without the presence of hypergamma­ globulinaemia, which has been ascribed to interference of paraprotein with some analytical proced­ ures used for phosphate measurement.13,14 It has also been reported in patients with acute leukaemia, which is probably secondary to the increased uptake of phosphate by leukaemic cells in vitro, but could also result from interference by mannitol and bilirubin. From a clinical point of view, hypophosphataemia in adults can be subdivided into mild (serum phosphate of 0·6–0·8 mmol/L; 1·8–2·5 mg/dL), moderate (0·4–0·5 mmol/L; 1·0–1·7 mg/dL), or severe (serum phosphate lower than 0·3 mmol/L; 0·9 mg/dL).12,15 This distinction is important, since severely low circulating concentrations of phosphate are invariably accompanied by clinical symptoms, the most important being muscle weakness, bone pain, and even cardiac dysfunction.1 In general, from a pathophysiological point of view, acute hypophos­ phataemia results from redistribution of phosphate into the intracellular compartment without total body phosphate depletion. By contrast, chronic hypophos­phataemia is usually accompanied by total body phosphate depletion.16 No systematic studies have addressed the prevalence and incidence of hypophosphataemia in the general population. However, there are data from specific clinical situations: hospitalised patients (2·2–3·1%), intensive care units (29–34%), patients with sepsis (65–80%),

Serum phosphate (mg/dL)

Serum phosphate (mmol/L)

0–5 days

4∙8–8∙2

1∙5–2∙6

1–3 years

3∙8–6∙5

1∙2–2∙1

4–11 years

3∙7–5∙6

1∙2–1∙8

12–15 years

2∙9–5∙4

0∙9–1∙7

16–19 years

2∙7–4∙7

0∙9–1∙5

≥20 years

2∙5–4∙5

0∙8–1∙4

Lancet Diabetes Endocrinol 2020 Published Online January 7, 2020 https://doi.org/10.1016/ S2213-8587(19)30426-7 Department of Endocrinology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile (P Florenzano MD); Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA (P Florenzano, K L Roszko MD, M T Collins MD); Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome, Italy (C Cipriani MD, S Minisola MD, J Pepe MD); and Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan (S Fukumoto MD) Correspondence to: Dr Cristiana Cipriani, Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome 00161, Italy [email protected]

Table 1: Normal age-dependent values of serum phosphate

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chronic alcoholism (2·5–30·4%), major trauma (75%), and chronic obstructive pulmonary disease (21·5%).15 In this context, a retrospective study of 1088 patients enrolled in phase 1 oncology clinical trials showed an unexpected 32% prevalence of hypophosphataemia, suggesting that hypophosphataemia might be a common condition in certain populations.17 Hypophosphataemia can also be seen with malnutrition or exposure to certain drugs. Malnutrition, in association with low protein energy intake, can cause hypophos­ phataemia in children in low-income countries. Additionally, serum phosphate concentrations inversely correlate with mortality in these children.18 With regards to drugs being a cause, in 29·1% of patients receiving a single course of ferric carboxymaltose, hypo­ phosphataemia was present and persisted up to 5 weeks after treatment.19 Moreover, according to some authors, hypophosphataemia is not an uncommon biochemical finding in patients older than 65 years that are admitted to hospital, and can be seen in up to 14% of patients.20 It has also been observed in the majority of patients with refeeding syndrome. Finally, the disorder is a biochemical component of heritable disorders of phosphate meta­bolism.

Phosphate metabolism in physiological and pathological conditions In the human body, most phosphate (85%) is found in the skeleton. Having both an extracellular and intracellular distribution, phosphate has multiple functions. In the cell, it has a pivotal role in energy storage (ATP generation), metabolism, and cell signalling, through phosphorylation and other essential functions.21 It is also involved in osteopontin gene expression, chondrocyte apoptosis, and vascular smooth muscle differentiation.21 In the extra­ cellular space, the metabolically active, unbound inorganic phosphate concentration is maintained in adults within a serum concentration range of 0·8–1·45 mmol/L (2·5–4·5 mg/dL). Over the day, this value varies slightly, from the lowest concentration in the morning to the highest concentration in the evening.22,23 The maintenance of phosphate homoeostasis occurs as a result of a dynamic balance between urinary phosphate losses and net phosphate absorption from the gastro­ intestinal tract, and the equal amounts deposited and reabsorbed from bone. This homoeostatic control, the so-called bone–kidney–intestine network, operates through multiple endocrine negative feedback loops involving parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23) with its coreceptor klotho, and active vitamin D.22,24 As previously mentioned, children have the highest concentration of circulating phosphate, compared with adolescents and adults. During growth, the increased requirement for phosphate due to bone formation is provided by high growth hormone concentrations that amplify phosphate tubular reabsorption.25 2

In older individuals, there is a small, negative phosphate balance due to several factors, among which bone loss (related to the ageing process) is the main cause. The primary daily physiological cause of perturbation in phosphate homoeostasis is phosphate bolus derived from food intake. The bone–kidney–intestine network operates to maintain phosphate homoeostasis. The specific require­ ment for phosphate intake in humans is not well defined, contrary to other minerals normally present in the human diet such as calcium. The rate of phosphate absorption is directly related to dietary phosphate load.26 About 60–65% of dietary phosphate intake is absorbed by the small intestine; the remaining portion (approximately 35–40%) is absorbed by the colon. If the dietary intake of phosphate is low, absorption is mostly active and mediated through 1,25-dihydroxyvitamin D, also named 1,25(OH)2D. In the case of high phosphate intake, passive absorption is more prevalent.27 The active transport of phosphate is regulated by several factors. 1,25(OH)2D is able to induce the expression of NPT2b (sodium-phosphate transport protein 2B), which is a sodium-phosphate cotransporter on the apical membrane of intestinal epithelial cells.28 Furthermore, phosphatonins influence phosphate absorption: FGF-23 downregulates the conversion of 25(OH)D to 1,25(OH)2D and matrix extracellular phos­ phoglycoprotein (MEPE) has an effect independent of 1,25(OH)2D.29 Driven by glucose ingestion and insulin release, serum phosphate concentrations can be lowered through the transfer of phosphate into cells. The lowering of phosphate is also observed during muscle activity and hyperventilation.22 In the kidney, phosphate is ultrafiltered: the major site of phosphate reabsorption is the proximal convoluted tubule, accounting for 70% of the filtered load. When the filtered load of phosphate decreases, renal reabsorption of phosphate progressively increases until a maximum tubular reabsorption rate for phosphate (TmP) is reached.30 Two sodium-dependent phosphate cotransporters on the brush border membrane are mainly responsible for phosphate reabsorption, namely NPT2a and NPT2c.31 In particular, the cotransporter NPT2a is internalised and subsequently degraded by lysosomes in the presence of a high phosphate diet.32 PTH is also able to induce NPT2a internalisation.33 Conversely, 1,25(OH)2D can stimulate NPT2a to increase phosphate reabsorption. NPT2c is typically increased during a low phosphate diet, but reduced in response to a high phosphate diet. 1,25(OH)2D stimulates both the functional role and biosynthesis of NPT2c. These cotransporters are negatively modulated by FGF-23, which results in a reduction of renal phosphate reabsorption.34 Moreover, FGF-23 influences vitamin D metabolism and thus indirectly affects phosphate homoeostasis. FGF-23 inhibits 1-α-hydroxylase, an enzyme that converts the inactive 25(OH)D to the active 1,25(OH)2D form, independently of PTH, which reduces

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the renal synthesis of 1,25(OH)2D, and stimulates 25-vitamin D-24 hydroxylase, an enzyme in the 1,25(OH)2D degradation pathway.34 Other non-classic actions of FGF-23 are less well understood and substantiated.35 It stimulates the reabsorption of sodium and calcium in the distal tubule; FGF-23 might have an inhibitory effect on the parathyroid glands, thus inhibiting PTH secretion.36 With declining renal function due to ageing, a rise in physiological FGF-23 serum concentrations is observed.36 The serum phosphate concentrations remain within normal limits in patients affected by kidney failure until their renal function becomes severely affected. Despite these aforementioned physiological mechan­ isms, the control of phosphate concentration in the blood is less tightly maintained than the control of calcium. The more efficient mobilisation of calcium from bone in the case of hypocalcaemia, compared with the mobilisation of phosphate in the case of hypophosphataemia, could possibly be the main causative difference. Thus, with regards to primary hypophosphataemia, kidney and intestinal absorption appear to have a major role in the maintenance of serum phosphate concentrations within the normal range. Perturbation of the FGF-23, vitamin D, and PTH axis can result in hypophosphataemia. The main patho­ physiological mechanisms that can explain the decrease of serum phosphate are (1) redistribution from extracellular fluids into cells, frequently seen in cases of acute respiratory alkalosis, hungry bone syndrome, refeeding syndrome, and during the treatment of diabetic ketoacidosis; (2) decreased phosphate intestinal absorption; (3) excessive phosphate loss due to a high renal phosphate excretion, explained by excessive action of PTH, FGF-23, or by a renal proximal tubular dysfunction; and (4) decreased proximal phosphate reabsorption and reduced activation of vitamin D, as seen in distal renal tubular acidosis type 1, a state characterised by metabolic acidosis and osteo­ malcia.22,37–42 In children, hypophosphataemia is most frequently seen in the setting of rickets caused by low vitamin D and calcium intake.

Biochemical and clinical consequence of acute and chronic hypophosphataemia Clinical findings

Symptoms associated with hypophosphataemia can vary depending on the severity, rapidity of onset, underlying disorder, and patient age. Multiple organ systems can be affected and the depletion of intracellular phosphate has several consequences. For instance, the reduction in the concentration of erythrocytic 2,3-diphosphoglycerate increases the affinity of haemoglobin for oxygen, inducing tissue hypoxia. In the skeletal muscle, a decrease in intracellular ATP synthesis, and abnormalities in signal transduction and phosphocreatine content, have been described.43,44

Acute hypophosphataemia Acute hypophosphataemia is associated with clinical manifestations in many organs, particularly when there is a severe reduction in serum phosphate concentrations. For example, it can cause rhabdomyolysis.45 Haema­ tological complications include haemolysis and leucocyte dysfunction with a resultant increased risk of infection and sepsis.46,47 In critically ill patients, acute hypophos­ phataemia was linked to respiratory failure, increased duration of mechanical ventilation, and higher all-cause mortality, whereas phosphate supplementation was associated with a higher incidence of recovery from acute kidney injury.48,49 Reduction of myocardial contractility leading to cardiomyopathy has been reported in association with severe hypophosphataemia; improvement of the left ventricular performance has been observed after correction of hypophosphataemia.46,49,50 Cardiac arrhyth­ mias might also be linked to hypophosphataemia, even in the absence of structural cardiac disease.46,50 Cardiac abnormalities are more common in intensive care patients with acute and severe hypophosphataemia.46 Similarly, diaphragmatic contractility can be affected by severe acute hypophosphataemia, resulting in respiratory insufficiency.46 Neurological manifestations such as fatigue, weakness, neuropathy, tremors, paresthesias, seizures, encephalopathy, and altered mental status, including hallucinations, delirium, paranoid delusions, and coma can be seen in severe, acute hypo­ phosphataemia.46,49,51 Neurological disturbances resem­ bling the Guillain-Barre syndrome have also been described.46,52

Chronic hypophosphataemia The skeletal system is prominently affected by chronic hypophosphataemia. It leads to impaired mineralisation, which results in osteomalacia in adults and rickets in children. Typically, muscle weakness is reported in chronic hypophosphataemia and some authors have postulated that sarcopenia could develop.44 Patients with chronic hypophosphataemia report bone pain and weakness; they develop a waddling gait and insufficiency, and osteomalacic fractures can be seen in adults. Children often present with growth retardation, muscle weakness, bone pain, fractures, bowing (once they start ambulating), and wrist and ankle expansion due to widening of the metaphysis and growth plate (figure 1).44,53 Other skeletal findings include vertebral compression fractures causing loss of height in adults, and, in longstanding hypophosphataemia, mineralisation of tendons and ligaments with paradoxical enthesopathies, which, in severe cases, can lead to spinal stenosis. Osteophytes and osteoarthritis can also be found in long-standing disease.44,53 Rarer manifestations of the hereditary forms of chronic hypophosphataemia are craniosynostosis, frontal bossing, midfacial hypoplasia, and Chiari I malformation.44,53

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A

B

C

Figure 1: Skeletal consequences of chronic hypophosphataemia (A) Anteroposterior wrist radiograph showing active rachitic changes (arrow) in a 16-month-old girl with X-linked hypophosphataemic rickets due to a PHEX gene mutation. (B) Bilateral femur anteroposterior radiograph showing bilateral femoral and tibial bowing associated with coarse trabeculation of proximal femoral metaphysis in a 3-year-old girl with X-linked hypophosphataemic rickets. (C) Bilateral femur anteroposterior radiograph showing a pseudofracture (arrow) in the left tibia in a 32-year-old man with X-linked hypophosphataemia.

Abnormalities of the teeth are associated with chronic hypophosphataemia, especially the genetic forms of hypophosphataemia. The main determinants of teeth abnormalities are poor dentin mineralisation and enamel deficit, with resulting microcracks, tooth decay, and dental abscesses.44,54 Moreover, and particularly in the X-linked form of hypophosphataemia, periodontitis is frequent and severe (discussed later).54 Abnormalities of the inner ear and the otic capsule, endolymphatic hydrops, loss of spiral ganglion cells, and involvement of the cochlea are reported in the genetic forms of hypophosphatemia.53,55 Hearing loss progressively develops even before the structural degeneration, particularly in adulthood, although cases have been reported in children.53,55–57 Tinnitus and Meniere’s disease are other possible complications of these genetic forms of the disease.53

Biochemical findings We have summarised the biochemical findings in patients with hypophosphataemia (table 2). Serum calcium might be reduced (eg, nutritional osteomalacia), increased (eg, primary hyperparathyroidism), or normal (eg, tumour-induced osteomalacia) in association with hypophosphataemia.58 High PTH concentrations are observed in primary hyperparathyroidism, where hypophosphataemia develops as a consequence of the phosphaturic effect of PTH, and in hyper­parathyroidism secondary to nutritional vitamin D deficiency or inherited disorders of vitamin D metabolism.59,60 Secondary increase of PTH can also be seen in FGF-23mediated causes of hypophosphataemia, where hyper­ para­thyroidism is a normal response to low 1,25(OH)2D and prolonged phosphate supplementation.61 In several other forms of hypophosphataemia, PTH is within the normal range.53,61 Circulating 25(OH)D concentrations are normal in most disorders presenting with hypo­ phosphataemia, with the exception of nutritional 4

vitamin D deficiency, in which low serum 25(OH)D represents the primary defect.61 However, as 25(OH)D insufficiency and deficiency are frequently observed in the general population, low 25(OH)D concentrations from other causes might be found in patients with hypophosphataemia. Serum 1,25(OH)2D concentrations are usually low or inappropriately normal in patients with hypophos­ phataemia. Hypophosphataemia stimulates 1,25(OH)2D biosynthesis, which is secondarily increased in primary hyperparathyroidism, nutritional rickets, and in hereditary hypophosphataemic rickets with hyper­calciuria.53,61 Elevated 1,25(OH)2D concentrations might also be observed in dietary phosphate deficiency, as seen in infants who are breastfed and have very low birthweights, or fed the elemental formula, Neocate (Nutricia, Gaithersburg, MD) and have hypo­phosphataemic rickets.62,63 FGF-23 concentrations can be primarily elevated in hypophosphataemic syndromes associated with rickets (X-linked hypophosphataemia, autosomal recessive hypo­phosphataemic rickets, autosomal dominant hypo­ phosphataemic rickets, McCune-Albright syndrome and fibrous dysplasia, cutaneous skeletal hypophos­phataemic rickets), and is the primary driver in tumour-induced osteomalacia.61 Bone turnover markers are elevated in many forms of osteomalacia and rickets.53,64 Metabolic acidosis in association with hypophosphataemia is seen in the setting of Fanconi syndrome. Additionally, metabolic acidosis causing phosphate depletion can be rarely seen in young patients with diabetic ketoacidosis.46

Diseases characterised by hypophosphataemia Diseases characterised by low serum phosphate values can be divided into those mediated by FGF-23, and those independent of FGF-23, with both groups containing acquired and inherited forms of the disease.65

Acquired causes of FGF-23-mediated hypophosphataemia Tumour-induced osteomalacia is an acquired disease of FGF-23-mediated hypophosphataemia. It is caused by benign mesenchymal tumours known as phosphaturic mesenchymal tumours.66 A substantial proportion (40–60%) of these tumours appear to arise as a result of a translocation involving the genes encoding the FGF receptor (FGFR1) and the genes encoding fibronectin (FN1).67 The resultant fusion gene, FN1-FGFR1, is placed under the control of the strong FN1 promoter, presumably increasing FGFR1 signalling.67,68 Tumours can be located anywhere from the head to the feet, and, because of their wide distribution and small size (most are 2–3 cm), they are often difficult to find.68 To locate the tumour, functional imaging studies such as ¹⁸F-dotatate-PET-CT or ¹¹¹ Inoctreotide-PET-CT should be used first, followed by anatomical imaging with CT and MRI.69,70 If necessary, selective venous sampling can be used to confirm FGF-23

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Serum calcium

Urinary calcium

Parathyroid hormone

25(OH)D

1,25(OH)2D TmP:GFR

FGF-23

sBTM

Phosphate deficiency or malabsorption Low or normal

High or normal

Normal

Normal

High or normal

High

Low or normal

High or normal

Vitamin D deficiency*

Low or normal

Low or normal

High

Low

Low or normal

Low or normal

Low or normal

High or normal

Primary hyperparathyroidism

High

High or normal

High or normal

Normal

High

Low

High

High or normal

Fanconi syndrome

Normal

High or normal

Normal

Normal

Normal

Low

Low or normal

High

Normal

Low or normal

High or normal

Normal

Low or normal

Low

High or normal

High or normal

Normal

Low or normal

High or normal

Normal

Low or normal

Low

High or normal

High or normal

Hereditary hypophosphataemic rickets High or with hypercalciuria normal

High

Low or normal

Normal

High

Low

Low or normal

··

Hypophosphataemic rickets with hyperparathyroidism

High or normal

High

Normal

Low or normal

Low

High

··

Nutritional

Main endocrine and renal conditions

Other acquired conditions Tumour-induced osteomalacia Genetic conditions FGF23-mediated hereditary hypophosphataemic diseases (XLH, ARHR, ADHR, MAS and FD, CSHS)

Normal

25(OH)D=25-hydroxyvitamin D. 1,25(OH)2D=1,25-dihydroxyvitamin D. TmP:GFR=maximum renal tubular phosphate reabsorption per unit of glomerular filtration rate. FGF-23=fibroblast growth factor 23. sBTM=serum bone turnover markers. XLH=X-Linked hypophosphataemia. ARHR=autosomal recessive hypophosphataemic rickets. ADHR=autosomal dominant hypophosphataemic rickets. MAS/FD=McCune Albright syndrome and fibrous dysplasia. CSHS=cutaneous skeletal hypophosphataemic rickets. *Low 25(OH)D concentrations in the population need to be interpreted in the context of hypophosphataemia and corrected.

Table 2: Biochemical findings in patients with hypophosphataemia from different clinical conditions

secretion and thus tumour location.71 Surgical resection with wide margins is curative and the treatment of choice. For inoperable lesions, radiofrequency ablation or cryoablation have been shown to be effective.72 Although phosphaturic mesenchymal tumours are the most common cause of acquired diseases of excess FGF-23 secretion, metastatic malignant tumours, such as prostate or colon cancer, can also rarely present with elevated circulating concentrations of this phosphatonin.73 Specific preparations of intravenous iron therapy have been shown to cause FGF-23-mediated hypophosphataemia.74

Genetic causes of FGF-23-mediated hypophosphataemia Inherited forms of FGF-23-mediated hypophosphataemia include X-linked hypophosphataemia, autosomal dominant hypophosphataemic rickets, and autosomal recessive hypophosphataemic rickets. X-linked hypo­ phosphataemia is the most common of the inherited diseases, with a prevalence of one in 20 000 people, and is caused by mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene.75 This gene is expressed in osteocytes and its inactivation leads to increased FGF-23 concentrations by an unclear mechanism.53 The disease typically presents in childhood, but milder forms of the disease might remain undetected until adulthood. This type of hypophosphataemia presents with relatively minor elevation of alkaline phosphatase compared with the more frequent vitamin D deficiency.76

Autosomal dominant hypophosphataemic rickets is caused by mutations in the FGF23 gene. FGF-23 is glycosylated by the enzyme polypeptide N-acetyl­ galactosaminyltrans­ ferase 3 (GALNT3) and has a proprotein cleavage site.77 Mutations affecting this site are believed to result in impaired inactivation of FGF-23 into its inactive fragments, with the consequent accumulation of biologically active FGF-23.78 Autosomal dominant hypophosphataemic rickets is characterised by a variable clinical presentation, which, in some female patients, presents or worsens at puberty. Frequently presenting after menarche, low iron states increase FGF-23 transcription, translation, and secretion.79 In healthy individuals, this increase in FGF-23 secretion is compensated for by an increase in post-translational inactivation, resulting in elevated concentrations of inactive fragments with normal intact FGF-23 and serum phosphate values. This compensatory mechanism is not effectively initiated in patients with autosomal dominant hypophosphataemic rickets, causing them to become increasingly hypo­ phosphataemic. Studies have also linked increased erythropoietin to increased FGF-23 concentrations.80 Autosomal recessive hypophosphataemic rickets is divided into two types: type 1 is the result of dentin matrix acidic phosphoprotein 1 (DMP1) and type 2 is caused by ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutations.81 DMP1 is highly expressed in osteocytes, and its loss-of-function is associated with impaired osteocyte development.82 Dysfunctional

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osteocytes secrete increased amounts of FGF-23, leading to hypophosphataemia.82 Loss-of-function ENPP1 mutations cause both autosomal recessive hypophos­ phataemic rickets type 2 and generalised arterial calcification of infancy. Patients who survive generalised arterial calcification of infancy often develop FGF-23mediated hypophosphataemia by some unknown mechanism.83–85 Fibrous dysplasia is a mosaic disease caused by gain-offunction mutations in GNAS, a gene encoding Gαs, and severity can vary from monostotic to polyostotic involvement. If fibrous dysplasia is seen in association with café‑au-lait skin lesions and hyperfunctioning endocrinopathies, it is referred to as McCune-Albright syndrome.86 In patients with considerable bone disease, there is a hypersecretion of FGF-23 by the skeletal lesions and resultant hypophosphataemia.87 Altered processing of FGF-23 in fibrous dysplasia results in relatively higher amounts of biologically inactive FGF-23 fragments. For this reason, some patients with high FGF-23 do not develop frank osteomalacia.88 Cutaneous skeletal hypophosphataemia syndrome is due to mosaic gain-of-function mutations in HRAS or NRAS, and is characterised by large skin lesions and abnormal bone that inappropriately secretes FGF-23.89–91 Other rare diseases of altered FGF-23 secretion include: osteoglophonic dysplasia, caused by mutations in FGFR1, and hypophosphataemic rickets with hyperparathyr­ oidism, the result of a translocation near the klotho gene on chromosome 13 elevating klotho, FGF-23, and PTH concentrations.92,93

Non-FGF-23-mediated causes of hypophosphataemia There are also hereditary and acquired causes of non-FGF-23-mediated hypophosphataemia. Acquired vitamin D deficiency can be due to a lack of adequate sun exposure or dietary insufficiency. Renal disease and liver disease can impair 1-α-hydroxylation and 25-hydroxylation of vitamin D metabolites, leading to a deficiency of the active form of vitamin D, 1,25(OH)2D. Because of reduced concentrations of 1,25(OH)2D, intestinal absorption of calcium and phosphate is impaired, and PTH becomes elevated, increasing phosphate excretion in the urine. Severe malnutrition, alcoholism, and intracellular phosphate shifts can lead to hypophosphataemia. This hypophosphataemia is especially apparent in cases of insulin administration or refeeding after starvation, and in respiratory or metabolic alkalosis, which shifts phosphate into cells. Other acquired causes of non-FGF-23-mediated hypophosphataemia are due to direct renal tubular damage by a drug or toxin, which result in a generalised tubulopathy. The more common causes of acquired Fanconi syndrome include heavy metal exposure (cadmium, lead, and arsenic), cancer chemotherapy agents (cisplatin and ifosfamide), antiretroviral drugs (tenofovir and adefovir),94 anticonvulsants such as 6

sodium valproate,95 and monoclonal gammopathies (multiple myeloma, light chain proteinuria, and amyloidosis).96 They are clinically distinguishable from other acquired causes of hypophosphataemia, such as tumour-induced osteomalacia, by patient medical history and the extent of the renal tubular dysfunction. In Fanconi syndrome, dysfunction extends beyond simple phosphate wasting and includes a more generalised proximal tubular dysfunction that leads to excessive urinary excretion of amino acids, glucose, phosphate, bicarbonate, uric acid, and other solutes usually reabsorbed by this nephron segment.96 Hereditary causes of non-FGF-23-mediated hypo­ phosphataemia include hypophosphataemic rickets with hypercalciuria. This autosomal recessive disorder results from loss-of-function mutations in the SLC34A3 gene encoding the proximal tubule cotransporter NPT2c.97 It is characterised by reduced renal phosphate reabsorption, hypophosphataemia, and rickets. This disorder can be distinguished from other forms of hypophosphataemia by appropriately low-to-normal FGF-23 concentrations and increased serum concen­trations of 1,25(OH)2D. Elevated 1,25(OH)2D induces hypercalciuria by enhancing intestinal calcium absorption and reducing PTH-dependent calcium reabsorption in the distal tubules.44 This induction leads to a significantly increased risk of nephrocalcinosis and nephrolithiasis.98 Unlike the specific defect in phosphate reabsorption present in hypophosphataemic rickets with hypercalciuria, several inherited diseases, including nephropathic cystinosis, galactosemia, hereditary fructose intolerance, tyrosinemia, Wilson’s disease, Lowe syndrome, Dent’s disease, glycogenolysis, and mito­ chondrial cytopathies, can manifest as a Fanconi syndrome. The most important feature that distinguishes these genetic causes of hypophosphataemia from the common genetic causes (X-linked hypophosphataemia, autosomal dominant hypophosphataemic rickets, and autosomal recessive hypophosphataemic rickets) is that plasma FGF-23 remains appropriately low-to-normal for the hypo­ phosphataemic state.41,97

Approach to patients with hypophosphataemia: differential diagnosis Given that phosphate concentrations have a circadian pattern and vary substantially after food intake, whenever possible, serum phosphate should be measured on a morning fasting blood specimen.23 After hypophosphataemia is confirmed, taking into account serum phosphate age-specific and sex-specific normal ranges, the next step is to do a thorough clinical evaluation to rule out any acute clinical condition associated with hypophosphataemia. These acute causes include acute respiratory alkalosis, hungry bone syndrome after parathyroidectomy, refeeding syndrome, diabetic ketoacidosis, and hyperosmolar hyperglycaemic state.45 Obtaining a complete pharmacological history is important to identify the use of drugs sometimes

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associated with hypophosphataemia (intravenous iron, phosphate-binding antacids, chemotherapy agents, and antiretroviral drugs). In addition, initial evaluation should include a detailed personal and family history to ascertain the age of onset of symptoms and the presence of dental abnormalities such as enamel hypoplasia or dental abscess, and a history of nephrocalcinosis or nephrolithiasis, or other affected family members.99 In general, the younger the patient is at presentation, the more likely their hypophosphataemia is the result of a genetic disorder (X-linked hypophosphataemia, autosomal dominant hypophosphataemic rickets, auto­ somal recessive hypophosphataemic rickets, hypo­phos­ phataemic rickets with hypercalciuria, and inherited renal Fanconi syndromes). For adults, hypophos­ phataemia is more commonly due to acquired causes such as tumour-induced osteomalacia, malnutrition, malabsorptive diseases, exposure to toxins and drugs, or comorbidities associated with acquired Fanconi syndrome.61 If the initial clinical evaluation does not provide a clear cause for the hypophosphataemia, the next step is to establish the presence of renal phosphate wasting.68 This step can be done either by calculating the tubular reabsorption of phosphate (TRP) or the ratio of the TmP to glomerular filtration rate (TmP:GFR).76 TmP:GFR is the most accurate reflection of renal phosphate reabsorption, however TRP is simpler and more convenient.99 Both calculations require simultaneous urine and serum phosphate and creatinine measure­ ments. TmP:GFR necessitates fasting values at peak phosphate absorption, usually taken from a second morning void, but TRP can be calculated from random collections.61,99 Vitamin D deficiency must be corrected before making the causal diagnosis, since secondary hyperparathyroidism asso­ ciated with vitamin D deficiency can confound the calculation of percentage of TRP and TmP:GFR. In addition, patients must have stopped all phosphate supplementation and care should be taken to use consistent units when using either formula.99 Online calculators and downloadable applications are available for the computation of these values. Both TmP:GFR and blood phosphate concen­trations vary with age, and so the use of the appropriate age-specific normal range is recommended.99 Under normal physiological conditions, 85–95% of filtered phosphate is reabsorbed by the proximal tubule. A percentage of TRP less than 85–95% in the setting of hypophosphataemia or a TmP:GFR lower than the reference range is indicative of renal phosphate wasting.68 In the context of hypophos­ phataemia, a percentage of TRP greater than 85–95% would show an appropriate tubular response, with a clinically significant increase in phosphate reabsorption, and so would be suggestive of inadequate phosphate intake and intestinal absorption (figure 2).58,61 If renal phosphate wasting is confirmed, measuring calcium, 1,25(OH)2D, PTH, and FGF-23 plasma

concentrations is recommended. The interpretation of these results will help to distinguish patients with FGF-23-mediated hypophosphataemic diseases from patients with primary tubular defects. The study of patients with hypophosphataemia should include FGF-23 measurement and an evaluation of renal function to properly interpret FGF-23 values. The typical biochemical pattern of FGF23-mediated diseases is characterised by normal concentrations of calcium and PTH, low or lowto-normal concentrations of 1,25(OH)2D, and high or normal-to-high concentrations of FGF-23.53,61 Occasionally, secondary hyperpara­thyroidism is seen, which is a typical response to low 1,25(OH)2D and prolonged phosphate supplementation. Prolonged secondary hyper­para­ thyroidism can lead to tertiary hyperparathyroidism.61 Several FGF-23 assays are available, three of which measure the intact FGF-23 molecule (assays from Kainos Laboratories International [Tokyo, Japan], Immutopics International, Quidel Corporation [Athens, OH, USA], and DiaSorin [Stillwater, MN, USA]).61 The fourth measures the intact hormone and the carboxy-terminal fragments of the molecule, C-terminal FGF-23 (assay from Immutopics International). In most cases, Hypophosphataemia*

• Complete medical, family, and pharmacological history • Physical examination • Laboratory evaluation

• Acute causes or redistribution • Known hereditary diseases • Vitamin D deficiency • Hyperparathyroidism

%TRP, TmP:GFR, or both

Normal TmP:GFR, or TRP≥85–95%, or both

Low TmP:GFR, or TRP<85–95%, or both

Decreased phosphate intake or absorption

Renal phosphate wasting

Measure FGF-23

Low values: • HHRH† • Hereditary forms of Fanconi syndrome† • Acquired Fanconi syndrome

Normal or elevated values: • Hereditary forms of FGF-23-dependent renal phosphate wasting (XLH, ARHR, and ADHR)† • MAS and FD • CSHS • TIO • Drugs (intravenous Iron)

Figure 2: Diagnostic algorithm of hypophosphataemia TRP=tubular phosphate reabsorption. Tmp:GFR=maximum renal tubular phosphate reabsorption per unit of glomerular filtration rate. FGF-23=fibroblast growth factor 23. HHRH=hereditary hipophosphataemic rickets with hypercalciuria. XLH=X-Linked hypophosphataemia. ARHR=autosomal recessive hypophosphataemic rickets. ADHR=autosomal dominant hypophosphataemic rickets. MAS and FD=McCune-Albright syndrome and fibrous dysplasia. CSHS=cutaneous skeletal hypophosphataemic rickets. TIO=tumour-induced osteomalacia. *After confirming diagnosis excluding interfering factors. †Genetic testing available as part of a hereditary hypophosphataemia panel.

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Panel: Drugs for patients with hypophosphataemia General treatment • Acute symptomatic hypophosphataemia: intravenous sodium phosphate or potassium phosphate • Acute asymptomatic hypophosphataemia: oral phosphate salt (sodium phosphate or potassium phosphate) and active vitamin D • Chronic hypophosphataemia: oral phosphate salt (sodium phosphate or potassium phosphate) and active vitamin D Cause-specific treatment • FGF-23-mediated hypophosphataemic diseases: oral phosphate and active vitamin D • X-linked hypophosphataemia: burosumab* • Fanconi syndrome: oral phosphate, with active vitamin D for some patients • Hereditary hypophosphataemic rickets with hypercalciuria: oral phosphate • Vitamin D deficiency: native vitamin D *Burosumab inhibits FGF-23 actions and was approved for patients with X-linked hypophosphataemia in Europe, the USA, Canada, and Brazil. Burosumab requires evaluation in patients with other FGF-23-mediated hypophosphatemic diseases. FGF-23=fibroblast growth factor 23

C-terminal fragment concentrations are negligible, and the measurement acquired from assays that detect these fragments alongside intact FGF-23 reflects the amounts of intact FGF-23.61 An intact FGF-23 value found by a Kainos assay of greater than 30 pg/mL, in the presence of hypophosphataemia, has been proposed to suggest an underlying FGF-23-mediated disease.100 The specific cutoff point for the more commercially available C-terminal assay has not been defined to date. Elevated or normal (unsuppressed) concentrations of FGF-23 in the presence of hypophosphataemia indicate a derangement in the inverse relationship between the hormone and phosphate concentration and is an indication of pathological FGF-23 excess.61 For adults, indicators that favour the differential diagnosis of hereditary disease versus tumour-induced osteomalacia are short stature relative to predicted parental height and a history of substantial childhood dental abnormalities. A family history of hypophosphataemia and consanguinity suggests an inherited form of phosphate wasting; in these cases, specific genetic testing is indicated. McCuneAlbright syndrome, which consists of fibrous dysplasia, café-au-lait macules, and hyperfunctioning endo­ crinopathies, can also be associated with FGF-23 hypersecretion from bony lesions. However, the phosphate wasting in McCune-Albright syndrome only occurs in patients with extensive bone disease and the diagnosis is seldom confused.101 The same applies to cutaneous skeletal hypophosphataemia syndrome, in which extensive skin lesions and abnormal bone will guide the clinician to identify this diagnosis as the cause of the hypophosphataemia.90 8

Finally, hypophosphataemia in the setting of low FGF-23 and normal-to-elevated 1,25(OH)2D concentrations would suggest an alternative cause, such as hypophosphataemic rickets with hypercalciuria, or an acquired or inherited Fanconi syndrome. In this context, other parameters should be measured, such as arterial blood gas, serum and urine concentrations of sodium, potassium, chloride, bicarbonate, and immunoglobulins, and urinary concen­ trations of amino acids (figure 2).41,96

Old and new therapeutic drugs for management of different conditions General treatment

The treatment of choice for patients with hypo­ phosphataemia varies depending on the cause. Clear causes of hypophosphataemia, such as diuretic or phosphate-binding antacid use, can be easily corrected by drug discontinuation. In patients whose medications cannot be stopped, phosphate supplementation might be necessary. Drip infusion of either sodium phosphate or potassium phosphate might be required for symptomatic patients, especially in severe, acute hypophosphataemia. However, intravenous administration of phosphate can cause hypocalcaemia and hyperphosphataemia. When renal function is impaired, serum potassium concen­ tration also needs to be monitored if potassium phosphate is administered. We have summarised the therapeutic options for hypophosphataemia (panel). Oral phosphate is usually the first choice for patients with acute asymptomatic and chronic hypophosphataemia. Various formulations of either sodium phosphate, potassium phosphate, or both, are available. Oral phosphate is rapidly absorbed in the small intestine and excreted into the urine within several hours. Therefore, oral phosphate needs to be administered three or four times per day. Even with this frequent administration, attaining stable serum phosphate concentrations by oral phosphate is impossible. Oral phosphate can also cause several adverse events, including gastrointestinal symptoms such as diarrheoa and abdominal pain, and, with chronic treatment, secondary or tertiary hyperparathyroidism, nephrocalcinosis, and renal impairment.76 The dose of oral phosphate should be modified to avoid the development and exacerbation of these adverse events. Because of these limitations, medication compliance can be a considerable clinical problem.

Treatment for patients with FGF-23-mediated hypophosphataemic diseases In the case of tumour-induced osteomalacia, the first choice is complete removal of responsible tumours with wide surgical margins to prevent late recurrence. By contrast, for patients with FGF-23-mediated hypophos­ phataemic diseases, including those with tumour-induced osteomalacia whose tumors cannot be resected, treatment with oral phosphate and active vitamin D (such as calcitriol and alfacalcidol) should be instituted.76 Medication dose

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should be adjusted depending on the age of the patient, symptoms, signs, and laboratory data. Phosphate and active vitamin D dose recommendations can be variable and there is no consensus on the optimal dose of oral phosphate (table 3).103 Starting with small doses and building up to the required amount is often needed to prevent the complication of diarrhoea. Active vitamin D enhances intestinal phosphate absorption. In addition, 1,25(OH)2D suppresses PTH synthesis and works to prevent the development of secondary and tertiary hyperparathyroidism. Administration of active vitamin D can cause hypercalciuria, hypercalcaemia, nephrolithiasis, and renal function impairment. Therefore, urine calcium monitoring every 3–6 months and renal ultrasonographic imaging every 1–2 years are essential.103 In 2018, burosumab, a human anti-FGF-23 monoclonal antibody that targets and blocks FGF-23, was approved for the treatment of X-linked hypophosphataemia in several countries.104 Burosumab is administered by subcutaneous injection every 2 weeks for paediatric patients and every 4 weeks for adult patients. It has been shown to increase serum phosphate and 1,25(OH)2D concentrations, improve impaired proximal tubular phosphate reabsorption, ameliorate rickets and symptoms such as stiffness, and improve healing of fractures.105–108 However, burosumab is an expensive drug and burosumab treatment is recommended in children and adolescents with growing skeletons with radio­ graphical evidence of overt bone disease, disease refractory to conventional therapy, complications related to conventional therapy, or an inability to adhere to conventional therapy.103 Because of the relatively short duration of reported clinical trials, whether burosumab influences growth in X-linked hypophosphataemia is not known. Burosumab also seems to be useful for symptomatic adult patients with X-linked hypophosphataemia. The long-term safety of burosumab needs to be confirmed by further studies. In addition, whether burosumab affects some complications of X-linked hypophosphataemia, such as enthesopathy, hearing disturbance, and dental problems, is not understood.

Treatment for patients with non-FGF-23-mediated causes of hypophosphataemia Fanconi syndrome is a heterogeneous condition. Hypo­ phosphataemia in patients with Fanconi syn­drome can be treated with oral phosphate or active vitamin D. Biochemical abnormalities in patients with hypo­ phosphataemic rickets with hypercalciuria can be corrected by oral phosphate alone, whereas active vitamin D is not indicated for patients with hypo­phosphataemic rickets with hypercalciuria.109 Administration of active vitamin D in patients with hypophosphataemic rickets with hypercalciuria further increases 1,25(OH)2D concen­ trations, which causes enhanced intestinal calcium absorption, leading to nephrolithiasis, nephrocalcinosis,

Phosphorus

Active vitamin D

Schouten et al (2009)74 Children Adult

20–40 mg/kg per day in 3–5 divided doses 20–30 ng/kg per day in 2–3 divided doses (calcitriol) 750–1000 mg/day in 3–4 divided doses

Start with 0∙5–0∙75 μg/day in 2 divided doses (calcitriol)

Linglart et al (2014)102 Infancy

55–70 mg/kg per day in 4 divided doses

1∙5–2∙0 μg/day in 1 dose (alfacalcidol)

Childhood

45–60 mg/kg per day in 3 divided doses

1∙0–2∙0 μg/day in 1 dose (alfacalcidol)

Puberty

35–50 mg/kg per day in 3 divided doses

1∙5–3∙0 μg/day in 1 dose (alfacalcidol)

Adult Pregnancy Menopause

0–2000 mg/day in 2 divided doses 2000 mg/day in 2 divided doses 0–2000 mg/day in 2 divided doses

0–1∙5 μg/day in 1 dose (alfacalcidol) 1–1∙5 μg/day in 1 dose (alfacalcidol) 0–1∙5 μg/day in 1 dose (alfacalcidol)

Table 3: Doses of phosphorus and active vitamin D for patients with hypophosphataemic rickets or osteomalacia

Search strategy and selection criteria We identified references for this Review through searches of PubMed for articles published from Jan 1, 2000, to June 30, 2019, by use of the terms “epidemiology”, “metabolism”, “pathophysiology”, “clinical findings”, “biochemistry”, “acquired disease”, “genetic disease”, “diagnosis”, “differential diagnosis”, “management”, and “treatment” in combination with the terms “hypophosphatemia” and “phosphorus”. We identified relevant articles published between 1970 and 1999 through searches in the authors’ personal files. We reviewed articles resulting from these searches and relevant references cited in those articles and included those published in English.

and renal impair­ment. Patients with vitamin D deficiency are treated with native vitamin D.

Future perspectives Increasingly recognised as an important disturbance of mineral homoeostasis, the state and treatment of hypophosphataemia are rapidly evolving areas of basic and clinical science, exemplified by the growing number of papers published in these areas over the past 5 years. Investigation of the pathophysiological mechanisms leading to hypophosphataemia in conditions such as tumour-induced osteomalacia, and the targeted therapies for specific diseases like X-linked hypophosphataemia, forms the basis of developing sectors of research. The human anti-FGF-23 monoclonal antibody burosumab has been approved for the treatment of X-linked hypo­ phosphataemia by several countries, and is being tested for efficacy in tumour-induced osteomalacia, cutaneous skeletal hypophosphataemia syndrome, epidermal nevus syndrome, and hypophosphataemic rickets in ongoing clinical trials (NCT02304367, NCT03581591). A particularly important area in which better understanding is needed is in the elucidation of the mechanism of phosphate sensing in humans. This

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understanding could rapidly promote the development of new strategies to prevent and treat diseases caused by hypophosphataemia.110 Another evolving area of investigation is the attempt to inhibit FGF-23 action by approaches other than anti-FGF-23 antibodies. One such approach involves targeting the klotho-FGF receptor complex, FGF receptor, or the downstream signalling pathways from the FGF receptor.111­ We are at the dawn of a new era, in which hypophosphataemia will hopefully be increasingly recognised, more accurately diagnosed, and effectively treated. Contributors All authors contributed to the literature search, manuscript preparation, and revision. PF contributed to the final draft of the manuscript, tables, and figures. CC contributed to the coordination of all authors’ revisions and table drafting. KLR and SF contributed to the drafting of the tables. MTC and SM contributed to manuscript ideation. JP contributed to the manuscript’s final revision. Declaration of interests SM served as speaker for Abiogen, Bruno Farmaceutici, Diasorin, Eli Lilly, Italfarmaco, and Shire. He also served in the Abiogen advisory board. He received consultation from Bruno Farmaceutici. SF reports personal fees from Kyowa Kirin, and grants from Teijin Pharma, Astellas, Chugai Pharmaceutical, Ono Pharmaceutical, Taisho Pharmaceutical, and Kyowa Kirin. All other authors declare no competing interests. References 1 Shaker JL, Deftos L. Calcium and phosphate homeostasis. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. South Dartmouth, MA: MDText.com, 2000. 2 Kovacs CS. Bone metabolism in the fetus and neonate. Pediatr Nephrol 2014; 29: 793–803. 3 Christov M, Juppner H. Insights from genetic disorders of phosphate homeostasis. Semin Nephrol 2013; 33: 143–57. 4 Takeda E, Taketani Y, Sawada N, Sato T, Yamamoto H. The regulation and function of phosphate in the human body. BioFactors 2004; 21: 34–55. 5 Land C, Schoenau E. Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition. Best Pract Res Clin Endocrinol Metab 2008; 22: 107–18. 6 Bugg NC, Jones JA. Hypophosphataemia. Pathophysiology, effects and management on the intensive care unit. Anaesthesia 1998; 53: 895–902. 7 Nagy GN, Leveles I, Vertessy BG. Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool. FEBS J 2014; 281: 4207–23. 8 Qi W, Baldwin SA, Muench SP, Baker A. Pi sensing and signalling: from prokaryotic to eukaryotic cells. Biochem Soc Trans 2016; 44: 766–73. 9 Lemann J Jr, Lennon EJ. Role of diet, gastrointestinal tract and bone in acid-base homeostasis. Kidney Int 1972; 1: 275– 9. 10 Khairallah P, Isakova T, Asplin J, et al. Acid load and phosphorus homeostasis in CKD. Am J Kidney Dis 2017; 70: 541–50. 11 Kliegman R, St. Geme J. Nelson Texbook of Pediatrics. Philadelphia, PA: Elsevier, 2019. 12 Glendenning P, Bell DA, Clifton-Bligh RJ. Investigating hypophosphataemia. BMJ 2014; 348: g3172. 13 Saad M, Moussaly E, Ibrahim U, Atallah JP, Forte F, Odaimi M. Quiz page September 2016: multiple myeloma and hypophosphatemia. Am J Kidney Dis 2016; 68: A17–20. 14 Dimeski G, Hamer A, Cooper C, Johnston J, Brown NN. Pseudohypophosphataemia secondary to paraproteinaemia may occur without the presence of hypergammaglobulinaemia. Pathology 2016; 48: 102–03. 15 Brunelli SM, Goldfarb S. Hypophosphatemia: clinical consequences and management. J Am Soc Nephrol 2007; 18: 1999–2003.

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