Review Article

Page 1 of 23

Investigative algorithms for disorders causing hypophosphataemia

and hyperphosphataemia: a narrative review
Kade C. Flowers1, Kate E. Shipman1,2, Alexa R. Shipman3, Neil J. L. Gittoes4
1
Department of Clinical Chemistry, University Hospitals Sussex NHS Foundation Trust, Worthing, UK; 2Department of Medical Education,
Brighton and Sussex Medical School, University of Sussex, Falmer Campus, Brighton, UK; 3Department of Dermatology, Portsmouth Hospitals
University NHS Trust, Portsmouth, UK; 4Centre for Endocrinology, Diabetes, and Metabolism (CEDAM), Queen Elizabeth Hospital, University
Hospitals Birmingham NHS Foundation Trust & University of Birmingham, Edgbaston, Birmingham, UK
Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: None;
(IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final
approval of manuscript: All authors.
Correspondence to: Kade C. Flowers, MSc. Department of Clinical Chemistry, University Hospitals Sussex NHS Foundation Trust, Worthing
Hospital, Lyndhurst Road, Worthing, BN11 2DH, UK. Email: [email protected].

Background and Objective: The following article is part of a special series to aid the reader in
diagnosing the cause of various blood abnormalities. By the end of the article, the reader should be able to
order and interpret appropriate laboratory investigations when faced with a patient with hypophosphataemia
or hyperphosphataemia.
Methods: A narrative, focused literature review was performed using PubMed, MedLine, OMIM and
Google Scholar during November 2023 to March 2024 to identify references published from database
inception to March 2024. Reference lists from identified articles, as well as expert opinion of the authors,
were also used. Language was restricted to English.
Key Content and Findings: Phosphate is an essential nutrient and its blood concentration is controlled
by multiple homeostatic hormones, including parathyroid hormone (PTH), fibroblast growth factor 23
(FGF-23) and 1,25-dihydroxyvitamin D. However, phosphate imbalance can occur in many disease states
and can lead to significant morbidity and mortality. Renal, endocrine and genomic syndromes can all cause
phosphate disturbances. It should be noted that phosphate results are susceptible to being falsely low or
falsely high, which can cause diagnostic confusion and inappropriate patient investigation/intervention.
Algorithms are presented from a laboratory perspective to help identify principal causes of abnormal
phosphate status.
Conclusions: Diagnostic flow charts are presented, and the limitations of the laboratory tests discussed.
By focusing on the approach to the laboratory investigation of hypophosphataemia and hyperphosphataemia,
these algorithms should support healthcare professionals to efficiently and rapidly diagnose the principal
causes of abnormal phosphate states.

Keywords: Phosphate; diagnosis; laboratory; hyperphosphataemia; hypophosphataemia

Received: 28 March 2024; Accepted: 28 August 2024; Published online: 21 October 2024.
doi: 10.21037/jlpm-24-35
View this article at: https://dx.doi.org/10.21037/jlpm-24-35

Introduction metabolism and ribonucleic acid structure, and it is one of

Phosphate is the most abundant anion in the human body (1) the most important contributors to overall bone health (3).
and makes up approximately 1% of total body weight Although phosphate is 100× more concentrated in the
in adults (2). Phosphate has essential roles in energy intracellular compartment compared to the extracellular

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Page 2 of 23 Journal of Laboratory and Precision Medicine, 2024

Table 1 The narrative review search strategy

Items Specification

Date of search November 2023 to March 2024

Databases and other sources searched PubMed, Medline, Google Scholar, OMIM

Search terms used Phosphate, hypophosphataemia, hyperphosphataemia, drugs, investigations, algorithms,

guidelines, diagnosis, causes, aetiology, human

Timeframe Database inception to March 2024

Inclusion criteria All papers and reviews were included, but language was restricted to English

Selection process A.R.S. and K.E.S. conducted initial search, with most of the refinement and technical
additions done by K.C.F. and N.J.L.G. All authors obtained consensus and agreement

Any additional considerations, if applicable Seminal texts were also searched and the references of important articles and texts were
obtained and checked for relevance

compartment (4), phosphate is commonly measured in Medline, OMIM and Google Scholar. The diagnostic
plasma or serum as part of a ‘bone profile’. Phosphate algorithms were then created using the information
homeostasis in humans is complex (5), but it is important to gathered from the literature review as well as the expert
understand the basics to be able to elucidate the principal opinion of the authors. Literature was searched over the
causes of abnormal phosphate concentrations in the blood. period November 2023 to March 2024 and language was
The following article presents algorithms designed to restricted to English (see Table 1 for further information).
provide a systematic approach to the diagnostic work up
of a patient with hypo- or hyperphosphataemia. These
Background
algorithms will not address treatments and are not designed
to replace local guidelines or specialist endocrinological Phosphorus and phosphate terminology and types
knowledge/advice. The reader is still encouraged to refer The terms “phosphorus” and “phosphate” are frequently
more complex and/or rare phosphate abnormalities to used interchangeably throughout the medical literature.
specialist departments for appropriate investigation and Technically however, they are different because phosphorus
treatment, particularly if a genetic condition in a child is refers to the phosphorus atom (P) only, whereas phosphate
suspected. Instead, these algorithms are most useful as entry is a compound comprising of one phosphorus atom and
level general diagnostic aids to identify common causes four oxygen atoms (PO 43−) (4). This technicality is not
of phosphate derangements. Important laboratory and clinically important when the international system of units
analytical considerations, which are frequently encountered (SI) (common in Europe) are used—which express the
in routine practice but are often not mentioned in guidelines phosphorus concentration as the number of particles per
and other reviews, will also be discussed. For conditions unit of volume—because one mole of phosphate contains
where the primary clinical abnormality usually causes a one mole of phosphorus (4,8). Importantly however, this
concurrent calcium disturbance—e.g., parathyroid disease— difference is certainly relevant if conventional mass units
the reader is directed to the companion article in this series (common in the United States) are used—which express
on calcium (6), and to other comprehensive open-access phosphorus concentration as the mass per unit of volume—
clinical guidelines (7). We present this article in accordance where the extra weight of the additional oxygen atoms in
with the Narrative Review reporting checklist (available at phosphate has a significant effect (9,10). For example, a
https://jlpm.amegroups.org/article/view/10.21037/jlpm-24- phosphorus (P) concentration of 4 mmol/L represents a
35/rc). phosphate (PO43−) concentration of 4 mmol/L. Conversely,
a phosphorus (P) concentration of 4 mg/dL represents
a phosphate (PO43−) concentration of 12.3 mg/dL as the
Methods
molar mass of phosphate (94.97 g/mol) is 3.07 times the
The literature review was created by searching PubMed, molar mass of phosphorus (30.97 g/mol) (4). It is, therefore,

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Journal of Laboratory and Precision Medicine, 2024 Page 3 of 23

Phosphorus Phosphate

Molar mass =30.97 g/mol Molar mass =94.97 g/mol

P O P
O
O

Same
mmol/L mmol/L
Same

×0.32 ×3.07 ×0.11 ×9.42

×3.07

mg/dL mg/dL
×0.32

Figure 1 The difference in structure between phosphorus and phosphate which affects their mass. The use of SI units (e.g., mmol/L) to
express concentration—which express the number of particles per unit of volume—negates the requirement to correctly differentiate the
terms “phosphorus” and “phosphate”. The use of conventional mass units (e.g., mg/dL)—which express the mass per unit of volume—
can lead to conversion errors if the terms “phosphorus” and “phosphate” are not correctly used. Approximate conversion factors are also
displayed. SI, international system of units.

important that the correct “phosphate” or “phosphorus” preservatives and added salts in ultra-processed foods (9).
term is used if conventional mass units are utilised, Dietary Pi can significantly increase phosphate intake as
especially when converting from SI units where either term conversely to organic phosphate, Pi are easily dissociable
is accurate. See Figure 1 for a summary of the difference salts, meaning that more than 90% is absorbed in the
between phosphorus and phosphate as well as approximate gastrointestinal tract (9).
conversion factors. For consistency and clarity, the term Pi in blood is 85% free (PO43−), 10% bound to plasma
“phosphate” expressed in mmol/L will be used throughout proteins and 5% complexed with calcium, magnesium
this review, and conversions to mg/dL units will be to and sodium (4). The free Pi form is the form measured by
“phosphorus”. laboratory methods and is the biologically active form that
Elemental phosphorus is very reactive and does not is the driver of homeostatic mechanisms (8).
exist by itself in nature (4). Therefore, in the human body,
phosphorus exists as part of two forms of phosphate:
Phosphate functions and balance
organic and inorganic. Organic phosphate is mostly
bound to proteins and carbon containing molecules, and Important functions of phosphate include: part of adenosine
high amounts are found naturally in protein rich food (9). di- and tri-phosphate (ADP and ATP) that are the main
Approximately 30% to 60% of dietary organic phosphorus energy molecules in humans; part of nicotine adenine
is hydrolysed and absorbed into the circulation as inorganic diphosphate (NADP) that is a buffer and enzyme activator;
phosphate (Pi) (9). Direct dietary sources of Pi include part of cell signalling molecules such as cyclic adenosine

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Page 4 of 23 Journal of Laboratory and Precision Medicine, 2024

75 kg person
Total body phosphorus = ~775 g or 25 mol

Bone Soft tissue

85% in hydroxyapatite crystals,
15% as calcium phosphate

Dietary phos intake

~1,500 mg/day
~48 mmol/day
85% 15%

Formation Resorption
Absorption ~225 mg/day ~225 mg/day
~1,200 mg/day ~7 mmol/day ~7 mmol/day
~40 mmol/day Filtration

<1%

Secretion In blood and extracellular fluid

Reabsorption
~225 mg/day
~7 mmol/day

Faecal excretion Urinary excretion

~525 mg/day ~975 mg/day
~17 mmol/day ~31 mmol/day

Figure 2 Phosphorus balance in a healthy 75 kg adult (e.g., diet consumption ~20 mg/kg/day) with neutral bone turnover. In health, the net
phosphorus balance (intake − excretion) is approximately zero as demonstrated. However, many disease states and physiological states—e.g.,
growth and ageing—can lead to net positive or negative phosphorus status.

or guanosine monophosphate (cAMP or cGMP); and an osteomalacia (11).

oxygen transporter (5). Phosphate is also important in bone
and teeth maintenance (and structure) as well as muscle
Phosphate homeostasis
function (11). The normal reference interval for phosphate
in blood for adults is approximately 0.80 to 1.45 mmol/L The homeostatic regulation of phosphate is complex due to
(2.48 to 4.50 mg/dL) (8). Most (85%) of the total body the number of different hormones and transporters that are
phosphate is stored in bones and teeth (11), therefore active at the same time. A full review of the most up to date
plasma phosphate concentrations may not reflect the true insights into phosphate homeostasis is beyond the scope of
body store of phosphate. this article; the reader is directed to other comprehensive
Figure 2 shows the phosphate balance in adults; values reviews if more information is required (5,11), particularly
are approximated for a 75 kg person (3,5). Children have the recent review by Levi et al. (12) and the seminal review
a positive balance of 2–3 mmol/day (6.2–9.3 mg/day) of of renal regulation by Farrow and White (2). However, a
phosphate as they increase the phosphate stored in their simplified overview will be provided here to provide context
bones and teeth (5). There is negative balance later in life for interpreting phosphate results in clinical practice.
due to age related bone loss (5) and a higher risk of dietary The major hormones involved in phosphate metabolism
deficiency and/or decreased absorption, which may lead to are parathyroid hormone (PTH), 1,25-dihydroxyvitamin

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Journal of Laboratory and Precision Medicine, 2024 Page 5 of 23

D, and fibroblast growth factor 23 (FGF-23) (11). Other homeostasis disorders can manifest if these do not function
important hormones include insulin, ectonucleotide correctly (16,17).
pyrophosphatase/phosphodiesterase-1 (ENPP1) (13), FGF-23 may also be useful as a marker of bone disease
growth hormone, adrenaline (epinephrine), thyroid and a very early marker of CKD (18). There are strong
hormones and steroids (12). associations between high levels of circulating FGF-23 and
multiple cardiovascular (CV) abnormalities (16). However,
PTH a very recent large study found no association between
The primary function of PTH is to regulate blood ionised increased CV abnormalities and genetically predicted
(free) calcium concentration, where hypocalcaemia stimulates FGF-23 concentration, suggesting that there is indeed no
PTH release from the parathyroid glands (14). The important causal link that would make targeting FGF-23 an
phosphate relevant renal effects of increased PTH action effective CV disease treatment (19).
is the endocytosis and destruction of sodium-phosphate FGF-23 and PTH are both key to phosphate metabolism,
co-transporters type 2a (NPT2a) in the proximal tubules, and excess or deficiency of either result in hypophosphataemia
resulting in reduced phosphate reabsorption from the renal and hyperphosphataemia respectively (20). However, PTH
filtrate and hence increased urinary excretion (2). The increases the production of active 1,25-dihydroxyvitamin D
importance of the effect of PTH on phosphate homeostasis whilst FGF-23 decreases the production (21). See Figure 3
is evident in patients with primary hyperparathyroidism (high for a simplified overview of the main effects of PTH,
PTH) where there is renal phosphate wasting and possible FGF-23 and vitamin D on phosphate regulation in the
hypophosphataemia. In hypoparathyroidism (low PTH), kidneys and the gut (2,5,22).
there is increased renal phosphate reabsorption and possible
hyperphosphataemia (2).
Diurnal variation
PTH also upregulates the renal enzyme 1α-hydroxylase,
which in turn converts inactive 25-hydroxyvitamin D to An important but often forgotten property of blood
active 1,25-dihydroxyvitamin D (14). 1,25-dihydroxyvitamin phosphate concentration is its diurnal variation. Blood
D increases phosphate and calcium absorption from phosphate is known to be at its lowest point—approximately
the gut to allow an increase in blood calcium whilst 1.07 to 1.16 mmol/L (3.32 to 3.60 mg/dL)—between
keeping blood phosphate stable (2,14). Therefore, a high 08:00 and 11:00, and at its highest point—≥1.49 mmol/L
1,25-dihydroxyvitamin D in hypophosphataemia is expected (≥4.62 mg/dL)—between 02:00 and 04:00 (23). This
in health in an attempt to increase gut absorption. circadian variation is also present to a similar degree in
It should be noted that the routine immunoassay tests patients with end stage renal disease (24), but fasting for 96
used to measure PTH can cross react with biologically hours blunts this circadian variation (25). It may, therefore,
inactive fragments and overestimate the concentration, be appropriate to take a blood sample for phosphate
particularly in patients with chronic kidney disease (CKD). measurement at a different time of day than a sample that
Consequently, clinicians should ensure that the test used in showed a borderline abnormal phosphate concentration,
their local laboratory is at least a second (preferably third) or after a period of fasting (if safe to do so), to confirm a
generation immunoassay, especially if the PTH result is genuine phosphate imbalance.
causing diagnostic confusion [see Smit et al. (15), or the
calcium article within this series (6), for more information
Fasting state
on PTH testing].
Compared to baseline concentrations, plasma phosphate
FGF-23 concentration decreases by approximately 4% (26) to
FGF-23 is primarily released from osteocytes and 8% (27) one hour after a meal, and then increases by
osteoblasts in bone tissue in response to increased approximately 5% (27) to 12% (26) four hours after a
phosphate and 1,25-dihydroxyvitamin D in the blood (16). meal. Consequently, patients who have a borderline low
Similarly to PTH, FGF-23 down regulates NPT2a and or high phosphate concentration in the blood should have
NPT2c in the kidney to increase phosphate excretion in a fasting phosphate measured to confirm the abnormal
the urine (16). FGF-23 exerts these effects in the kidney via phosphate status at baseline. However, significant phosphate
FGF receptors and its co-factor α-Klotho, and phosphate abnormalities, especially in conjunction with other clinically

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Page 6 of 23 Journal of Laboratory and Precision Medicine, 2024

Blood phosphate Blood calcium

Figure 3 Simplified overview of regulation and mechanisms of transcellular movement of phosphate in the gut and kidneys. Of the filtered
phosphate in the kidney, 70% is reabsorbed in the proximal tubule. 1,25-OHVTD, 1,25-dihydroxyvitamin D; FGF23, fibroblast-growth
factor 23; NPT2a, sodium phosphate cotransporter type 2; Pi, inorganic phosphate; PTH, parathyroid hormone.

relevant factors, are unlikely going to be explained by non- biochemical categorisations may not reflect the clinical
clinically significant post-prandial variation. The proposed significance of hypophosphataemia, therefore clinicians
investigative algorithms below will assume that abnormal must consider other factors—including the speed of
phosphate concentrations are present in samples taken decrease and other relevant pathologies—when determining
during fasting, the clinical urgency.
Biochemically low phosphate may be present in
approximately 11% of all patients who have blood
Hypophosphataemia
phosphate analysis requested (28). Almost all (99%) samples
Hypophosphataemia can be defined as a plasma phosphate from patients with moderate to severe hypophosphataemia
concentration <0.80 mmol/L (<2.48 mg/dL) (5), although (≤0.5 mmol/L) come from hospitalised patients, and
this may vary slightly depending on the local population patients in intensive care units make up 45% of this
and the laboratory method utilised. Biochemically moderate hospitalised patient group (28). There is a higher incidence
hypophosphataemia is generally considered to be between of hypophosphataemia in those who are critically ill (29),
0.31 and 0.50 mmol/L (0.96 and 1.55 mg/dL) (28), and and it is associated with poorer outcomes in hospitalised
biochemically severe hypophosphataemia is ≤0.30 mmol/L patients with coronavirus disease 2019 (COVID-19) (30).
(≤0.93 mg/dL) (5). Importantly however, these crude The commonest causes and clinical presentations

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Journal of Laboratory and Precision Medicine, 2024 Page 7 of 23

associated with hypophosphataemia in hospitalised patients normal phosphate after rapid analysis on a fresh sample
are (28,31-34): transported to the laboratory on ice (42). The exact
 Unwell enough to be in intensive care (and more mechanism is uncertain, but it is possible that the continued
frequent in the sickest of intensive care unit patients); metabolism of leucocytes in vitro expend extracellular
 Neoplasms; phosphate in the sample before separation of serum/plasma
 Refeeding syndrome (RFS); from the cells occurs in the laboratory (42).
 Sepsis; High bilirubin concentrations can cause falsely low
 Gastrointestinal loss; phosphate results in biochromatic phosphomolybdate
 Intravenous fluid replacement (non-phosphate methods, but the use of a reducing agent can negate
containing); this effect (43). Mannitol treatment can cause
 Diabetic ketoacidosis (DKA); pseudohypophosphataemia by binding to molybdate in
 Excessive alcohol intake; the laboratory method (44-46), causing a decreased rate of
 Mechanical ventilation. colour development and a lower endpoint measurement.
Symptoms of hypophosphataemia can be non-specific However, mannitol therapy can also contribute to genuine
but can be life-threatening, and include muscle weakness, hypophosphataemia as it has an osmotic effect and mildly
impaired myocardial contractility and ventricular increases phosphate excretion in the urine (32,47). Finally,
arrhythmias, respiratory failure, rhabdomyolysis, falsely low phosphate results has also been demonstrated
ileus, immune dysfunction and encephalopathy (35). A in patients receiving high dose antifungal liposomal
proposed algorithm for the laboratory investigation of amphotericin B therapy (48).
hyperphosphataemia is shown in Figure 4. Hyperventilation due to anxiety and/or needle phobic
panic attacks can cause a respiratory alkalosis, which in turn
can cause hypophosphataemia. Although this is technically a
Pseudohypophosphataemia
true hypophosphataemia, this is usually mild and not clinically
The possibility of a falsely low plasma phosphate result significant, and usually does not require further investigation
should always be considered in order to prevent unnecessary if no other relevant clinical factors are present (49).
investigation and treatment (36), especially if the result is
unexpected due to an absence of symptoms or risk factors,
Treatments and medications
and/or the results do not respond to treatment.
Although more commonly associated with Once pseudohypophosphataemia has been excluded,
pseudohyperphosphataemia, the presence of a paraprotein known treatments and medications should be reviewed
in lymphoproliferative disorders—including multiple to determine if these may be causing/contributing to the
m y e l o m a , Wa l d e n s t r o m m a c r o g l o b u l i n a e m i a a n d genuine hypophosphataemia [see Table 2, and Figure 4B
lymphoma—can cause falsely low phosphate results due box 2, for a non-exhaustive list of medications and
to interference with the laboratory method (37-39). If treatments that are associated with hypophosphataemia
suspected, serum protein electrophoresis, and urine protein (47,50-52)]. Many cancer therapies have been implicated in
electrophoresis or serum free light chains, should be drug induced hypophosphataemia; see the comprehensive
requested to identify potential interfering paraproteins (40). review by Adhikari et al. (32) for more information. Once
If present, paraprotein interference can be confirmed identified, it may be appropriate to stop the relevant
by analysis using a different laboratory method, where a medication(s), review the dose or just monitor depending
significantly different result is suspicious. If this is not possible, on the severity of hypophosphataemia, requirement of the
precipitation of plasma/serum using polyethylene glycol (PEG) medication, and availability of alternatives.
can remove the interfering paraprotein and provide a more If no known hypophosphataemia causing medications
reliable result, a method which has been successfully used to are being taken, the degree of hypophosphataemia
confirm paraprotein interference in other analytes (41). is not consistent with the particular medication, or
Falsely low phosphate (and potassium) results have hypophosphataemia persists when the drug is discontinued
also been reported in samples from patients with extreme or the dose is reduced, then further investigation is likely
leucocytosis, which can be confirmed by a subsequent appropriate.

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A Fasting hypophosphataemia Consider pseudohypophosphataemia,

(↓ plasma PO43−) see box 1
Not applicable

Review treatments and medications, see box 2

Measure paired urine and plasma phosphate and

creatinine to calculate TmP/GFR, see box 3

Low Normal/high

Inappropriate renal phosphate wasting Appropriate renal reabsorption

Measure plasma intact PTH Measure plasma 25-OH vitamin D, see box 5

Low/normal High

Hyperparathyroidism Consider poor phosphate intake

Consider Fanconi syndrome, see box 4 Consider malabsorption, see box 6

Consider other causes including tumour Consider other causes including

induced osteomalacia, post renal prolonged vomiting, nasogastric suction,
transplant, vitamin D dependent rickets, alkalosis, haematological malignancy,
hepatic resection, post burn hungry bone syndrome

B Box 1 - Pseudohypophosphataemia Box 2 - Treatments and medications

Paraprotein interference should be considered if Some treatments and medications that can cause
the result does not fit clinically and/or is extreme ↓ PO43− include (see Table 2 in main article for
(<0.2 mmol/L). ↑ WBCs can also be a cause more information):
due to ongoing in vitro cellular metabolism. • Diuretics (↑ renal loss)
Mannitol and amphotericin B therapy, and high • Bisphosphonates (↑ renal loss)
bilirubin, are also implicated. Anxiety attacks • Phosphate binding antacids (↓ absorption)
(hyperventilation) when taking blood sample • Oestrogen therapy (↑ renal loss)
should also be considered. • Glucocorticoids [cortisol] (↓ absorption)
•M  annitol (false result - molybdate based
Box 3 - TmP/GFR laboratory methods only)
• IV iron replacement (↑ FGF-23)
Helps to determine if ↓ PO43− is due to renal loss •T  PN and/or refeeding (refeeding syndrome/
or non-renal causes. See Table 3 in the main under-replacement)
article for TmP/GFR reference intervals. • Insulin and glucose (cellular shift)
Step 1) calculate tubular reabsorption: •S  alicylate toxicity (respiratory alkalosis)
[ P ] urine × [Cr ] plasma •M  echanical ventilation (respiratory alkalosis)
TRP =
1− •A  drenaline [epinephrine] (cellular shift)
[ P ] plasma [Cr ] urine
Step 2) lf TRP is ≤0.86, use the following: Box 4 - Fanconi Syndrome
= TRP × [ P ] plasma
TmP GFR There is no single test to diagnose Fanconi
syndrome. However, ↑ excretion of multiple amino
if TRP is >0.86, use the following instead: acids shown by urine amino acid analysis, as
0.3 × TRP well as concurrent glycosuria, hyperchloraemic
TmP GFR
= × [ P ] plasma metabolic acidosis and hypokalaemia, is
1 − ( 0.8 × TRP )
consistent with the diagnosis.

Box 5 - 25-OH vitamin D deficiency

Box 6 - Malabsorption/malnutrition
↓ Plasma 25-OH vitamin D may be consistent
There is no single test to diagnose malabsorption with deficiency. Concurrent blood ↓ Ca2+, ↑ PTH
and malnutrition. Risk factors include IBD, and ↑ ALP activity, particularly in the presence
poor diet, alcoholism, poor food intake, chronic of related symptoms and risk factors, is also
diarrhoea/vomiting etc. consistent with deficiency.

Figure 4 Suggested algorithm with supportive information for the laboratory investigation of hypophosphataemia. (A) Algorithm.

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Journal of Laboratory and Precision Medicine, 2024 Page 9 of 23

(B) Supporting information for the algorithm. Created by BioRender.com. TmP/GFP, tubular maximum reabsorption of phosphate;
PTH, parathyroid hormone; WBCs, white blood cells; FGF-23, fibroblast growth factor 23; TPN, total parenteral nutrition; TRP, tubular
reabsorption of phosphate; IBD, inflammatory bowel disease; IV, intravenous; ALP, alkaline phosphatase.

Table 2 Non-exhaustive list of treatments and medications that can cause hypophosphataemia
Mechanism of action Examples of drugs/therapies

Pseudohypophosphataemia Mannitol, liposomal amphotericin B

Proximal tubule injury (drug induced Fanconi Chemotherapy, e.g., cisplatin, ifosfamide, alkylating agents. New classes including
syndrome) nivolumab, ipilimumab, imatinib, vemurafenib

Hypomagnesaemia and hypocalcaemia leading to Antimetabolite agents, azacitidine, antacids

vitamin D resistance and PTH secretion

Inhibition of PDGF receptor expressed in bone Imatinib or sunitinib

and proximal tubular cells

Vitamin D deficiency/resistance Sorafenib, phenytoin, phenobarbital

Inhibition of IGF-1 receptor in proximal tubule Ceritinib

+
Downregulation of type 2a Na –phosphate Oestrogen
cotransporter in proximal tubule

Reduction of intestinal absorption Antacids, glucocorticoids, elemental feeds, PPIs, phosphate binders (e.g., aluminium
hydroxide), laxatives, calcium supplements

Increased concentration of FGF-23 Iron infusions (particularly FCM)

Shift of phosphate into cells Salicylic acid poisoning (leading to respiratory acidosis), glucose, dextrose, fructose,
insulin, parenteral nutrition, catecholamines, β-adrenergic drugs (e.g., salbutamol or
theophylline), EPO and GM-CSF (causing cell proliferation). Likely cause in neuroleptic
malignant syndrome (rare complication of typical and atypical antipsychotic drugs)

Increased urinary phosphate excretion Carbonic anhydrase inhibitors, diuretics (hydochlorthiazide, furosemide), theophylline,
bronchodilators, corticosteroids, bisphosphonates, aciclovir

Drug induced metabolic acidosis Alcohol and toluene

Unknown Paracetamol (acetaminophen)

PTH, parathyroid hormone; PDGF, platelet derived growth factor; IGF-1, insulin-like growth factor 1; PPIs, proton pump inhibitors; FGF-23,
fibroblast growth factor 23; FCM, ferric carboxymaltose; EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor.

Iron infusion (intravenous) The particular formulation of iron infusion significantly

A particularly topical and relatively recently appreciated affects the risk of iron induced hypophosphataemia. The
cause of hypophosphataemia is iron infusion (intravenous). highest risk is associated with ferric carboxymaltose (FCM)
The main mechanism is due to increased urinary phosphate (Ferinject ® , Injectafer ® )—which is associated with an
excretion as a consequence of increased concentrations of incidence of hypophosphataemia of 47% to 75%—compared
full length biologically active FGF-23 (53), which increases to an incidence of <10% with ferric derisomaltose (FDI)
three to six fold within the first day of infusion (54). (formerly known as iron isomaltoside 1000), ferumoxytol
The increased FGF-23 activity additionally decreases (FMX) (Feraheme ® ) and low molecular weight iron
1,25-dihydroxyvitmain D (53), resulting in the compounding dextran (LMWID) (INFeD ®, Cosmofer ®) (53). Blood
effect of reducing phosphate and calcium absorption from phosphate concentrations are usually lowest two weeks
the diet and secondary hyperparathyroidism. Iron infusion- after FCM administration, and hypophosphataemia
induced hypophosphataemia can be severe enough to cause can be difficult to correct and can persist for weeks to
fragility fractures and symptomatic osteomalacia (54-57). several months (54). Risk factors for severe iron infusion-

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Page 10 of 23 Journal of Laboratory and Precision Medicine, 2024

Table 3 Some age-related reference intervals for TmP/GFR and creatinine. There are two steps to the calculation.
Age Range Firstly, calculate the tubular reabsorption of phosphate
0 to <3 months 1.43–3.43
(TRP) using the equation in Figure 4B box 3. If the TRP
is ≤0.86, the renal reabsorption of phosphate is maximal
3 to <6 months 1.48–3.30
and there is a linear relationship between plasma phosphate
6 months to <2 years 1.15–2.60 concentration and urinary excretion, and the TmP/GFR
2 to 15 years 1.15–2.44 is simply calculated by multiplying the TRP by the plasma
phosphate concentration. However, if the TRP is >0.86, the
25 to 35 years
renal reabsorption of phosphate is not maximal and there
Male 1.00–1.35 is a curvilinear relationship between plasma phosphate
Female 0.96–1.44 concentration and urinary excretion. A different equation
45 to 55 years needs to be used to calculate TmP/GFR in these situations
(see Figure 4B box 3) (59). If phosphate is measured
Male 0.90–1.35
in mmol/L, the TmP/GFR is expressed as mmol/L of
Female 0.88–1.42 glomerular filtrate.
65 to75 years Table 3 displays age-related reference intervals for TmP/
Male 0.8–1.35
GFR (59). If the TmP/GFR is less than the age related
reference interval, inappropriate renal phosphate wasting
Female 0.80–1.35
is suggested, and renal causes of hypophosphataemia
From Payne (59). TmP/GFR, tubular maximum reabsorption rate should be explored (59). Normal/high TmP/GFR suggest
of phosphate to glomerular filtration rate.
appropriate renal reabsorption of phosphate, and non-renal
causes are more likely.

induced hypophosphataemia include lower baseline

serum phosphate, normal kidney function (poor kidney High urinary phosphate excretion (low TmP/GFR)
function reduces renal loss), severe iron deficiency, lower
High urinary phosphate excretion (low TmP/GFR) in the
body weight and repeated doses of iron infusion (53). See
presence of hypophosphataemia (indicating renal phosphate
Martens and Wolf (53) for more information.
wasting) demonstrates that physiologically inappropriate
renal handling of phosphate is the likely cause. DKA should
Urine phosphate measurement—tubular maximum always be considered and ruled out due to the clinical
reabsorption [tubular maximum reabsorption rate of urgency. DKA causes hypophosphataemia due to osmotic
phosphate to glomerular filtration rate (TmP/GFR)] diuresis from renal glucose excretion, leading to increased
urinary phosphate excretion. Treatment with insulin can
The concentration of phosphate in the urine depends exacerbate the low phosphate due to the shift from the
on t h e p la s m a c onc entra ti o n a nd the g l o mer ular extracellular to the intracellular compartment. DKA has not
filtration rate (GFR), assuming the renal tubules are been included in the algorithm in Figure 4 as the clinical
working maximally. A crude cut-off of <1 mmol/L of presentation is unlikely to cause diagnostic confusion (60).
phosphate in urine (from a 24-hour collection) during PTH analysis is a useful next step to determine
hypophosphataemia can be used to suggest that renal loss is if the inappropriate renal phosphate wasting is
not the cause of hypophosphataemia (58). However, during caused by hyperparathyroidism or something else.
hypophosphataemia, it is generally more reliable to calculate Hyperparathyroidism (primary and tertiary) is an important
the TmP/GFR to estimate if the urinary phosphate and common cause of renal phosphate wasting, detected
indicates inappropriate renal loss (phosphate wasting from by inappropriately normal or high PTH concentrations
renal causes) or appropriate renal reabsorption (non-renal in the presence of hypercalcaemia. Hyperparathyroidism
causes) (59). has been covered elsewhere; the reader is recommended to
To calculate the TmP/GFR, a second void early morning review the companion article in this series on calcium (6)
random/spot urine sample, and a plasma sample taken and other sources for a full discussion (7). Secondary
at a similar time, should both be analysed for phosphate hyperparathyroidism is notable as this diagnosis of exclusion

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Journal of Laboratory and Precision Medicine, 2024 Page 11 of 23

Table 4 Non-exhaustive causes of inherited and acquired causes of Fanconi syndrome, which can cause hypophosphataemia due to renal
phosphate wasting
Inherited Acquired

Wilson disease (↓ plasma copper, ↓ plasma caeruloplasmin, ↑ urinary Excessive immunoglobin light chain production in multiple
copper excretion) (63) myeloma, amyloidosis etc. (SPE, and UPE or SFLCs) (64)

Cystinosis (↑ intracellular cysteine in WBCs) (65) Renal transplant

Hereditary fructose intolerance (ALDOB genomic analysis, aldolase Nephrotic syndrome (↓ plasma albumin, ↑ plasma lipids, ↑ urinary
B activity on liver biopsy) (66) protein:creatinine ratio)

Galactosaemia (↓ Gal-1-PUT in RBCs, GALT/GALE/GALK genomic Drugs: cisplatin, gentamicin, azathioprine, valproate, etc. (62)
analysis) (67)

Tyrosinaemia (↑ blood succinylacetone) (68,69) Toluene exposure [glue sniffing] (70)

Glycogen storage disease [glycogenosis] (71,72)

Dent disease (73)

Brackets contain potentially useful additional tests to further investigate if suspected. SPE, serum protein electrophoresis; UPE, urine
protein electrophoresis; SFLCs, serum free light chains; WBCs, white blood cells; Gal-1-PUT, galactose-1-phosphate uridyl transferase;
RBCs, red blood cells.

is defined as a persistently elevated PTH concentration in the Tumour induced osteomalacia (TIO)
presence of normocalcaemia (7). Hyperphosphataemia (61) TIO—also known as oncogenic osteomalacia—is a rare
and FGF-23 dependent (62) hypophosphataemia stimulate syndrome characterised by the overproduction of FGF-23
PTH secretion, therefore phosphate metabolism issues usually (but not exclusively) by phosphaturic mesenchymal
may be the cause of secondary hyperparathyroidism. If tumours (PMTs) (64). Excess FGF-23 leads to decreased
the primary cause of secondary hyperparathyroidism is maximum TRP, which in turn leads to renal phosphate
not hyperphosphataemia (i.e., renal failure causes less wasting and hypophosphataemia (64). Over time, this
excretion of phosphate and PTH secretion is increased to phosphate wasting leads to osteomalacia/rickets due to
compensate), hypophosphataemia may be a consequence decreased bone mineralisation, and decreased muscle
of the secondary hyperparathyroidism from other causes function which can cause myopathy (64).
instead (e.g., due to calcium/vitamin D deficiency). TIO is notoriously difficult to accurately diagnose, and
time from symptom onset to diagnosis can be as high as
Fanconi syndrome 28 years (64). This is due to two main reasons. TIO
Fanconi syndrome is a general dysfunction of renal is largely a diagnosis of exclusion, and the FGF-23
proximal tubules, leading to excessive excretion (wasting) secreting PMTs can be difficult to locate as they can be
of amino acids, phosphate, glucose, bicarbonate, uric acid found anywhere in the body (64). Symptoms of TIO
and other solutes (63). Fanconi syndrome in children can include musculoskeletal pain, muscle weakness and bone
lead to excess phosphate loss and cause rickets. See Table 4 insufficiency fractures, which are usually a consequence of
for a non-exhaustive summary of inherited causes (which hypophosphataemia rather than the frequently small and
often present in young patients) and acquired causes of slow growing PMTs (64).
Fanconi syndrome (63). Due to its syndromic nature, there Laboratory tests and results useful to help to diagnose
is no single test to diagnose Fanconi syndrome, which is TIO include low TmP/GFR {section “Urine phosphate
often diagnosed when one of the conditions in Table 4 are measurement—tubular maximum reabsorption [tubular
diagnosed or met. Urine amino acid analysis can be helpful maximum reabsorption rate of phosphate to glomerular
to demonstrate excess urinary excretion of multiple amino filtration rate (TmP/GFR)]”}, high blood FGF-23, high
acids, which may be consistent with Fanconi syndrome. blood alkaline phosphatase (ALP), normal blood calcium,
Other findings which may suggest Fanconi syndrome in normal blood PTH and low blood 1,25-dihydroxyvitamin
the appropriate clinical context include hypokalaemia, D (which can in turn sometimes cause a high PTH via
glycosuria and hyperchloraemic metabolic acidosis (63). secondary mechanisms). Although FGF-23 analysis can

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Page 12 of 23 Journal of Laboratory and Precision Medicine, 2024

be of benefit in suspected cases, FGF-23 is currently Other causes of acquired increased urinary phosphate
not easily available in many parts of the world due to excretion (phosphate wasting)
difficulty with accurate quantification and poor assay Other (non-exhaustive) causes of acquired renal phosphate
standardisation, therefore the majority of available wasting leading to hypophosphataemia include hepatic
immunoassays are for research use only. In practice, TIO can resection (69) and severe burns requiring high volume
be diagnosed without FGF-23 analysis when other causes haemofiltration (70).
of hypophosphataemia—including vitamin D deficiency,
malabsorption, hyperparathyroidism, medications, poor diet,
Low urinary phosphate excretion (normal/high TmP-GFR)
Fanconi syndrome, hereditary forms of FGF-23 dependent
and independent causes of renal phosphate wasting, Low urinary phosphate excretion (normal/high TmP-GFR)
McCune-Albright syndrome etc.—have been excluded, in the presence of hypophosphataemia indicates that there
but locating a potential PMT can still be difficult (64). The is appropriate renal reabsorption of phosphate, suggesting
location of a potential PMT makes the diagnosis more that the primary abnormality is not the kidneys and is more
likely, but other causes of hypophosphataemia should still likely to be vitamin D deficiency, poor intake, malabsorption
be excluded as multiple factors can be present at the same or another cause outlined in Figure 4.
time. The diagnosis can often only be confirmed when
normophosphataemia occurs after the PMT is removed/ Vitamin D deficiency
destroyed. Due to the difficulty of diagnosing and treating If calcium is also low, vitamin D deficiency should be
TIO, suspected cases should be referred to specialist centres considered by assessing risk factors—including poor diet,
for diagnostic work up and management. poor sunlight exposure, high skin surface area coverage, etc.—
in the presence of other relevant presentations including bone
Post-renal transplant pain, bone malformation, high PTH, high ALP etc. Although
Hypophosphataemia presents in 40% to 90% of patients testing for 25-hydroxyvitamin D is available, routinely
one month after successful kidney transplant (65). The available immunoassays have limitations. For example,
exact mechanism is not completely understood and is 25-hydroxyvitamin D assays tend to measure the circulating
debated, but is likely due to a combination of tertiary concentration of total vitamin D, which includes the majority
hyperparathyroidism and chronically elevated FGF- (~85%) of vitamin D that is bound to vitamin D binding
23 leading to continued renal phosphate wasting post- protein (VDBP) (71). The ratio of VDBP-25-OH vitamin
transplant, as well as the increased incidence of vitamin D D complexes to free 25-OH vitamin D affects the overall
deficiency associated with this population group (65,66). biological activity of circulating vitamin D (72), therefore
Interestingly, factors associated with a good response to the the total circulating concentrations may not reflect the true
transplant—including pre-transplant hyperparathyroidism, physiological status. This is particularly true in patients
living kidney donor, lower donor age, etc.—are associated who have chronic inflammation (73), pregnant or are taking
with an increased incidence of post-renal transplant hormonal replacement therapy (74,75). In reality, testing for
hypophosphataemia (66). 25-OH vitamin D is not required to confirm deficiency as
normalisation of biochemical abnormalities, and alleviation
Vitamin D dependent rickets (VDDR) of relevant symptoms, after vitamin D replacement more
VDDR can be complex to diagnose and manage due to many accurately confirms vitamin D deficiency as the primary cause.
inherited and acquired causes, therefore suspected cases
should be referred to specialist centres. Hypophosphataemia Poor phosphate intake and malabsorption
is the causative abnormality in all forms of rickets (67). Although rare, poor dietary phosphate intake should be
Both calcipaenic and phosphopaenic rickets result in renal considered in some cases, particularly in patients with anorexia
phosphate wasting and hypophosphataemia. As phosphate nervosa and chronically high alcohol intake. Malabsorption
is required for the normal apoptosis of hypertrophic can also cause hypophosphataemia and can be caused by many
chondrocytes (68), the resulting hypophosphataemia different conditions including inflammatory bowel disease,
prevents growth plate maturation and directly causes the chronic diarrhoea, cystic fibrosis, pancreatic insufficiency,
clinical features associated with rickets. See Levine (67) for short bowel syndrome, etc. (76). Low dietary intake of
an open access overview of VDDR. phosphate only is likely a rare cause of hypophosphataemia (77),

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Journal of Laboratory and Precision Medicine, 2024 Page 13 of 23

and in extreme cases of malnutrition, hypophosphataemia to specialist centres for work up and management. For
is usually combined with multiple deficiencies including context and potential diagnostic direction, Table 5 outlines
vitamin D, exacerbating the presentation and biochemistry. some of the genetic causes of hypo- and hyperphosphataemia
Parenteral nutrition may exacerbate hypophosphataemia if (2,86-90).
not adequately balanced (78). There is no gold standard test
to diagnose poor dietary intake and malabsorption, therefore
Hyperphosphataemia
investigation of suspected cases needs to be guided by specific
patient presentations and other detectable abnormalities (76). Hyperphosphataemia can be defined as a blood phosphate
The work up of suspected malabsorption will not be discussed concentration >1.45 mmol/L (>5.00 mg/dL) (8). Severe
here as it has been comprehensively covered elsewhere (76). hyperphosphataemia can be loosely defined as a blood
phosphate concentration >2.00 mmol/L (>6.20 mg/dL) (8),
Transcellular shift of phosphate although factors including the speed of increase and
Many situations can lead to extracellular phosphate moving other relevant conditions will affect the clinical urgency.
into the intracellular compartment, leading to acute Hyperphosphataemia has a wide prevalence of between
hypophosphataemia. Panic attacks, which can present in 5.6% to 67.9% in critically ill patients depending on the
patients who are particularly needle phobic, can result in cause of illness (91). The prevalence in end stage renal
an acute respiratory alkalosis that can cause non-clinically failure (ESRF) is between 50% and 74% (92). Symptoms
significant hypophosphataemia (49). Metabolic alkalosis can are usually mild when chronic, but can cause symptoms of
also lead to hypophosphataemia by a similar mechanism hypocalcaemia—including seizures and tetany—when acute
of increasing the activity of phosphofructokinase, resulting due to calcium phosphate salt deposition in tissues (92).
in increased intracellular phosphate demand (79). RFS can There are three main categories of situations that can
result upon refeeding, both enterally and parenterally, after cause hyperphosphataemia. These include large phosphate
prolonged periods of malnutrition. There is no official defining load, inappropriate increased renal reabsorption, or
feature of RFS, but the majority of RFS studies use a low or renal failure (93). As with the majority of laboratory
decreasing phosphate as part of the diagnostic criteria (80), tests, false elevations should also always be considered
and hypokalaemia, hypomagnesaemia and low blood thiamine if the hyperphosphataemia is unexpected and does not
(vitamin B1) are also commonly present. Patients with a very fit the clinical picture in order to avoid unnecessary
low body mass index (<16 kg/m2), and patients who have had (and possibly dangerous) investigation and treatment. A
little or no nutritional intake for >10 days, are at particularly proposed algorithm for the laboratory investigation of
increased risk of developing RFS upon refeeding (81). hyperphosphataemia is shown in Figure 5.
Therefore, care must be taken when refeeding patients at
high risk, and national and local refeeding guidance should be
Pseudohyperphosphataemia
followed. Some of the drugs outlined in Table 2 can also cause
acute shifts of phosphate into cells. As phosphate is 100× more concentrated in red blood cells
As the name suggests, hungry bone syndrome (HBS) (RBCs) than in extracellular fluid (including the blood),
refers to translocation of minerals to bone, usually after any in vitro process which disturbs RBCs, or alters their
a definitive treatment such as parathyroidectomy for metabolism, can lead to spurious hyperphosphataemia.
hyperparathyroidism (82). A reduction in serum phosphate, For example, in vitro haemolysis causes the release of
calcium and magnesium is frequently seen. HBS is unlikely intracellular phosphate into the blood and can cause a
to cause diagnostic confusion because it is only seen after falsely high result (94), but this is usually easily identified
significant procedures, but is still important to identify and by laboratories due to the red colour of free haemoglobin
correct to avoid long term morbidity. in plasma. Delayed sample centrifugation and separation
of the plasma from the RBCs (4–6 hours) will cause
intracellular phosphate to leak into the blood (5), but this is
Genomic causes
not a reflection of the in vivo phosphate status.
The genomic causes of hypophosphataemia are numerous Although liposomal amphotericin B (antifungal)
and can be very complex to diagnose. These will not be therapy and the presence of a paraprotein (e.g., myeloma,
discussed in detail here as suspected cases should be referred Waldenstrom macroglobulinaemia etc.) have been

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Page 14 of 23 Journal of Laboratory and Precision Medicine, 2024

Table 5 Non-exhaustive summary of congenital causes of low and high plasma phosphate concentrations in humans. Note low TmP/GFR is
associated with renal phosphate wasting
Condition name Genetics and/or mechanism Low TmP/GFR FGF-23 1,25 Vit D PTH

Hypophosphataemia

Hereditary hypophosphataemic Autosomal recessive, loss of function of Present Low High Low/
rickets with hypercalciuria (HHRH) NPT2c (heterozygotes can have isolated normal
hypercalciuria)

Fanconi syndrome Damage of proximal tubule secondary to Present Low Low/ Low/
many different inherited conditions e.g., normal normal
cystinosis, tyrosinaemia

X-linked hypophosphataemia (XLH)a X-linked, loss of function of PHEX (which Present High Low/ Normal/
cleaves and thus inactivates FGF-23) normal high

Autosomal dominant Autosomal dominant, gain of function Present Highb Low/ Normal/
hypophosphataemic rickets (ADHR) FGF-23 (inactivating cleavage site is normal high
mutated, maintaining activity)

Autosomal recessive Autosomal recessive, loss of function Present High Low/ Normal/
hypophosphataemic rickets (ARHR) of DMP1 normal high

Hypophosphataemic rickets and Gain of function in α-klotho Present High Normal/ High
hyperparathyroidism high

Jansen’s metaphyseal Activating mutation of the PTH receptor Present High Normal Low/
chondrodysplasia (PTHR1) Normal

Polyostotic fibrous dysplasia GNAS1, abnormal osteogenic cells can Present High Low/ Normal/
associated with McCune-Albright release FGF-23 in approximately 50% normal high
syndrome

Autosomal recessive Autosomal recessive, loss of function Present High Normal Normal/
hypophosphataemic rickets type 2 causing deficiency of ENPP1 resulting in high
(ARHR2) increased FGF-23

Raine syndrome Autosomal recessive, loss of function Present High High High
FAM20C, kinase that acts on FGF-23 and
DMP1 among others

Hyperphosphataemia

Hyperphosphataemic familial Autosomal recessive, loss of function of Absent Low/normald Normal/ Normal
tumoural calcinosis (HFTC)c (83) FGF-23, unstable intact protein high

Autosomal recessive, loss of function of Absent Low/normald Normal/ Normal

GALNT3e, glycosylation defects lead to high
proteolysis and hence reduction of FGF-23

Autosomal recessive, loss of function in Absent High (very) High High

α-klotho
a
, previously/also known as adult-onset vitamin D resistant hypophosphataemic rickets. b, disease phenotype associated with FGF-23
concentration. c, there is an acquired autoimmune variant of this condition associated with antibodies to FGF-23 (83,84). d, in tumoural
calcinosis, all conditions have high concentrations of C-terminal fragments of FGF-23, but concentration of intact FGF-23 varies
(see table). Therefore, the results will depend on whether the assay measures both intact and C-terminal FGF-23 or intact only (85).
e
, hyperostosis-hyperphosphataemia syndrome (HHS) was found to be a clinical phenotype of tumoural calcinosi caused by identical
mutations in GALNT3. TmP/GFR, tubular maximum reabsorption rate of phosphate to glomerular filtration rate; FGF-23, fibroblast
growth factor 23; 1,25 Vit D, 1,25-dihydroxyvitamin D; PTH, parathyroid hormone; DMP1, dentin matrix acid phosphprotein 1; ENPP1,
ectonucleotide pyrophosphatase/phosphodiesterase-1.

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Journal of Laboratory and Precision Medicine, 2024 Page 15 of 23

A Fasting hyperphosphataemia Consider pseudohyperphosphataemia,

(↑ plasma PO43−) see box 1
Not applicable
Review treatments and medications, see box 2

Not applicable

Calculate eGFR - also consider AKI, see box 3

eGFR <30 or AKI eGFR ≥30 and no AKI

Renal impairment Consider cellular shift, see box 4

Not applicable
Low
Measure plasma PTH Measure plasma calcium

Low/normal High

• Pseudohypoparathyroidism
Hypoparathyroidism Normal/high
• Very ↑ phosphate intake

• Vitamin D toxicity (↑↑↑ 25-OH vitamin D)

• Thyrotoxicosis (↓ TSH)
• Granulomatous disease (syphilis and TB, chest x-ray, ACE/IL-2R)
• Acromegaly (↑ IGF-1, OGTT)
• Hyperphosphataemic familial tumoural calcinosis
• Myeloma (SPE, and SFLC or UPE)
• Bone metastasis (bone scan)
• Hypophosphatasia (↓ ALP, ↑ vitamin B6, ↑ urine phosphoethanolamine, genomics)

B Box 1 - Pseudohyperphosphataemia Box 2 - Treatments and medications

Most commonly caused by haemolysis or delayed Treatment and medications that can cause ↑ PO43−
sample centrifugation/separation. include:
• TPN (increased intake)
Although rare, a falsely ↑ PO43− result caused by • PO43− containing enema (increased intake)
paraprotein interference should be considered • PO43− containing laxative (increased intake)
if the result does not fit clinically. If possible, the • Vitamin D toxicity (increased intake)
presence of a paraprotein should be screened for by
requesting serum protein electrophoresis, and serum
free light chains OR urine protein electrophoresis. Box 3 - Renal impairment
Renal dysfunction is the most common cause of ↑
Box 4 - Cellular shift PO43−.
PO43− is predominantly an intracellular molecule, Measure blood creatinine and urea (blood urea
therefore any process which affects PO43− movement nitrogen) which are both elevated in chronic kidney
across cell membranes can cause ↑ PO43−. disease and acute kidney injury.
•A  cidaemia (↓ blood pH)
Measure urine albumin (high in chronic kidney
• Tumour lysis syndrome (↑ blood uric acid, ↓ blood
disease) and monitor urine output (low in acute
ionised Ca2+, ↑ blood K+)
kidney injury).
•R habdomyolysis (↑ blood CK, ↓ blood ionised
Ca2+, ↑ blood K+) See the Kidney Disease: improving global outcomes
• In vivo haemolysis (↓ blood ionised Ca2+, ↑ blood (KDIGO) guidelines for diagnosing and staging
K+, ↑ LDH, ↓ haptoglobin) chronic and acute kidney disease.

Figure 5 Suggested algorithm with supportive information for the laboratory investigation of hyperphosphataemia. (A) Algorithm. The
brackets include additional investigations and expected results that may be helpful to further investigate. (B) Supporting information for
the algorithm. eGFR, estimated glomerular filtration rate; AKI, acute kidney injury; PTH, parathyroid hormone; TSH, thyroid stimulating
hormone; TB, tuberculosis; ACE, angiotensin converting enzyme; IL-2R, interleukin 2 receptor; IGF-1, insulin-like growth factor 1;
OGTT, oral glucose tolerance test; SPE, serum protein electrophoresis; SFLC, serum free light chains; UPE, urine protein electrophoresis;
ALP, alkaline phosphatase; TPN, total parenteral nutrition; CK, creatine kinase; LDH, lactate dehydrogenase.

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Page 16 of 23 Journal of Laboratory and Precision Medicine, 2024

reported to cause pseudohypophosphataemia (see section in chronic and acute renal failure and adversely affects
“Pseudohypophosphataemia”), there are many more outcome (120,121). However, hyperphosphataemia in
case reports of these causing pseudohyperphosphataemia chronic renal failure is not a reliable finding, and differences
(36,83-85,95-111). This suggests that these situations in a population’s phosphate intake—e.g., in carbonated
more commonly cause falsely high rather than falsely low beverages—and food supplementation with vitamin D,
phosphate results. Analysis using a different phosphate may all affect the likelihood of developing the biochemical
method, or removal of potentially interfering paraproteins disturbance (122). If suspected, renal function should be
from serum (112), can identify false elevations of phosphate assessed by measuring blood creatinine (with or without
results from these causes. blood urea), and this is usually done at the same time as
Heparin and alteplase therapy have been implicated in blood phosphate assessment. The estimated glomerular
causing falsely high phosphate results (36). It is important filtration rate (eGFR) should be calculated to grade CKD,
that any dilutions of plasma in the laboratory are done with and an eGFR <30 mL/min/1.73 m 2 typically leads to
appropriate phosphate free media to avoid overestimating the hyperphosphataemia (although this can vary depending
in vivo concentration (113). Endogenous high concentrations on other factors) (123). AKI—which can be present with
of lipids and bilirubin have additionally been reported to an eGFR >60 mL/min and is defined by an acute change
cause pseudohyperphosphataemia (36), but similarly to in blood creatinine—can also be a renal failure cause of
haemolysis, laboratories should not release false results from hyperphosphataemia and should always be ruled out. See
these mechanisms as these interferences are detectable. the Kidney Disease: Improving Global Outcomes 2012
guidelines (124) for information on the diagnosis and
management of AKI.
Treatments and medications

Once pseudohyperphosphataemia has been excluded, the

Cellular shift
next step should be to review if any recent treatments
or medications may be the explanation. Patients on Causes of phosphate shift from the intracellular compartment
total parenteral nutrition (TPN) (114), or intravenous to blood—including tumour lysis syndrome, rhabdomyolysis,
replacement (115), should have their phosphate intake acidaemia and in vivo haemolysis—also frequently cause
assessed as this may need to be reduced if there is a low risk hyperkalaemia. See the hyperkalaemia section in the open
of RFS, particularly if there is concurrent CKD or acute access article on potassium in the previous series in the
kidney injury (AKI). Enemas and laxatives containing high journal (125) for more information.
concentrations of phosphate can cause acute and dangerous
hyperphosphataemia (116,117), although newer formulations
Calcium and PTH analysis
are less of a risk (118). Exogenous vitamin D toxicity can
cause hyperphosphataemia due its effect of increasing As a general guide during hyperphosphataemia, calcium
intestinal absorption. However, this is rare in practice due is usually low when PTH activity is inappropriately low.
to renal 1α-hydroxylation regulation, and plasma 25-OH If the measured PTH is inappropriately low/normal
vitamin D levels typically need to exceed 375 nmol/L during concurrent hypocalcaemia, this is consistent with
(150 ng/mL) for acute toxicity or be 125–375 nmol/L hypoparathyroidism [see calcium article within this series for
(50–150 ng/mL) for chronic toxicity (119). The diagnosis more information (6)]. If the measured PTH is high during
of vitamin D toxicity should be clinically led in the presence hypocalcaemia, this suggests that PTH is being appropriately
of relevant symptoms and history, and extra consideration secreted but it is not having the appropriate end organ effects
should be given to patients who are taking high doses of to increase calcium and decrease phosphate. This may be
supplements and have a granulomatous disease (sarcoidosis, consistent with pseudohypoparathyroidism which is a rare
lymphoma, tuberculosis) that can independently convert the end organ resistance to the effects of PTH, and can cause
25-OH vitamin D to active 1,25-dihydroxyvitamin D (119). a very similar biochemical pattern to hypoparathyroidism
with the exception of a high plasma PTH (126). If suspected,
GNAS mutations analysis may be helpful, but this is not
Renal failure
always required for a diagnosis (126) [see Linglart et al. (126)
Hyperphosphataemia is a well described phenomenon for more information]. Very high levels of phosphate

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Journal of Laboratory and Precision Medicine, 2024 Page 17 of 23

Table 6 Paediatric reference intervals for phosphate (mmol/L), split by sex in adolescence where noted
Age Lower limit Upper limit Sample size Lower confidence limits Upper confidence limits

0 to <15 days 1.8 3.4 408 (1.73, 1.90) (3.29, 3.47)

15 days to <1 year 1.54 2.72 288 (1.35, 1.63) (2.62, 2.79)

1 to <5 years 1.38 2.19 368 (1.29, 1.45) (2.11, 2.39)

5 to <13 years 1.33 1.92 704 (1.31, 1.35) (1.89, 1.95)

13 to <16 years

Female 1.02 1.79 95 (0.98, 1.06) (1.73, 1.84)

Male 1.14 1.99 95 (1.10, 1.17) (1.93, 2.04)

16 to <19 years 0.95 1.62 374 (0.87, 1.01) (1.58, 1.82)

Based on a CALIPER study (130) of healthy children and adolescents (newborn to 18 years of age) from a multiethnic population and
measured using the Abbott Architect analyser.

intake may also cause hyperphosphataemia and a high the receptors (see Table 5). Similarly to hypophosphataemia,
PTH in attempt to increase excretion of the excess, and genomic causes are complex to diagnose and should be
hypocalcaemia as the excess phosphate forms calcium referred to specialist centres for work up and management,
phosphate salts that are deposited in tissues (5). therefore they will not be discussed in detail here.

Other (including hypophosphatasia) Special states

Other, less common, causes of hyperphosphataemia are Paediatric

outlined in the final box in the flowchart in Figure 5A. The
Phosphate concentrations are higher in children and reduce
majority of these are very rare causes of hyperphosphataemia
as they get older (Table 6) until they reach adulthood. As
and more commonly cause hypercalcaemia, therefore the
phosphate requirements in infants is high due to rapid bone
reader is directed to the calcium article within this series
for further information (6). A particularly phosphate formation, phosphate deficiency can occur in breast fed
relevant diagnosis is hypophosphatasia, which is a very infants if the concentration of phosphate in human breast
rare genomic condition affecting the activity of tissue non- milk is low. Consequently, there is a higher risk if the mother
specific ALP (127). This can cause issues with bone and is hypophosphataemic before and during breast feeding (131).
teeth mineralisation, and can be diagnosed in child or
adulthood (127). The main biochemical feature of Pregnancy and lactation
hypophosphatasia is a persistently lower ALP activity than
expected for age, but hypophosphataemia is also frequently In a limited study in Africa, where various serum measurements
present (127). High blood pyridoxal 5’-phosphate (major were taken, phosphate concentrations in pregnancy did not
circulating form of vitamin B6) (128), and high urinary appear to change during various gestational stages (132,133).
excretion of phosphoethanolamine (urine amino acid An earlier study did not describe any phosphate concentration
analysis) (129), are consistent with (but not pathognomonic) changes during pregnancy, but did note an increase in
for hypophosphatasia, particularly in the presence of low phosphate concentration during lactation. A paper with the
ALP activity and relevant bone/teeth presentations. primary aim of assessing caffeine’s effect on vitamin D levels in
pregnancy demonstrated that phosphate levels are within the
reference interval during pregnancy (134).
Genomic causes

Inheritable hyperphosphataemia—called hyperphosphataemic

Conclusions
familial tumoural calcinosis (HFTC)—is primarily driven by
mutations reducing FGF-23 concentration or inactivation of This article presents a laboratory approach to help diagnose

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Page 18 of 23 Journal of Laboratory and Precision Medicine, 2024

the principal causes of phosphate disturbances after the K.E.S. served as the unpaid Guest Editor of the series
exclusion of commonly encountered false results. These and serves as the editorial board member of the Journal
algorithms provide a practical approach in daily clinical of Laboratory and Precision Medicine from September 2022
practice to help guide investigations and elucidate the to August 2024. N.J.L.G. declares consulting fees from
reasons for the biochemical derangement, but it is not a Takeda Pharma, Ascendis Pharma, and UCB Pharma, and
substitute for clinical assessment and expert guidelines; rare serves as Chair for the Royal Osteoporosis Society and the
genomic causes and abnormalities in children should be Specialised Endocrinology Clinical Reference Group for
referred to expert centres. National Health Service England Improvement, and as
The strength of this review is that it is based on Global Co-Chair for the PARADIGHM patient registry for
established practice and aimed at being applicable for most hypoparathyroidism (Takeda supported). The authors have
health care settings, focussed on common presentations, no other conflicts of interest to declare.
and accessible for all users. The limitations are that a critical
appraisal or systematic review were outside the scope Ethical Statement: The authors are accountable for all
of the article, and also that some special patient groups aspects of the work in ensuring that questions related
may not be well represented, e.g., neonatal. The cost and to the accuracy or integrity of any part of the work are
clinical efficiency of such proposed algorithms are therefore appropriately investigated and resolved.
unknown, but by providing the suggested approach, this
will allow pathways to be validated and the performance Open Access Statement: This is an Open Access article
quantified if implemented. We hope to provide a framework distributed in accordance with the Creative Commons
for clinicians to consider an approach to further diagnostics Attribution-NonCommercial-NoDerivs 4.0 International
when facing clinical conundrums related to abnormal License (CC BY-NC-ND 4.0), which permits the non-
phosphate results. commercial replication and distribution of the article with
the strict proviso that no changes or edits are made and the
original work is properly cited (including links to both the
Acknowledgments
formal publication through the relevant DOI and the license).
Funding: None. See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Intervals: A CALIPER Database of 40 Biochemical

doi: 10.21037/jlpm-24-35
Cite this article as: Flowers KC, Shipman KE, Shipman AR,
Gittoes NJL. Investigative algorithms for disorders causing
hypophosphataemia and hyperphosphataemia: a narrative
review. J Lab Precis Med 2024;9:33.

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