Investigating hypophosphataemia
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g3172 (Published 28 May 2014) Cite this as: BMJ 2014;348:g3172
- Paul Glendenning, clinical associate professor12,
- Damon A Bell, associate professor12,
- Roderick J Clifton-Bligh, associate professor3
- 1School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, WA, Australia
- 2Department of Clinical Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, WA, Australia
- 3Kolling Institute Royal North Shore Hospital, St Leonards, NSW, Australia
- Correspondence to: P Glendenning, Department of Clinical Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital, Perth, WA 6000, Australia Paul.Glendenning{at}health.wa.gov.au
Learning points
Chronic or mild hypophosphataemia is often asymptomatic or may present with non-specific symptoms; severe cases may present with myopathy, respiratory or cardiac failure, altered mentation, haemolysis, or rhabdomyolysis
Beware of spurious preanalytical or analytical causes of hypophosphataemia such as a non-fasting sample or paraproteinaemia
Useful initial tests include serum electrolytes (potassium, bicarbonate, magnesium, and calcium) to assess for renal tubular disease or extrarenal causes
Check ionised calcium, parathyroid hormone, and 25 hydroxyvitamin D if the cause is unknown or if musculoskeletal symptoms, hypomagnesaemia, or hypoalbuminaemia are present
Referral for specialist management is advised if the cause of hypophosphataemia remains uncertain, severe (<0.3 mmol/L), or symptomatic, or if there is a family history of short stature or skeletal deformities consistent with rickets
A 55 year old man with a squamous cell carcinoma of the head and neck was investigated before referral for chemotherapy. He was asymptomatic and not taking any drugs. Blood test results showed phosphate 0.7 mmol/L (reference limit 0.8-1.5) and total calcium 2.34 mmol/L (2.15-2.60).
The concentration of circulating phosphate depends on intestinal absorption, renal handling, and skeletal storage, and consequently is regulated by parathyroid hormone, vitamin D, and fibroblast growth factor 23. Internal cellular redistribution of phosphate is also important and results in hypophosphataemia under specific circumstances. The box outlines the causes of hypophosphataemia, based on the physiological regulation of phosphate metabolism.
Possible causes of hypophosphataemia
Extrarenal (common)
Gastrointestinal—reduced intestinal absorption; insufficient oral, enteral, or parenteral phosphate intake
Increased intracellular sequestration (common)—refeeding syndrome; leukaemia or lymphomas; bone matrix uptake (hungry bone syndrome); diabetic ketoacidosis; respiratory alkalosis
Renal
Parathyroid hormone dependent (common)—primary, secondary, or tertiary (chronic kidney disease) hyperparathyroidism
Fibroblast growth factor 23 dependent causes (rare)—acquired (tumour induced osteomalacia) or inherited
Primary renal phosphate leak—acquired (common): drugs (for example, aminoglycosides, cisplatin, tenofovir), heavy metal poisoning or antacids containing magnesium, aluminium, or zinc), toxins, or Fanconi syndrome; inherited (rare)
Chronic or mild hypophosphataemia (plasma phosphate 0.6-0.8 mmol/L; 1.86-2.5 mg/dL) may be asymptomatic and therefore can be easily overlooked. A history outlining recent bone pain, muscle weakness, use of prescription drugs (including aminoglycosides, cisplatin, tenofovir), or exposure to toxins, heavy metals, or antacids containing magnesium, aluminium, and zinc, should be obtained. Inquiring about a family history of skeletal disease is important.1 Short stature skeletal deformities consistent with rickets, such as bowed extremities, widened wrists, cranial and chest deformities, or a familial history of hypophosphataemia or rickets should alert clinicians to a heritable cause. X linked hypophosphataemic rickets is, however, rare, occurring in 1 in 20 000 live births but accounting for more than 80% of familial disease.
What are the next investigations?
The next investigations are to consider preanalytical causes or analytical interference; to measure electrolytes, including potassium, bicarbonate, magnesium, and calcium; and to assess ionised calcium, parathyroid hormone, and vitamin D under certain circumstances. The figure⇓ outlines a suggested approach to the investigation of hypophosphataemia.
Hypophosphataemia is relatively uncommon but can occur in up to 5% of patients admitted to hospital.2 In certain clinical settings such as alcoholism, sepsis, malnutrition, or intensive care, however, the incidence of acute hypophosphataemia may be as high as 30-50%, due to a combination of phosphate redistributed between extracellular and intracellular compartments, low phosphate intake, or reduced intestinal absorption of phosphate.3 Patients with severe hypophosphataemia (plasma phosphate <0.3 mmol/L; <0.93 mg/dL) more commonly have clinical symptoms or signs, including muscle weakness or bone pain. The diagnosis should also be considered in certain clinical circumstances: respiratory or cardiac failure, haemolysis, altered mentation, and myopathy or rhabdomyolysis, which could present with muscle pain.
Consider preanalytical causes or analytical interference
Preanalytical factors that may cause spurious hypophosphataemia include those related to biology (age), physiology (acid base or fasting status), and sampling (for example, plasma versus serum sample or delayed sample testing). Hypophosphataemia in an adult is defined as a plasma phosphate concentration of less than 0.8 mmol/L. Newborn infants and young children have a higher reference limit, and therefore age specific intervals are necessary. Spurious hypophosphataemia can occasionally occur in the presence of paraproteinaemia and transiently with respiratory alkalosis or after meals. Paraproteinaemia should be considered if the serum globulin level is increased, hypophosphataemia is severe, or there are other suspicious clinical symptoms or signs such as anaemia, renal dysfunction, bone pain, or hypercalcaemia. Light chain paraproteins are directly toxic to the renal tubule and may cause true hypophosphataemia as a result of acquired Fanconi syndrome (proximal tubulopathy resulting in failure to reabsorb phosphate as well as other nutrients). Phosphate levels are marginally lower in serum than in heparinised plasma and there is some diurnal variation, but neither accounts for major changes in phosphate concentration. Even if mild, persistent hypophosphataemia should be investigated because more serious diagnoses (such as inherited or malignant causes) could be missed. Delayed sample separation or haemolysis can falsely increase phosphate levels and mask the diagnosis of hypophosphataemia.
Case review
A plasma sample was collected from the patient after an overnight fast to retest his phosphate level. The test result was within reference limits.
The patient re-presented to an emergency department seven days after the fourth dose of chemotherapy with severe muscle pain and weakness. He was only taking paracetamol (acetaminophen). Serum creatine kinase was appreciably increased, at 4600 U/L (30-170). The patient had no history of paraesthesias or seizures and no bone tenderness or deformity on clinical examination. Other initial blood investigations included serum creatinine 89 µmol/L (60-110), estimated glomerular filtration rate 74 (90-120), phosphate 0.25 mmol/L (0.8-1.5). Severe hypophosphataemia is the most likely cause of rhabdomyolysis and this degree of hypophosphataemia makes a preanalytical cause unlikely.
Check electrolytes, including magnesium and calcium plus renal function
Serum electrolytes, magnesium, and calcium should be assessed, as renal tubular disease or extrarenal causes are common and may result in deficiencies of other electrolytes. Dietary intake of phosphate is typically more than sufficient to meet daily requirements unless severe malnutrition is present. However, chronic diarrhoea can cause hypophosphataemia by reducing intestinal absorption of phosphate, and steatorrhoea may be associated with hyperparathyroidism secondary to vitamin D deficiency resulting in parathyroid hormone induced renal phosphate wasting. Antacids that contain magnesium, zinc, or aluminium may reduce phosphate absorption by the formation of insoluble complexes.
Rapid redistribution of intracellular phosphate can cause sudden onset hypophosphataemia in certain clinical scenarios: treatment of diabetic ketoacidosis; hungry bone syndrome, which can occur after parathyroidectomy for severe hyperparathyroidism; sudden rapid cell formation, which occurs in certain haematological malignancies; and refeeding after malnutrition.4 5 A reduced serum calcium indicates possible hungry bone syndrome.
Case review
The results of subsequent investigations were: sodium 136 mmol/L (134-146), potassium 2.6 mmol/L (3.4-5.0), bicarbonate 26 mmol/L (22-32), urea 2.8 mmol/L (3.0-8.0), creatinine 89 µmol/L (60-110), estimated glomerular filtration rate 74 (90-120), albumin 24 g/L (35-50), magnesium 0.6 mmol/L (0.7-1.1), and adjusted total calcium 2.49 mmol/L (2.15-2.60).
In this patient the degree of hypophosphataemia was severe and the coexistent less severe hypokalaemia along with hypomagnesaemia in the context of known cancer and treatment are highly suspicious of refeeding syndrome. Refeeding syndrome results in multiple changes to electrolytes that may occur when nutrition is administered after a period of low or absent oral intake. The patient’s low serum urea and albumin levels reflect recent malnutrition. Electrolyte changes are more common in people with a low body mass index and prolonged malnutrition, including those with malnutrition, anorexia nervosa, HIV, chronic alcoholism, or cancer. Electrolyte changes may occur after as little as 48 hours of impaired oral intake. Enteral or parenteral carbohydrate preparations are the most common precipitants because they induce glycolysis and as a consequence there are large, sudden, and non-sustainable increased requirements for phosphate worsened by the redistribution of phosphate between extracellular and intracellular compartments. Hypophosphataemia is almost universal (>95%) in patients with refeeding syndrome; half of cases also experience hypomagnesaemia or hypokalaemia, and hypocalcaemia occurs in approximately a quarter of cases.6 Refeeding syndrome is often clinically mild, but severe muscle weakness, paraesthesias, congestive heart failure, arrhythmias, and cardiac arrest have been described.
Check ionised calcium, parathyroid hormone, and vitamin D
When hypophosphataemia occurs in the presence of musculoskeletal symptoms, hypomagnesaemia, or hypoalbuminaemia, or the cause is still unknown, then ionised calcium, parathyroid hormone, and vitamin D should be assessed. Calcium and phosphate homeostasis are important, as both are essential for cellular function, predominantly stored in bone, and regulated by the same factors: parathyroid hormone, vitamin D, and fibroblast growth factor 23.7
Measurement of calcium and parathyroid hormone are important to exclude primary and secondary hyperparathyroidism, as both can present with hypophosphataemia. In case series, ionised calcium identified 25% more cases of primary hyperparathyroidism than did either total calcium or albumin adjusted total calcium, especially in the presence of major hypoalbuminaemia (as in this case), critical illness, or chronic kidney disease.8 According to a large observational case series, approximately 10-20% of patients with primary hyperparathyroidism will have hypophosphataemia, although it is usually mild.9 In a recent case series, phosphate levels were appreciably lower in patients with 25 hydroxyvitamin D (25(OH)D) <60 nmol/L and therefore concomitant vitamin D deficiency and primary hyperparathyroidism may present more commonly with hypophosphataemia.10
Secondary hyperparathyroidism in association with severe vitamin D deficiency leads to hypophosphataemia, hypocalcaemia, and osteomalacia, with a characteristic finding of increased alkaline phosphatase levels and muscle weakness.11 The threshold 25(OH)D concentration that is associated with osteomalacia is debated but current consensus suggests that osteomalacia occurs with prolonged moderate or severe vitamin D deficiency (25(OH)D <30 nmol/L). Conversely, under-mineralised bone is rare when 25(OH)D concentration is >50 nmol/L.12
In patients with chronic kidney disease, secondary hyperparathyroidism typically occurs before appreciable changes in serum calcium or phosphate levels. In view of the respective hormonal changes and the decline in nephron mass, hypophosphataemia does not occur in early chronic kidney disease. Hypophosphataemia is, however, reported often in patients after transplantation for end stage renal disease and is attributed to autonomous parathyroid function (tertiary hyperparathyroidism).13
Case review
Subsequent investigations revealed: 25(OH)D 55 nmol/L (reference limit >50 nmol/L), parathyroid hormone 6.4 pmol/L (1.2-7.8), and ionised calcium 1.22 mmol/L (1.12-1.30).
An ionised calcium within reference limits helped to exclude primary parathyroid disease, especially in the presence of severe hypoalbuminaemia. Measurement of ionised calcium may not always be available in regional centres, although most tertiary hospital laboratories will offer this service. Timely analysis is required for optimal interpretation.
Case review
This patient’s result for urine TmP/GFR was >0.8 mmol/L, excluding renal phosphate wasting and supporting the diagnosis of refeeding syndrome.
What subsequent specialist investigations are appropriate?
Patients need to be referred for specialist management if the cause is uncertain, hypophosphataemia is chronic, severe (phosphate <0.3 mmol/L), or symptomatic, and is accompanied by short stature or skeletal deformities consistent with rickets, or a family history of skeletal deformities or hypophosphataemia. If hypophosphataemia is mild and the diagnosis is clear, continued monitoring is appropriate in such cases. Measurement of urine phosphate with calculation of TmP/GFR (renal tubular phosphate reabsorption) is useful, and serum fibroblast growth factor 23 should be measured if TmP/GFR is reduced—that is, when renal phosphate wasting is present.
Urine phosphate and calculation of TmP/GFR
Assessment of urine phosphate excretion helps to determine if the cause is due to renal phosphate wasting. TmP/GFR requires the measurement of phosphate and creatinine in a fasting plasma sample and second voided urine sample in the morning.14 TmP/GFR approximates the fraction of filtered phosphate that appears in the urine, is determined by nomogram or algorithm, and normative reference limits are age and sex specific, although in adults the reference limits for TmP/GFR are approximately the same as for plasma phosphate.15 A low urine TmP/GFR indicates renal phosphate wasting, which may be due to hyperparathyroidism, increased fibroblast growth factor 23 levels, or a primary renal tubular process such as Fanconi syndrome.
Measuring fbroblast growth factor 23 if urine TmP/GFR is reduced
Fibroblast growth factor 23 is the phosphaturic substance produced by mesenchymal tumours associated with osteomalacia and the gene responsible for autosomal dominant hypophosphataemic rickets.16 Fibroblast growth factor 23 is typically increased in tumour induced osteomalacia but low in more common causes of hypophosphataemia with renal phosphate wasting, such as drug induced tubulopathies or Fanconi syndrome (see box). The diagnosis of tumour induced osteomalacia is often delayed owing to small tumour size, scattered location, and clinical inattention to hyphophosphataemia as the cause of bone pain and muscle weakness.15 16
Outcome
The patient began eating a solid diet 10 days before attendance after resolution of dysphagia following chemotherapy treatment. Consequently, he represented one of the higher risk groups for refeeding syndrome. The presence of reduced albumin and urea were consistent with recent malnutrition, and the acute onset of symptomatic hypophosphataemia with rhabdomyolysis and coexistent hypokalaemia and hypomagnesaemia were consistent with refeeding syndrome. In view of the severity of hypophosphataemia and symptoms, intravenous replacement was started. Plasma phosphate and serum magnesium, potassium, and creatine kinase normalised uneventfully and muscle symptoms resolved within seven days.
Notes
Cite this as: BMJ 2014;348:g3172
Footnotes
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor, head of department of academic endocrinology, diabetes, and metabolism, Hull York Medical School; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at practice@bmj.com.
Contributors: Each author contributed to the literature search, article content, and editing. PG collated each contribution, edited the final version, and all authors approved the version submitted for publication. PG is the guarantor.
Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent: Patient consent not required (patient anonymised, dead, or hypothetical).