Hypophosphataemia

A low level of blood phosphate is defined as a level below 0.8mmol/L (the normal range should be given by the assaying laboratory but is about 0.8 to 1.4mmol/L in adults and slightly higher in children). Significant hypophosphataemia (below 0.4 mmol/L) may occur due to redistribution into cells, renal losses or decreased intake. Patients with low phosphate often also have hypokalaemia.¹

A normal diet contains plenty of phosphate, usually about 1000 mg a day and about two thirds is absorbed in the upper small intestine. Vitamin D increases uptake, and homeostasis in terms of bone content of phosphate and renal excretion are controlled by vitamin D, parathormone, sex hormones and acid base balance. In one study, nearly half of hospital patients with severe hypophosphataemia were unrecognised or inappropriately treated.²

• Inadequate intake:
  • Poor intake may be due to poor diet, including eating disorders such as anorexia nervosa, difficulty with chewing and swallowing, and alcoholism.
  • Malnutrition due to malabsorption or persistent vomiting.
  • The severely ill patient is most at risk when they starts to recover and move from a catabolic state to an anabolic state.
  • Vitamin D deficiency or resistance.
  • Gut phosphate binders, e.g. aluminium hydroxide.
• Increased renal excretion:
  • Hyperparathyroidism: parathormone reduces reabsorption by the proximal renal tubal.
  • High salt load causes reduced reabsorption of sodium by the proximal tubule but also reduced phosphate reabsorption.
  • Vitamin D deficiency, including hypophosphataemic rickets.
  • Renal tubular disorders, including Fanconi syndrome, Dent's disease.
  • Heavy metal poisoning and paraproteinaemias by impairing renal tubule function.
  • Oncogenic osteomalacia is a paraneoplastic syndrome of osteomalacia, hypophosphataemia, renal phosphate loss, bone pain, and muscle weakness.³ Several tumours can cause this but most are benign tumours of mesenchymal origin.
• Move from extracellular to intracellular compartment:
  • Treatment of diabetic ketoacidosis (insulin drives phosphate into cells).
  • Carbohydrate re-feeding after fasting. Other risks of re-feeding include low potassium, low magnesium and abnormal glucose metabolism.⁴ Low phosphate appears to increase insulin resistance.⁵
  • Acute respiratory alkalosis, especially with mechanical ventilation.⁶
  • The hungry bone syndrome follows treatment of vitamin D deficiency or after parathyroidectomy.

• Of patients in hospital, low phosphate occurs in about 1 to 5% but can reach 40 to 60% in diseases with high risk.
• Hypophosphataemia is more likely in alcoholism, diabetic ketoacidosis, burns and sepsis. It is a feature of the rare x-linked hypophosphataemic rickets.
• In adolescents it is often due to eating disorders but in older people it tends to be associated with alcoholism, malignancy or vitamin D deficiency.

A study of patients in general practice found that 8.3% of males and 12.1% of females had phosphate levels below the lower limit of their respective reference ranges. In 0.2% of results the plasma phosphate concentrations was 0.4 mmol/L or less in 0.2%. On follow-up, only 2 of these 18 patients had any attributable cause for their severe hypophosphataemia. In the remainder, it was unexpected and unexplained.⁷

• Most patients with hypophosphataemia have no specific symptoms or perhaps fatigue.
• Muscle weakness (diaphragmatic, cardiac and skeletal), bone pain, rhabdomyolysis, and altered mental status (confusion, hallucinations) are the most common presenting features.
• Severe acute hypophosphataemia may present with disorientation, seizures, focal neurological deficits, congestive heart failure, and muscle pain
• Syndromes of chronic phosphate loss usually present with bone pain, muscular weakness and skeletal disorders.
• Markedly low phosphate with bone pain and excessive phosphate loss in urine in an adult suggests an oncogenic osteomalacia.

Examination

• There are usually no physical signs.
• If hypophosphataemia starts in childhood, there is usually short stature and perhaps bowed legs from rickets.
• In adults firm palpation of bones may show tenderness.

• Calcium, phosphate, magnesium, plasma proteins: in the presence of low phosphate, high calcium suggests hyperparathyroidism, low calcium suggests lack of vitamin D or malabsorption and low magnesium suggests dietary deficiency.
• Liver function tests may show elevated alkaline phosphatase.
• Parathormone (PTH) and vitamin D levels.
• If respiratory alkalosis is considered, arterial blood gases are required.
• If renal loss is considered, 24-hour urine for phosphate content.
• If Fanconi syndrome is considered, get plasma bicarbonate and urate and test urine for glucose and amino acids. A full Fanconi syndrome consists of renal glycosuria, aminoaciduria, renal tubular acidosis, low blood urate due to high urinary loss, and excessive urinary loss of phosphate.
• X-rays can help evaluate osteopenia, osteomalacia, or hyperparathyroidism. Looser zones suggest osteomalacia. Erosions of the distal phalanges and clavicles and circular punched-out lesions in the long bones are typical of primary hyperparathyroidism.
• Ultrasound of the neck may help identify enlarged parathyroid glands but 99mTc scanning can be more accurate and easier to locate ectopic glands.
• DEXA scan: chronic phosphate deficiency will cause loss of bone density.
• If x-rays are inconclusive, bone biopsy may be required.

Mild hypophosphataemia often resolves without treatment but severe hypophosphataemia may cause diaphragmatic weakness requiring artificial ventilation.

• Treatment is dependent upon cause, severity and duration.
• Phosphate supplements:
  • Phosphate supplements should be given where hypophosphataemia may be anticipated as in re-feeding after anorexia, starvation or alcoholism.
  • Usually oral phosphate is well tolerated although very high doses may cause diarrhoea.
  • Where there is an acute situation or lack of intestinal function, parenteral phosphate may be used but this is much more dangerous and requires monitoring of calcium and phosphate levels every 6 hours.
  • After phosphate levels have returned to normal there remains a risk of them falling over the next few days.⁸
  • In septic shock, the rapid correction of hypophosphataemia improves myocardial contractility and helps to maintain circulation.⁹ It may also improve the respiratory function of the critically ill.¹⁰
• In coeliac disease or Crohn's disease the underlying disease should be treated but vitamin D supplements may be required.
• Oral phosphate supplements may be beneficial in genetic disorders that lead to urinary phosphate loss although they do not correct the underlying abnormality. Monitor blood calcium and phosphate, bone density and growth.
• In oncogenic osteomalacia, phosphate supplements are useful until the tumour has being identified and removed.
• Vitamin D deficiency is usually treated with oral vitamin D but in severe renal disease the kidneys may be unable to convert hepatic 24 hydroxyvitamin D-3 to 1,25 dihydroxyvitamin D-3 and so this form may need to be given.
• Hyperparathyroidism requires identification and removal of the offending tumour.
• After renal transplantation, addition of pH neutral oral phosphate may be beneficial.¹¹
• Patients with diabetic ketoacidosis are at high risk of developing hypophosphataemia but the value of parenteral phosphate is uncertain.¹²

• Acute hypophosphataemia can produce seizures, delirium, coma, or focal neurological findings.
• There may be heart failure, rhabdomyolysis, acute haemolysis, leucocyte dysfunction, and abnormal liver function tests.
• Heart failure, rhabdomyolysis, and haemolysis can produce acute renal failure.
• Leucocyte dysfunction increases susceptibility to infection.
• They can also exhibit platelet dysfunction, glucose intolerance, and metabolic acidosis.
• Chronic hypophosphataemia due to phosphate loss causes mostly bone pathology.
• In children, rickets leads to short stature and bony deformities with abnormal bone mineralisation.
• Adults may develop osteomalacia with severe bone pain and fractures.

• Problems such as alcoholism and eating disorders require intervention and possibly psychiatric help.
• Congenital phosphate wasting syndromes require long term supplementation.
• Correction of acute hypophosphataemia tends to leave no long term complications but failure to recognise and treat an acute, severe situation can lead to fatality.
• X-linked hypophosphataemia rickets and vitamin D-resistant rickets are only incompletely treatable and result in lifelong skeletal deformities.

Those at high risk, such as alcoholics requiring inpatient detoxification and patients who have just had parathyroidectomy, should be monitored and given appropriate oral or parenteral supplementation if required.