5th April 2024

Disorders of Phosphate

The normal serum phosphate level in adults is 0.8 – 1.5 mmol/L. As it is present in all living organisms, a normal diet contains plenty of phosphate. Serum phosphate exhibits a circadian rhythm with a peak around 03:00 and a nadir around 11:00.

It is absorbed in the intestinal tract and reabsorbed by renal tubular cells with its uptake increased by vitamin D. 

Phosphate and calcium homeostasis in terms of bone content and renal excretion is regulated by parathyroid hormone, vitamin D, calcitonin and fibroblast growth factor 23.

Hypophosphatemia 

The three main ways significant hypophosphatemia (< 0.4 mmol/L) may result include inadequate intake; renal losses or through redistribution into cells.

• Inadequate intake:
  • Secondary to poor diet, eating disorders such as anorexia nervosa and alcohol dependency 
  • Malabsorption or recurrent vomiting 
  • Vitamin D deficiency
  • Use of phosphate binders such as aluminium hydroxide
• Renal losses:
  • Hyperparathyroidism – PTH reduces reabsorption at the proximal renal tubules
  • Renal tubular disorders – Fanconi’s syndrome and Dent’s disease
  • Vitamin D deficiency – including hypophosphatemic rickets
  • Drugs – aminoglycoside, cisplatin and tenofovir cause renal phosphate leak
  • Post renal transplantation – low phosphate is common, especially after a prolonged period of dialysis
  • Paraproteinemias and heavy metal poisoning that impair renal tubule function
  • Oncogenic osteomalacia 
• Redistribution:
  • Treating diabetic ketoacidosis – insulin drives phosphate into cells
  • Refeeding syndrome 
  • Acute respiratory alkalosis 
  • Hungry bone syndrome post parathyroidectomy
  • Lymphomas or leukaemia

Clinical manifestations

Many patients with mild (0.6 – 0.8 mmol/L) hypophosphatemia will report no specific symptoms. Common presentations include diaphragmatic, skeletal and cardiac muscle weakness, bone pain, altered mental status and rhabdomyolysis. Low phosphate states increase predisposition to haemolysis and thrombocytopenia. 

Severe and acute hypophosphatemia ( < 0.3 mmol/L) may present with focal neurological deficits, myalgia, congestive cardiac failure, seizures and altered mental status. 

If hypophosphatemia started from childhood, there may be short stature and bowed legs from rickets.

In an adult, marked hypophosphatemia with bone pain and excess urinary phosphate loss is suggestive of oncogenic osteomalacia.

Investigations

In addition to serum phosphate levels, calcium, magnesium and plasma protein should be taken. In the presence of low phosphate:

• Hypercalcaemia indicates hyperparathyroidism
• Hypocalcaemia suggest malabsorption, vitamin D deficiency or hungry bone syndrome
• Hypomagnesemia suggests dietary deficiency 
• Paraproteinaemia should be suspected in severe hypophosphatemia with high globulins and suspicious features such as bone pain; hypercalcaemia, reduced renal function and anaemia. 

Other investigations include:

• Renal function – renal tubular disease or extra renal causes can cause electrolyte abnormalities
• Liver function may show raised alkaline phosphatase due to osteomalacia in chronic hypophosphatemia
• PTH and vitamin D levels 
• Arterial blood gas to check for respiratory alkalosis
• Plasma bicarbonate and urate, urine glucose and amino acids if considering Fanconi’s syndrome
• X Rays of affected joints – Looser zones suggest osteomalacia 
• Bone scintigraphy can show increased uptake in multiple areas in severe osteomalacia 
• Ultrasound neck or technetium 99mTc scan to identify enlarged parathyroid or ectopic glands
• Dual energy xray absorptiometry (DEXA) bone density scan as chronic hypophosphatemia will result in loss of bone density

Management

Treatment depends on the cause, severity and duration of low phosphate. Mild hypophosphatemia can be treated with oral phosphate replacement. Parenteral phosphate is usually indicated when levels reach < 0.3 mmol/L with close monitoring of phosphate, calcium and renal function as there is a risk of hypocalcaemia, over treatment resulting in hyperphosphatemia and hyperkalemia. Those with poor renal function are at increased risk from intravenous replacement. 

Where low phosphate is secondary to Coeliac disease or Crohn’s, the underlying condition should be treated. Similarly, problems with alcohol dependency or eating disorders need appropriate input from specialist teams and in hyperparathyroidism, the causative tumour should be identified and removed.  In oncogenic osteomalacia, phosphate supplements are useful until the tumour has been found and removed. 

In vitamin D deficiency, oral vitamin D is usually sufficient but in severe renal disease where the kidneys are unable to convert hepatic hydroxyvitamin D3 to 1, 25 dihydroxy vitamin D3, active vitamin D should be given.

Hyperphosphatemia

The most common cause of hyperphosphatemia is renal failure as filtration of inorganic phosphate is significantly reduced when the glomerular filtration rate falls < 30 mL/min, increasing the serum phosphate concentration. Other causes include:

• Rhabdomyolysis
• Tumour lysis syndrome 
• Excessive use of phosphate containing laxatives/enemas
• Vitamin D intoxication increasing intestinal phosphate absorption
• Hypoparathyroidism, acromegaly and thyrotoxicosis enhance renal phosphate reabsorption 
• Tumoral calcinosis, which can be genetic or secondary, seen in patients undergoing renal dialysis
• Pseudohypoparathyroidism – characterised by resistance to PTH at its receptor and resultant hyperphosphatemia, hypocalcaemia and raised PTH levels. 

Pseudohyperphosphatemia is a laboratory artefact due to interference in phosphate assay and is sometimes seen in patients with hyperglobulinemia, hyperlipidaemia and hyperbilirubinemia.

Clinical manifestations

The majority of patients with hyperphosphatemia are asymptomatic with the underlying pathology contributing to presenting symptoms. 

Long term bone demineralization can result in bone fractures and raised phosphate levels may induce symptomatic hypocalcaemia resulting in:

• Tetany
• Muscle spasms
• Seizures
• Chvostek’s sign 
• Trousseau’s phenomenon

Calcium-phosphate complexes deposited throughout the body lead to ectopic vascular calcification and atherosclerosis. This results in hypertension and eventually, left ventricular hypertrophy.

Investigations

Diagnosis is made by measuring serum phosphate concentrations. Renal function, serum calcium, PTH levels, thyroid function tests and vitamin D levels provide useful information. As haemodialysis removes phosphate, if the patient is on renal replacement therapy, the timing between the last dialysis sessions and sampling is important. 

High calcium and phosphate levels with increased vitamin D levels indicates vitamin D intoxication.

Marked hyperphosphatemia with hyperkalemia; hyperuricemia and hypocalcaemia suggests tumour lysis syndrome.  

In rhabdomyolysis, serum uric acid and creatinine kinase levels are elevated while in tumour lysis syndrome, there is markedly raised serum uric acid but normal or slightly elevated creatinine kinase. 

Management 

In normal renal function, intravenous saline can facilitate renal elimination of excess phosphate. Dietary phosphate restriction and phosphate binders are used to avoid high phosphate levels in chronic hyperphosphatemia. Examples of phosphate binders include Sevelamer, Lanthanum carbonate, calcium carbonate and calcium acetate. 

Calcium based phosphate binders are most commonly prescribed as they also address hypocalcaemia which often accompanies hyperphosphataemia. However, the main concern is hypercalcaemia and accelerated vascular calcification, particularly when combined with vitamin D therapy. Non calcium based binders include Sevelamer and Lanthanum carbonate. A common side effect of phosphate binders is constipation. 

Haemodialysis may be indicated in severe cases of hyperphosphatemia with symptomatic hypocalcemia and impaired renal function.

References

• Phosphate replacement. UpToDate. Available at: https://www.uptodate.com/contents/search?search=phosphate
• Hypophosphatemia. Patient information professional article. Available at: https://patient.info/doctor/hypokalaemia