Hypophosphataemia

Hypophosphataemia is defined as a serum phosphate concentration < 0.8 mmol/L.

Hypophosphataemia is a common electrolyte abnormality that is often seen in patients with malnutrition and refeeding syndrome. It is estimated to affect up to 5% of patients admitted to hospital. 

The normal serum concentration of phosphate is 0.8-1.5 mmol/L. Hypophosphataemia is defined by a serum phosphate concentration <0.8 mmol/L.

In certain populations, hypophosphataemia is extremely common. In alcoholics it may be seen in up to 50%. In patients with paracetamol overdose it is a good prognostic markers that signifies hepatic recovery.

The human body contains approximately 1000 g of phosphate of which 80-90% is found in bone.

Phosphate is an essential ion for formation of nucleic acids, normal cellular function and bone mineralisation. The addition (by a kinase) or removal (by a phosphatase) of a phosphate molecule is important for the regulation of enzymes

Approximately 1000 g of phosphate is contained within the human body, which is distributed between different structures:

• Bone: 80-90%
• Intracellular: 10-14%
• Extracellular: 1%

Therefore, the concentration of serum phosphate does not reflect the proportion of total body phosphate. 

Dietary phosphate

Our normal daily intake of phosphate is 800-1500 mg.  Most foods contain phosphate and the majority is absorbed from the gastrointestinal tract (70-90%) with the remaining being excreted in faeces.

The absorption of phosphate, which predominantly occurs in the small intestines, may be blocked by aluminum-/calcium-/magnesium-containing antacids. This forms the basis of therapy in CKD.

Phosphate regulation

Phosphate is predominantly an intracellular ion with only 1% composing the extracellular pool. This extracellular concentration is closely regulated by diet, hormones (e.g. parathyroid hormone) and acid-balance.

Excess phosphate can be excreted by the kidneys in the proximal and distal convoluted tubules. The proximal convoluted tubule may also reabsorb phosphate in the context of low levels via a sodium phosphate cotransporter. The principle regulators of this process are vitamin D and parathyroid hormone (PTH). 

Vitamin D

• Activation of vitamin D enhances intestinal phosphate reabsorption
• Vitamin D deficiency or inhibition of activation decreases intestinal phosphate reabsorption

PTH

• High levels inhibits phosphate reabsorption in the kidneys, which promotes excretion
• Low levels promote phosphate reabsorption in the kidneys

PTH also leads to bone resorption, which leads to an increase in extracellular phosphate and calcium. In normal renal function, the increased inhibition of phosphate reabsorption causes a net loss of phosphate. However, in the context of renal impairment the bone resorption causes a net gain of phosphate leading to chronic hyperphosphataemia.

Other molecules more recently discovered to play a role in phosphate regulation include fibroblast growth factor 23 (FGF23), phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and stanniocalcin.

Hypophosphataemia is a common manifestation of refeeding syndrome.

Hypophosphataemia develops by four main mechanisms:

• Redistribution of phosphate
• Decreased absorption of phosphate (intestines)
• Increased excretion of phosphate (kidneys)
• Removal by renal replacement therapy (RRT): commonly encountered in intensive care in patients on continuous RRT

Redistribution of phosphate

Increased cellular metabolism leads to the rapid utilisation of phosphate, which transfers phosphate from the extracellular pool leading to hypophosphataemia.

There are three conditions commonly associated with this phenomenon

• Refeeding syndrome: this refers to rapid shifts in serum electrolytes following reintroduction of food after a period malnourishment or starvation. It can cause life-threatening arrhythmias and sudden death.
• Respiratory alkalosis: acute hyperventilation leads to a reduction in the plasma concentration of carbon dioxide, which raises the pH. A similar effect occurs intracellularly, which stimulates phosphofructokinase. This enzymes stimulates glycolysis leading to increased use of phosphate and withdrawal from the extracellular pool. Phopshate may fall < 0.32 mmol/L.
• Hungry bone syndrome: commonly seen post-operatively (e.g. after parathyroidectomy) in patients with preexisting primary or tertiary hyperparathyroidism. The chronic demineralisation of bone from high PTH means as soon as the PTH stimulus is removed there is rapid remineralisation with removal of serum phosphate and calcium.

Decreased absorption of phosphate

Poor oral intake or medications that inhibit phosphate absorption (e.g. antacids, phosphate binders, proton pump inhibitors) can lead to hypophosphataemia.

Poor oral intake leading to hypophosphataemia is usually combined with a concurrent pathology (e.g. diarrhoea), otherwise the extracellular phosphate concentration is relatively preserved. However, marked intracellular depletion of phosphate then occurs on reintroduction of diet with dangerous hypophosphataemia.

Increased excretion of phosphate

Phosphate excretion may be increased in primary or tertiary hyperparathyroidism due to the effect of PTH on the kidneys. Other causes can include vitamin D deficiency, drugs and inherited disorders (e.g. Fanconi syndrome).

NOTE: Fanconi syndrome refers to defective proximal tubule function and may be due to inherited or acquired causes

Hypophosphataemia can cause a wide range of clinical manifestations due to intracellular phosphate loss.

Low phosphate levels leads to marked reduction in the intracellular phosphate pool that affects normal cellular function. As all cells in the body rely on phosphate for intracellular mechanisms, it can lead to a wide range of problems including neurological, cardiopulmonary, musculoskeletal and haematological.

There are two principle problems associated with hypophosphataemia:

• Reduced 2,3-diphosphoglycerate (DPG): this is important for the release of oxygen to peripheral tissue. Reduced levels leads to less release from haemoglobin in peripheral gas exchange.
• Reduced adenosine triphosphate (ATP): this is the cellular energy currency. Without ATP, energy-rich cellular functions fail. 

These two mechanisms lead to organ dysfunction

• Neurological: irritability, altered mental status, paraesthesia, seizure, coma
• Cardiopulmonary: arrhythmias, increased ventilator requirement in intensive care
• Musculoskeletal: dysphagia, ileus and in severe cases rhabdomyolysis.
• Haematological: haemolysis, reduce white cell function and coagulation defects may be seen (usually rare features)

Severe hypophosphataemia can lead to profound weakness, altered mental status and rhabdomyolysis.

Clinical features usually depend on the severity and chronicity of hypophosphataemia. Acute severe hypophosphataemia, as seen in refeeding syndrome, can be life-threatening.

Mild hypophosphataemia

• Typically asymptomatic

Severe hypophosphataemia

• Lethargy
• Weakness
• Bone pain
• Altered mental status
• Neurological sequelae (e.g. paraesthesia, seizures)
• Ileus (smooth muscle)
• Rhabdomyolysis (skeletal muscle)
• Arrhythmias

The diagnosis of hypophosphataemia is based on a serum phosphate <0.8 mmol/L.

A bone profile will identify the reduced phosphate level and this is commonly requested in patients who are acutely unwell presenting to hospital or at risk of malnutrition.

Other blood tests may be useful to determine the underlying cause, which include:

• Full blood count
• U&E
• Bone profile
• Magnesium
• Parathyroid hormone
• Vitamin D levels
• Creatine kinase (if rhabdomyolysis suspected)
• Arterial blood gas (if respiratory alkalosis suspected)

All patients require an ECG as hypophosphataemia is associated with a prolonged QT interval and cardiac arrhythmias. Further investigations depend on the underlying cause and may include urinary phosphate levels in suspected tubular disorders. 

The management of hypophosphataemia involves oral or intravenous replacement.

It is important to determine and treat the underlying cause. This includes assessing a patients body mass index, malnutrition score and risk of refeeding syndrome. Usually short courses of replacement are enough to replace deficit, but more extended courses may be needed, especially if active refeeding.

If hypophosphataemia is due to vitamin D deficiency, the treatment is vitamin D.

Dosing

• Phosphate-Sandoz (1 tablet) = 16.1 mmol phosphate, 20.4 mmol sodium, 3.1 mmol potassium
• Polyfusor (500 mls) = 50 mmol phosphate, 81 mmol sodium, 9.5 mmol potassium.
• Glycophos (20-40 mls) = 20-40 mmol phosphate, 40-80 mmol sodium, 0 mmol potassium

Oral replacement

• Phosphate-Sandoz (indicated for phosphate 0.5-0.8 mmol/L): up to 6 tablets daily. Typical dose one tablet BD. 

Common side-effects of oral phosphate replacement are diarrhoea and abdominal discomfort.

Intravenous replacement

Intravenous doses of phosphate are recommended for severe or symptomatic hypophosphataemia (<0.5 mmol/L). Intravenous phosphate replacement is potentially dangerous due to precipitation with calcium leading to hypocalcaemia. Therefore, intravenous replacement is often given slowly over 6-24 hours. Always follow local protocols.

• Phosphate polyfusor 500 mls over 6-12 hours: Max flow rate 15 mmol per hour (150mL per hour). Max dose recommenced is 50 mmol in 24 hours. Less may be given depending on body weight and phosphate concentration.
• Glycophos (sodium glycerophosphate 21.6%) 20-40 mls: needs to be diluted in 500 mls of 0.9% sodium chloride or 5% dextrose. Given over 8 hours. May be first choice as national shortage of Phosphate polyfusor.

Patients unable to tolerate oral preparations usually require intravenous administration. Care should be taken in patients with reduced renal function as it can lead to hyperphosphataemia.

Monitoring

Patients at risk of refeeding syndrome need daily monitoring of phosphate levels in addition to magnesium and potassium. Replacement should continue as long as necessary and usually combined with parenteral B vitamins (e.g. Pabrinex).