Hipofosfatemia

Los rangos de referencia para el fosfato sérico varían entre los laboratorios. El rango normal en adultos generalmente se considera de 0.8-1.5 mmol/L. El rango normal en niños está relacionado con la edad. El Royal College of Paediatrics and Child Health cita esto como 1.3-2.6 mmol/L (<1 año) y 0.9-1.8 mmol/L (1-16 años).

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 other electrolyte deficiencies.¹

A normal diet contains plenty of phosphate, as it is present in all living organisms. Normal dietary intake varies according to age and other physiological factors (eg, pregnancy). The recommended daily intake for children aged 1 year is 460 mg whilst for a 50-year-old adult it is 700 mg. Phosphate is absorbed in the intestinal tract.² Normalmente, la mayor parte de esto es reabsorbido por las células tubulares renales. La vitamina D aumenta la absorción, y la homeostasis en términos del contenido óseo de fosfato y la excreción renal es controlada por la vitamina D, la hormona paratiroidea (PTH) y el factor de crecimiento de fibroblastos 23 (FGF23).³

Causes of hypophosphataemia (aetiology)

• Ingesta inadecuada:
  

  • Poor intake may be due to poor diet, including eating disorders such as anorexia nervosa, difficulty with chewing and swallowing, and alcohol dependency.

  • Malnutrition due to malabsorption or persistent vomiting.

  • The severely ill patient is most at risk when they start to recover and move from a catabolic state to an anabolic state.

  • Deficiencia de vitamina D.

  • Gut phosphate binders - eg, aluminium hydroxide.

• Aumento de la excreción renal:
  

  • Hiperparatiroidismo: PTH reduces reabsorption by the proximal renal tubule.

  • 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's syndrome, Dent's disease.

  • La hipofosfatemia es común después de renal transplantation, especially after long periods of dialysis.

  • Drugs causing renal phosphate leak, including aminoglycosides, cisplatin and tenofovir.

  • Hypophosphataemia is a common complication of some formulations of intravenous iron therapy, caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23. Serum phosphate concentrations should be monitored in patients receiving repeated doses of intravenous iron formulations.⁴

  • 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. It is caused by excessive synthesis and secretion of FGF23, a phosphaturic hormone that is normally produced by osteocytes.⁵ Varios tumores pueden causar esto, pero la mayoría son tumores benignos de origen mesenquimal.

• Moverse del compartimento extracelular al intracelular:
  

  • Tratamiento de cetoacidosis diabética (la insulina impulsa el fosfato hacia las células).

  • Síndrome de realimentación - realimentación con carbohidratos después del ayuno. Otros riesgos de la realimentación incluyen bajo potasio, bajo magnesio, bajo calcio y metabolismo anormal de la glucosa.

  • Agudo respiratory alkalosis.

  • The hungry bone syndrome (increased uptake by bone matrix) which occurs after parathyroidectomy.⁶

  • Leukaemia or lymphomas.

How common is hypophosphataemia? (Epidemiology)

• La hipofosfatemia es rara en la población general, pero relativamente común en pacientes hospitalizados (2.2-3.1%) y aún más alta en aquellos en unidades de cuidados intensivos (45% de todos los pacientes hospitalizados), aquellos con sepsis (65-80%), aquellos con dependencia crónica del alcohol (30-40%), aquellos con trauma mayor (56-75%) y aquellos con enfermedad pulmonar obstructiva crónica (20%).^{7 8 9}

• Hypophosphataemia is more likely in alcohol dependency, diabetic ketoacidosis, burns and sepsis. It is a feature of X-linked hypophosphataemic rickets. This is rare, occurring in 1 in 20,000 live births.⁵

• In adolescents it is often due to eating disorders but in older people it tends to be associated with alcohol dependency, malignancy or vitamin D deficiency.

Symptoms of hypophosphataemia (presentation)

• Chronic or mild hypophosphataemia may be asymptomatic (phosphate levels 0.6-0.8 mmol/L).⁸ La mayoría de los pacientes con hipofosfatemia no presentan síntomas específicos o quizás fatiga.

• Muscle weakness (diaphragmatic, cardiac and skeletal), bone pain, rhabdomyolysis, and altered mental status (confusion, hallucinations) are the most common presenting features.

• Severe acute hypophosphataemia (level <0.3 mmol/L) 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.

Examen

• 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.

• Hepatomegaly may indicate chronic alcohol dependency or underlying malignancy.

Diagnosing hypophosphataemia (investigations)¹⁰

• Calcium, phosphate, magnesium, plasma proteins - in the presence of low phosphate:

  • High calcium suggests hyperparathyroidism.

  • Low calcium suggests lack of vitamin D or malabsorption, or hungry bone syndrome.

  • Low magnesium suggests dietary deficiency.

  • Consider paraproteinaemia if high globulins, severe hypophosphataemia with suspicious features such as anaemia, bone pain, renal dysfunction or hypercalcaemia.

• Renal function and electrolytes: renal tubular disease or extra renal causes commonly cause electrolyte disturbance.

• Liver function tests (LFTs): may show elevated alkaline phosphatase in chronic hypophosphataemia due to osteomalacia. They may also indicate chronic alcohol dependency.

• PTH and vitamin D levels.

• If respiratory alkalosis is considered, arterial blood gases are required.

• If renal loss is considered, fasting morning urine for phosphate content, along with blood sample.

• If Fanconi's syndrome is considered, obtain plasma bicarbonate and urate and test urine for glucose and amino acids. A full Fanconi's syndrome consists of renal glycosuria, aminoaciduria, renal tubular acidosis, low blood urate due to high urinary loss, and excessive urinary loss of phosphate.

• If a hereditary cause is suspected, genetic testing may be necessary.¹¹

• 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.

• Bone scintigraphy may demonstrate increased uptake at multiple areas in cases of severe osteomalacia.

• La ecografía del cuello puede ayudar a identificar glándulas paratiroides agrandadas, pero el tecnecio ^99mTc scanning can be more accurate and easier to locate ectopic glands.

• Dual-energy X-ray absorptiometry (DXA) bone density scan: chronic phosphate deficiency will cause loss of bone density.

• If X-rays are inconclusive, bone biopsy may be required.

Management of hypophosphataemia

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

• Treatment is dependent upon cause, severity and duration.

• There are no national guidelines for the treatment of acute hypophosphataemia.

• Treatment should address the underlying cause where possible.

• Patients should be referred to a specialist if:¹²

  • The cause is uncertain.

  • Hypophosphataemia is chronic or severe (phosphate <0.3 mmol/L).

  • They are symptomatic.

  • There is short stature or there are skeletal deformities consistent with rickets.

  • There is a family history of skeletal deformities or hypophosphataemia.

• Suplementos de fosfato:
  

  • Los suplementos de fosfato deben administrarse donde se pueda anticipar hipofosfatemia, como en la realimentación después de anorexia, inanición o dependencia al alcohol.

  • Usually oral phosphate is well tolerated although very high doses may cause diarrhoea.

  • Cuando hay una situación aguda o falta de función intestinal, se puede usar fosfato parenteral, pero esto es mucho más peligroso y requiere monitoreo de los niveles de calcio, fosfato y electrolitos cada seis horas, ya que la respuesta es impredecible. No hay consenso sobre el nivel en el que se debe introducir el fosfato parenteral, pero hay un acuerdo universal de que debe introducirse cuando los niveles de fosfato en suero están por debajo de 0.3 mmol/L. El riesgo es una hipocalcemia severa que puede ser potencialmente mortal, o un tratamiento excesivo que resulte en hiperfosfatemia e hipercalemia. Los pacientes con mala función renal tienen un mayor riesgo con el tratamiento intravenoso.

• 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 been 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 D3 to 1,25 dihydroxyvitamin D3 and so this form may need to be given.

• Hyperparathyroidism requires identification and removal of the offending tumour.

• Problems such as alcohol dependency and eating disorders require appropriate intervention.

• Congenital phosphate wasting syndromes require long-term supplementation.

• To reduce the risk of hypophosphataemia, patients having renal transplantation may be considered for parathyroidectomy before transplant surgery, or more recently the calcimimetic agent cinacalcet has been shown to improve phosphate levels.¹³

• Patients with diabetic ketoacidosis are at high risk of developing hypophosphataemia. This is mostly mild and asymptomatic and studies suggest that parenteral phosphate does not improve clinical outcome. However, severe hypophosphataemia (0.5 mmol/L or less) warrants parenteral treatment.¹⁴

Complications of hypophosphataemia

• Acute hypophosphataemia can produce seizures, delirium, coma, or focal neurological findings.

• Puede haber insuficiencia cardíaca, rabdomiólisis, hemólisis aguda, disfunción de leucocitos, y abnormal LFTs.

• La insuficiencia cardíaca, la rabdomiólisis y la hemólisis pueden producir lesión renal aguda.

• Leukocyte dysfunction increases susceptibility to infection.

• También pueden presentar disfunción plaquetaria, intolerancia a la glucosa y acidosis metabólica.

• Chronic hypophosphataemia due to phosphate loss causes mostly bone pathology.

• En los niños, rickets conduce a una estatura baja y deformidades óseas con mineralización ósea anormal.

• Los adultos pueden desarrollar osteomalacia con dolor óseo severo y fracturas.

Pronóstico

• 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.

• Whether hypophosphataemia itself increases mortality is difficult to ascertain, as many of the patients are critically unwell from the cause of the low phosphate. Prospective and retrospective studies have reported a 2- to 4-fold increase in mortality in hospitalised patients with severe hypophosphataemia, due to its effects on respiratory and cardiovascular stability.¹⁰

Prevention of hypophosphataemia

Those at high risk, such as renal dialysis and transplant patients, those with eating disorders, and patients who have just had parathyroidectomy, should be monitored and given appropriate oral or parenteral supplementation if required.