Causes and clinical manifestations of hypophosphataemia

The article was written by Specialist Doctor I Tran Ngoc Thuy Hang - Resuscitation - Emergency Doctor, Emergency Department - Vinmec Central Park International General Hospital

Hypophosphatemia causes a variety of symptoms and clinical manifestations, depending on the severity and chronic phosphate deficiency, commonly in patients with serum phosphate concentrations < 1 mg/dL (0.32 mmol/L).

Hypophosphatemia when blood phosphate concentration is <2.5mg/dL (0.80mmol/L) Severe hypophosphataemia when blood phosphate concentration is <1mg/dL (0.32mmol/L) Up to 5% of hospitalized patients have the condition Hypophosphataemia, rates greater than 30%-50% have been reported in alcoholic patients and in patients with sepsis or trauma.

There are 4 common mechanisms causing hypophosphataemia:
Redistribution of phosphate from extracellular fluid into cells Decreased intestinal absorption of phosphate Increase urinary phosphate excretion Phosphate loss through renal replacement therapy 2.1 Redistribution Release into Cells The stimulation of glucose hydrolysis increases the phosphorylation of carbohydrate compounds in the liver and skeletal muscle, which utilizes inorganic phosphate from the extracellular fluid, resulting in a decrease in blood phosphate concentration. This mechanism occurs in several situations.
Increased insulin secretion, especially during refeeding. In normal individuals, administration of insulin or glucose (stimulating endogenous insulin) causes small amounts of hypophosphataemia. Administration of Glucagon or Epinephrine also causes mild hypophosphataemia by a similar mechanism. However, in patients who already have baseline hypophosphataemia, it can lead to severe hypophosphatemia. This is often seen in patients with diabetic ketoacidosis or non-ketotic hyperglycemia – patients with osmotic diuresis due to hyperglycemia, which causes loss of phosphate in the urine; malnourished alcoholic patients or malnourished due to anorexia nervosa; patients receiving parenteral nutrition mixes. . . . Acute Respiratory Alkalosis: The decrease in CO partial pressure during respiratory alkalosis leads to an increase in intracellular pH, which stimulates Phosphofructokinase enzyme activity, causing increased hydrolysis of glucose. Excessive hyperventilation (PaCO2 < 20 mmHg) in a normal individual can cause severe hypophosphatemia (< 1 mg/dL). This is probably the most common cause of severe hypophosphatemia in hospitalized patients. Respiratory alkalosis is also a predisposing factor in hypophosphataemia induced by acute myolysis in alcoholic patients, however basal hypophosphataemia is often masked by the release of phosphate from damaged muscle cells. Hungry Bone Syndrome: Surgical removal of the parathyroid glands (due to primary or secondary hyperparathyroidism), or, rarely, in patients with thyroidectomy (due to hyperthyroidism) with pre-existing osteoporosis may cause calcium deposition and Phosphate in the bone immediately after surgery, leading to hypocalcemia and hypophosphataemia.

2.2 Reduced Intestinal Absorption In normal adults, Phosphate equilibrium is reached. Daily diet, the amount of Phosphate ranges from 800-1500mg/day. About 80% of phosphate is absorbed in the small intestine. Approximately 150-200mg/day is excreted and excreted through the large intestine. There are few mechanisms that regulate intestinal absorption of phosphate, with Calcitriol having some absorption-promoting effects.
Inadequate nutrition alone rarely causes severe hypophosphatemia, because of an adaptive mechanism of the kidneys, increasing phosphate reabsorption. However, prolonged phosphate intake below 100 mg/day, together with colonic excretion of phosphate, leads to hypophosphatemia. Normally, a low phosphate diet with prolonged diarrhea will cause a negative phosphate balance. These patients may have malabsorption disorders or poor nutrition of vitamin D. Drugs: Some drugs inhibit the absorption of phosphate in the intestine: antacids, especially those based on aluminum, magnesium, It will form bonds with ingested phosphate and be excreted in the intestines to form insoluble phosphate salts, which are excreted in the feces. Long-term and high-dose treatment with these drugs causes hypophosphataemia. Various other phosphate binders are used to increase phosphate excretion in patients with advanced kidney disease. Niacin and its derivatives also increase fecal phosphate excretion, but at normal doses rarely cause hypophosphataemia. Fatty stools and prolonged diarrhea: Fatty stools (due to intestinal fat absorption disorders) and prolonged diarrhea can cause mild to moderate hypophosphatemia due to decreased intestinal absorption of phosphate and increased urinary phosphate excretion (cause due to hyperparathyroidism secondary to combined vitamin D deficiency). 2.3 Increased Urinary Phosphate Excretion The kidneys are largely involved in the regulation of blood Phosphate balance. Phosphate is reabsorbed in the proximal tubule accounting for 60% - 70%, in the distal tubule 10% - 15%. Phosphate is absorbed by sodium binding via a co-transporter in the tubular membrane, which transports by an inward concentration gradient in favor of sodium (the intracellular sodium concentration at 25mEq/L is much lower than the concentration of 25mEq/L). sodium level in the tube 145mEq/L).
Mechanisms to regulate Phosphate reabsorption in the renal tubules include:
Decrease in blood phosphate concentration, stimulate phosphate reabsorption through the sodium-phosphate co-transporter in the proximal tubule, and increase the synthesis of transporters. increases the reabsorption of phosphate in the renal tubules. Parathyroid hormone (PTH) inhibits the activity of sodium-phosphate co-transporter, leading to inhibition of phosphate reabsorption in the kidney. Phosphatonins – including fibroblast growth factors FGF-23, FGF-7, extracellular phosphoglycoprotein substrate MEPE, sFRP-4 inhibit the Na-Phosphate co-transporter.

Inappropriate increase in phosphate secretion is usually due to 2 factors:
Presence of circulating factors that increase urinary phosphate loss: PTH, phosphatonins Intrinsic defect in Phosphate transport. Hyperparathyroidism: Increases PTH leading to hypophosphatemia. Primary hyperparathyroidism, typically with prominent hypercalcemia, mild hypophosphataemia. Whereas hyperparathyroidism secondary to any cause of vitamin D deficiency, hypophosphataemia may be aggravated by increased urinary phosphate excretion and reduced gastrointestinal absorption. Vitamin D deficiency and resistance: Causes hypophosphatemia due to reduced gastrointestinal absorption, hypocalcemia and secondary hyperparathyroidism – leading to increased urinary phosphate excretion. Vitamin D deficiency can occur due to decreased intake or absorption, decreased sun exposure, increased hepatic catabolism, decreased endogenous synthesis or resistance of internal organs. 2.4 Phosphate loss through renal replacement therapy Primary renal phosphate loss: Some rare syndromes causing renal phosphate loss alone due to genetic mutations: Vitamin D-resistant rickets: due to mutations in the PHEX gene causing motor defects phosphate transport in the proximal tubules, while encoding endopeptidases that alter the breakdown and production of FPF-23, promoting urinary phosphate excretion.
Fanconi syndrome - Refers to a complete decline in proximal tubular function leading to increased excretion of compounds that are normally reabsorbed in the proximal tubules. Consequences are hypophosphataemia, glucoseuria, hyponatremia, amino aciduria and proximal tubular acidosis due to urinary bicarbonate loss. Serum calcitriol levels are low or abnormal. This syndrome, which is rare in adults, is usually caused by multiple myeloma or by drugs (Tenofovir). In children, Wilson disease, and hereditary fructose intolerance syndrome are common causes.

Other causes : Osmotic diuresis (most often due to glucosuria); Proximal diuretics (acetazolamide and some thiazide diuretics also have carbonic anhydrase inhibitory activity); acute hypervolemia (reduces proximal sodium reabsorption); and intravenous iron, intravenous iron formulations containing carbohydrate moieties may increase phosphate excretion by causing an increase in circulating levels of FGF-23. Several classes of chemotherapeutic agents, including tyrosine-kinase inhibitors (in particular, imatinib mesylate has been reported to cause increased urinary phosphate excretion and hypophosphatemia. seen in many patients receiving continuous renal replacement therapy, largely due to phosphate removal along with postdialysis waste.

Hypophosphatemia causes a variety of symptoms and clinical manifestations, depending on the severity and chronic phosphate deficiency, usually in patients with serum phosphate levels < 1mg/dL (0.32mmol/L). Situations associated with symptomatic hypophosphataemia are chronic alcoholism, parenteral nutrition without phosphate supplementation, phosphate-depleting syndrome, and prolonged use of antacids or other phosphate binders.
Effects of hypophosphataemia on mineral metabolism:
Prolonged hypophosphatemia inhibits calcium and magnesium reabsorption in the distal tubules, hypercalciuria Bone hypercalciuria causes hypercalciuria ⇨ When condition Prolonged hypophosphataemia leads to rickets, osteomalacia due to decreased bone mineralization.
Other effects of phosphate deficiency: Most symptoms of hypophosphatemia are due to two consequences of intracellular phosphate depletion, affecting virtually all organ systems. Includes:
2,3-diphosphoglycerate (DPG) levels in red blood cells decrease, thereby increasing hemoglobin's affinity for oxygen and decreasing oxygen release to tissues.
Intracellular adenosine triphosphate (ATP) levels decrease with severe hypophosphatemia, and cellular functions that depend on energy-rich phosphate compounds begin to fail. ATP depletion affects the following organ systems:
Central nervous system - A wide range of neurological symptoms are associated with persistent phosphate depletion, ranging from mild irritability and paresthesias to more severe manifestations such as delirium, generalized convulsions, and coma. Severe phosphate depletion is also speculated to contribute to central extra-pontine demyelination. Cardiovascular and respiratory systems: - The contractility of the myocardium may be impaired and phosphate utilization seems to improve cardiac function, particularly in patients with severe hypophosphatemia, defined as serum phosphate. less than 1 mg/dL (0.32 mmol/L). In addition, hypophosphataemia is associated with a higher incidence of ventricular arrhythmias in the setting of acute myocardial infarction and an increased need for vasopressors after cardiac surgery. Lung function is also affected by persistent hypophosphataemia. Diaphragm contractility is significantly impaired and some studies suggest that hypophosphatemia is associated with prolonged ventilator dependence in critically ill patients. Smooth and skeletal muscle - Manifestations of muscle dysfunction include proximal myopathy (affecting skeletal muscle), dysphagia, and ileostomy (affecting smooth muscle). In addition, acute hypophosphataemia superimposed on pre-existing severe hypophosphataemia can lead to rhabdomyolysis. Although elevations in creatine phosphokinase (CPK) are common in hypophosphataemic patients, clinically significant rhabdomyolysis has been described almost exclusively in alcoholics and in patients treated for hyperpigmentation without adjuvant therapy. phosphate supplement. Rhabdomyolysis induces the release of phosphate from injured muscle cells with two clinical consequences: It may mask the underlying hypophosphataemia and thus may protect against the development of other symptoms of hypophosphataemia. Demonstration of low plasma phosphate levels before or after peak muscle breakdown may be the only clue to basal phosphate depletion.

Hematologic dysfunction: Red blood cells - Decreased intracellular ATP concentration increases erythrocyte stiffness, easily causing hemolysis, which can be seen when plasma phosphate concentration falls below 0.5mg/dL (0) ,16 mmol/L. However, clinically apparent hemolysis is rare due to hypophosphatemia alone. White blood cells - Decreased intracellular ATP levels reduce both phagocytosis and leukocyte chemotaxis This complication is also rare and occurs only with severe hypophosphataemia.The platelets can cause thrombocytopenia and thrombocytopenia, which can aggravate mucosal bleeding. Vinmec International General Hospital is one of the hospitals that not only ensures professional quality with a team of leading medical doctors, modern equipment and technology, but also provides examination, consultation and treatment services. Comprehensive, professional, civilized, polite, safe and sterile medical examination and treatment space.