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Hyperphosphatemia
Updated: Jan 31, 2008
Introduction
Background
Phosphorus is the sixth most abundant element in the human body. It is critical for bone mineralization, cellular structure, genetic coding, and energy metabolism. Many organic and inorganic forms exist. The adult body contains approximately 1000 g of phosphorus, of which 80-90% is in bone. An additional 10-14% is intracellular and the remaining 1% is extracellular.
The phosphorus in plasma is 12-17% protein bound. Free serum compounds represent much less than 1% of the total body phosphorus content. This fraction also varies with shifts between the intracellular and extracellular compartments. Thus, serum phosphorus levels may not reflect accurately the total body phosphorus content.
Levels are expressed in terms of serum phosphorus mass (mg/dL). One mg/dL of phosphorus is equal to 0.32 mmol of phosphate. The normal adult range is 2.5-4.5 mg/dL (0.81-1.45 mmol/L). Levels are 50% higher in infants and 30% higher in children because of growth hormone effects.
Hyperphosphatemia is considered significant when levels are greater than 5 mg/dL in adults or 7 mg/dL in children or adolescents.
Pathophysiology
Phosphorus homeostasis normally is maintained through several mechanisms. Gastrointestinal (GI) absorption must be matched by renal excretion, and cellular release is balanced by uptake in other tissues. Hormonal control is provided mainly by parathyroid hormone.
Hyperphosphatemia occurs when the phosphorus load (from GI absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake.
GI absorption
Phosphorus is present in nearly all foods, and GI absorption of dietary forms is very efficient. With low dietary intake, 80-90% is absorbed. When intake is greater than 10 mg/kg daily, 70% is absorbed. Normal daily dietary intake varies from 800-1500 mg.
Absorption occurs mainly in the jejunum, although some absorption occurs throughout the intestinal tract. A small amount of phosphorus is secreted into the GI tract.
Serum phosphorus levels
Serum phosphorus levels rise after a large meal. Antacids decrease absorption because calcium, aluminum, and magnesium bind phosphorus into insoluble complexes. Aluminum is the most efficient binder found in antacids.
Renal excretion and reabsorption
To maintain homeostasis, renal phosphorus excretion normally matches the amount of daily GI absorption. Excretion occurs in the proximal tubule and is largely dependent on the filtered phosphorus load. As the filtered load increases, a higher fraction of excreted phosphorus is reabsorbed.
Reabsorption is also dependent on concurrent sodium transport. However, while sodium that is not reabsorbed at the proximal tubule may be reabsorbed distally, this is not true for phosphorus. Proximal diuretics, which decrease sodium reabsorption, also increase phosphorus excretion. The usual load excreted is 5-15% of the filtered load or 600-800 mg/d in the normal net steady state. This amount may increase markedly in hyperphosphatemia. Marked hyperphosphatemia is unusual in chronic renal insufficiency unless the glomerular filtration rate (GFR) is less than 25 mL/min. Secretion plays an insignificant role in renal phosphorus excretion.
Hyperphosphatemia occurs most often in patients with renal insufficiency. Most patients with acute or chronic renal failure have hyperphosphatemia in some degree. To avoid hyperphosphatemia, patients with end-stage renal disease and a GFR <30 must restrict their intake of dietary phosphorus. If dietary restriction alone does not reduce serum phosphate levels into the normal range, oral phosphate binders should be added to reduce absorption.
Sequelae of hyperphosphatemia
Hyperphosphatemia causes hypocalcemia by precipitating calcium, decreasing vitamin D production, and interfering with parathyroid hormone-mediated bone resorption. Severe life-threatening hypocalcemia may result. Signs and symptoms of acute hyperphosphatemia are due to the effects of hypocalcemia.
Prolonged hyperphosphatemia promotes metastatic calcification, an abnormal deposition of calcium phosphate in previously healthy connective tissues such as cardiac valves and in solid organs such as muscles. The calcium-phosphate product predicts the risk of metastatic calcification.
Excess free serum phosphorus is taken up into vascular smooth muscle via a sodium-phosphate cotransporter. The increased cellular phosphate activates a gene, cbfa-1, that promotes calcium deposition in the vascular cell, making smooth muscle cells engage in osteogenesis. Vascular walls become calcified and arteriosclerotic, leading to increased systolic blood pressure, widened pulse pressure, and subsequent left ventricular hypertrophy.
Hyperphosphatemia is an independent risk factor contributing to the increased incidence of aortic and mitral stenosis and other cardiovascular disease among dialysis-dependent patients. A peripheral form known as calcific uremic arteriolopathy (calciphylaxis) can induce necrotic ulceration and gangrene in affected extremities.
Hyperphosphatemia-induced resistance to parathyroid hormone contributes to secondary hyperparathyroidism and renal osteodystrophy.
Frequency
United States
Patients with end-stage renal disease make up the bulk of patients with hyperphosphatemia. Approximately 250,000 persons are affected.
Mortality/Morbidity
Prolonged hyperphosphatemia is an independent risk factor for cardiovascular disease in patients with renal failure. Patients with chronic phosphate levels above 6.5 have an 18-39% higher mortality compared with patients with renal failure with near-normal serum phosphate levels.
Sex
Although women have physiologic elevation of serum phosphate levels after menopause, this has no known clinical significance.
Age
- Phosphorus levels are naturally higher in infants, children, and postmenopausal women.
- A phosphate-driven rise of erythrocyte 2,3-diphosphoglycerate and ATP in children may account for the physiologic anemia of childhood.
Clinical
History
- Patients with hyperphosphatemia most commonly complain of muscle cramping secondary to low calcium levels. This may progress to tetany, delirium, and seizures. A search for the following historical clues may help identify those patients at risk for increased phosphorus levels.
- Renal disease
- Past or present hemodialysis
- Adherence to renal (low phosphorus) diet
- Use of oral phosphate binders
- Cancer
- Leukemia
- Lymphoma
- Bone tumors
- Other cancers
- Chemotherapy treatment
- Endocrinopathies
- Trauma
- Burns or heat-related illnesses
- Prolonged immobilization
- Metabolic or hematologic disorders including genetic predisposition
- Medications
- Oral phosphate binders
- Potassium phosphate
- Antacid use
- Bisphosphonate therapy
- Use of laxatives (oral/rectal) and enemas
- Use of nutritional supplements or hyperalimentation
- Ischemic bowel (possible phosphorus elevations)
Physical
The nervous and cardiovascular systems are most commonly affected.
- Central nervous system (CNS)
- Altered mental status
- Delirium
- Obtundation
- Coma
- Convulsions and seizures
- Muscle cramping or tetany
- Neuromuscular hyperexcitability (ie, Chvostek and Trousseau signs)
- Paresthesias (particularly perioral and distal extremities)
- Cardiovascular system
- Hypotension and heart failure
- Prolongation of the QT interval
- Ocular - Cataracts
Causes
Phosphorus balance between intracellular and extracellular compartments and between bone and other tissues may be influenced by many factors. The most common cause of hyperphosphatemia is decreased renal excretion due to renal insufficiency from any cause. All marked elevations of phosphorus involve significant addition of phosphorus to the extracellular compartment, usually with some impairment of renal function.
- Renal insufficiency (acute or chronic)
- Medications - Liposomal amphotericin B
- Increased catabolism or cellular injury
- Rhabdomyolysis
- Trauma, burns, crush injuries, shock
- Exhaustive exercise
- Prolonged immobilization
- Heat-related illnesses
- Malignant hyperthermia
- Hypothermia
- Massive hemolysis
- Severe infections
- Ischemic bowel
- Endocrinopathies
- Hypoparathyroidism
- Pseudohypoparathyroidism
- Abnormal parathyroid hormone
- Acromegaly and other causes of growth hormone excess
- Thyrotoxicosis
- Glucocorticoid withdrawal or deficiency
- Poisoning, excessive intake or administration
- Bisphosphonate therapy
- Vitamin D intoxication or other causes of increased vitamin D (sarcoidosis)
- Ingestion or administration of phosphate salts (eg, oral/rectal laxatives, enemas, intravenous phosphate)
- Hyperalimentation (including lipid administration)
- White phosphorous burns
- Milk-alkali syndrome
- Transfusion of outdated blood
- Neoplasms
- Leukemia
- Lymphoma
- Bone tumors
- Tumor lysis after chemotherapy
- Acidosis
- Acute respiratory acidosis
- Lactic acidosis
- Diabetic ketoacidosis
- Alcoholic ketoacidosis
- Alkalosis
- Miscellaneous
- Tumoral calcinosis
- Cortical hyperostosis
- Syndrome of familial intermittent hyperphosphatemia
- Hyperbilirubinemia (controversial as cause)
More on Hyperphosphatemia |
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| Follow-up: Hyperphosphatemia |
| References |
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References
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Further Reading
Keywords
phosphorus homeostasis, high phosphorus level, hyperphosphatemia, renal insufficiency, acute renal failure, chronic renal failure, end-stage renal disease, hypocalcemia, calcific uremic arteriolopathy, calciphylaxis, managing hyperphosphatemia and chronic kidney disease
