OVERVIEW: What every practitioner needs to know
Are you sure your patient has a disorder of phosphorus? What are the typical findings for this disease?
Phosphorus exists in the body in multivalent forms bound to oxygen called phosphates (Phos), or as phosphorus bound to other macromolecules. A major intracellular anion and constituent of nucleic acids and phospholipid membranes, its central roles include storage of energy within the bonds it forms in ATP, modulation of signaling pathways, and buffering pH.
Normal ranges of serum Phos (in mg/dL) are age dependent: 4.8 – 8.2 in neonates, 3.8 – 6.5 in children 1 week to 3 years, 3.7 – 5.5 in children 3 to 12 years, and 2.9 to 5 for adolescents to age 19 years (ranges somewhat variable by analytical instruments). A serum Phos < 2.5 mg/dL is considered hypophosphatemia with < 1.5 being severe, whereas hyperphosphatemia is regarded as a serum Phos of > 4.5 mg/dL
Both hypo- and hyperphosphatemia are most often discovered in hospitalized children on routine evaluations of serum chemistry.
– Manifestations of hyperphosphatemia relate to the associated hypocalcemia which ensues. Cardiovascular dysfunction, seizures, and coma have been reported.
– Clinical symptoms of hypophosphatemia stem from energy (ATP) depletion and can result in fatigue and dysfunction of organs with high metabolic activity. Respiratory muscle weakness and failure, cardiac muscle dysfunction and heart failure, and arrhythmias have all been observed and reversed with correction of hypophosphatemia. Reported neurological symptoms have included seizures, peripheral neuropathy, Guillain-Barre like syndrome, and the full spectrum of altered mental status up to and including coma. In adult patients, hypophosphatemia has been reported to cause rhabdomyolysis, hemolysis, and central pontine myelinolysis.
What other disease/condition shares some of these symptoms?
Symptoms of hyperphosphatemia stem from, and hence overlap with the symptoms of, acute hypocalcemia.
What caused this disease to develop at this time?
Regulation of serum Phos level involves four organs, principally – the kidneys, intestinal tract, bone, and parathyroid gland – and three Phos pools – intracellular environments, the bony matrix, and ingested Phos. New Phos enters the body by oral intake, and more than 50%-65% is absorbed predominantly in the small intestine. Body Phos is lost either through colonic secretion or renal filtration. The renal proximal tubule is responsible for reabsorbing 80% of filtered Phos while the distal tubule can reabsorb the remainder; thus, it is possible for the normal kidney to eliminate all excretion of Phos, positioning it as the primary responder to serum Phos abnormalities.
Normally, even small increases in serum Phos levels trigger a reduction in tubular reabsorption, resulting in increased excretion. Hyperphosphatemia may develop, however, if an acute Phos load is too great, if there is severe renal insufficiency or failure, or if renal tubular reabsorption is abnormally elevated.
Multiple mechanisms can cause hyperphosphatemia. Because Phos is predominantly intracellular, any process that results in disruption of cells on a massive scale can release large amounts of Phos quickly. Tumor lysis syndrome is one such process. Risk for significant tumor lysis is especially high at chemotherapy initiation in malignancies with a large tumor burden such as B-cell lymphomas and some leukemias. Rhabdomyolysis and marked hemolysis are additional examples. Lactic and ketoacidoses diminish glycolysis, and hence, Phos consumption; these conditions may also be coupled with impaired glucose and Phos uptake.
Use of Phos-based enemas has been associated with severe complications and death in infants and young children. Aggressive Phos supplementation may overshoot renal Phos handling. Reasons for progressive renal impairment often accompany these conditions such as uric acid-mediated injury, pigment nephropathy, and systemic hypoperfusion.
Certainly the handling of an acute Phos load can be impaired with co-existing renal insufficiency, which increases the risk of hyperphosphatemia. As glomerular filtration declines, the diminution in Phos excretion may initially be offset by elevations in PTH (2o hyperparathyroidism) to promote phosphaturia. A rise in PTH also stimulates calcitriol (1,2(OH)2D) production by the proximal tubule, which can stimulate bone osteoclasts to produce a “phosphotonin” called FGF23 that further reduces renal Phos reabsorption. Below a certain GFR, however, Phos reabsorption is maximally suppressed and serum Phos rises. Eventually, in chronic renal failure FGF23 is no longer able to effect phosphaturic enhancement.
Primary hypoparathyroidism (as in after thyroid or parathyroidectomies) can be a cause for increased reabsorption of Phos. Vitamin D toxicity is also reported to result in hyperphosphatemia.
“Pseudohyperphosphatemia” is observed in the settings of hyperglobulinemia, hyperbilirubinemia, hyperlipidemia, and hemolysis.
Intra-/extracellular redistribution may be the most commonly encountered mechanism for hypophosphatemia in the inpatient setting. In respiratory alkalosis, a parallel rise in intracellular pH can trigger glycolysis and consumption of Phos into energy intermediates such as phosphocreatine. Exogenous or endogenous catecholamines (epinephrine and norepinephrine) reduce Phos in an analogous fashion. Insulin shifts Phos into cells in conjuction with glucose, though this results in a minimal drop in serum Phos in normal states. In contradistinction to massive cell lysis, rapid cellular proliferation on a large scale is reported to consume Phos and lower serum levels.
Excessive renal excretion of Phos can be caused by several mechanisms. Many drugs commonly used in the inpatient setting cause renal wasting: diuretics, particularly those with actions against carbonic anhydrase (acetazolamide, metolazone); antifungals (e.g., amphotericin B); chemotherapeutics (e.g., ifosfamide); and corticosteroids.
Non-pharmacological proximal tubular defects such as Fanconi’s syndrome are also encountered in complex, hospitalized patients. Fanconi’s is characterized by renal wasting of Phos, bicarbonate, glucose, amino acids, and uric acid. In children, Fanconi’s can be caused by Wilson’s disease, cystinosis, and hereditary fructose intolerance. Rare genetic syndromes that cause renal Phos wasting include X-linked, autosomal dominant, and autosomal recessive forms of hypophosphatemic rickets.
A few conditions in which hypophosphatemia is seen involve both cellular distribution and excessive renal excretion. In diabetic ketoacidosis (DKA), the inability to transport glucose into cells results in profound depletion of intracellular ATP, release of inorganic Phos, shift out of cells into serum, and renal wasting by osmotic diuresis. Severe or long-standing DKA (> few days) represents a state of body Phos depletion making recovery a particularly vulnerable time for hypophosphatemia; therapeutic insulin and glucose provision results in an abrupt shift of serum Phos into cells, exacerbating serum hypophosphatemia unless it is replenished concomitantly.
Protracted starvation, in which the body shifts to a primary lipid catabolism, can also result in body Phos depletion. In this setting, carbohydrate provision can lead to refeeding syndrome, in which there is an abrupt insulin-mediated shift of serum Phos into cells, precipitating severe hypophosphatemia.
Impaired intestinal absorption or increased intestinal wasting is infrequently the cause of hypophosphatemia if renal reabsorptive mechanisms are intact, but the latter is not always true in the inpatient setting. With prolonged periods of scarce intake, ongoing colonic secretion becomes a route of net Phos loss. This can be exacerbated by co-existing diarrhea, especially secretory or steatorrheaic. Inpatients can become vitamin D deficient, which not only reduces intestinal absorption but the ensuing 2° hyperparathyroidism can impair compensatory renal reabsorption as well. Vomiting and nasogastric suctioning can be contributory. Lastly, administration of enteric Phos binders can prevent intestinal absorption of Phos.
Hypophosphatemia is sometimes encountered as a result of continuous renal replacement therapy with insufficient Phos in the replacement fluid. High levels of interleukin-6 and tumor necrosis factor-α correlate inversely with serum Phos levels, though the relevant mechanisms are still being elucidated. This and other reasons may explain why hypophosphatemia is commonly encountered in the settings of sepsis, trauma, and certain post-operative states (esp. liver and cardiac). Burn patients have many reasons for hypophosphatemia including loss through skin.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
A careful review of the history, underlying problems, clinical course, and inpatient management strategy is often sufficient to identify putative causes of serum Phos derangement.
Hypophosphatemia – Calculating the fractional excretion of Phos (FEPO4) may be helpful: FEPO4 = [urine Phos x plasma creatinine x 100] / [plasma Phos x urine creatnine]. If the kidneys are working normally in the setting of hypophosphatemia, FEPO4 should be < 5%. In this instance, the derangement is probably due to cellular redistribution or reduced intestinal absorption of Phos. If FEPO4 is > 5%, renal wasting is present, implicating hyperparathyroidism or alternate etiologies of renal tubular defects.
Confirming the diagnosis
Due to the diverse nature of the disorders presented, overarching clinical decision algorithms are not applicable.
If you are able to confirm that the patient has a disorder of phosphorus, what treatment should be initiated?
Severe, acute hyperphosphatemia results in acute hypocalcemia and requires urgent attention and monitoring. In the absence of renal failure normal saline infusion can improve renal filtration and excretion, but further dilution of serum calcium should be guarded against. Acetazolamide may promote renal Phos wasting. All exogenous Phos (e.g., enteral and parenteral nutrition) should be stopped promptly until hyperphosphatemia is resolved. For chronic management, a variety of enteral Phos binders are now available, though calcium carbonate or acetate are typically first-line.
Hypophosphatemia requires Phos replacement. If severe or symptomatic, intravenous replacement is indicated; sodium or potassium phosphate is selected depending upon the levels of these other electrolytes. However, aggressive correction of hypophosphatemia can result in overshoot hyperphosphatemia. Intravenous infusions of Phos usually have limited compatibility with other solutions and require several hours to administer due to risk of transient, symptomatic hypocalcemia. The latter may occupy limited intravenous access in pediatric patients. Thus, assuming intact gastrointestinal motility and absorption moderate hypophosphatemia can be corrected with supplementation enterally. Careful monitoring of serum electrolytes should continue to keep up with source(s) of ongoing loss.
What are the adverse effects associated with each treatment option?
Please see “What treatment should be initiated?” above.
What are the possible outcomes of disorders of phosphorus?
Hyperphosphatemia – Uncontrolled hyperphosphatemia in the setting of chronic renal failure can result in vascular calcifications and early-onset cardiovascular disease. Acutely, cardiovascular collapse and other outcomes of severe hypocalcemia may ensue.
Hypophosphatemia – Long-standing hypophosphatemia can result in nephrolithiasis and rickets. Acutely, severe hypophosphatemia that goes untreated can result in respiratory failure, heart failure, arrhythmias, hepatic insufficiency, and neurological sequelae related to intracellular energy depletion.
Are additional laboratory studies available; even some that are not widely available?
Levels of PTH, calcitriol, and FGF23 may lend insight into the mechanism of disordered Phos regulation.
How can disorders of phosphorus be prevented?
Monitor for abnormal Phos levels in the context of conditions that present risk of derangement such as renal insufficiency, rhabdomyolysis, or use of amphotericin B. Anticipate Phos derangements in conditions which have associated Phos abnormalities such as DKA, hypoparathyroidism, or Fanconi’s syndrome. Avoid prolonged starvation of patients. Do not use Phos-based enemas in infants and young children. Prevent other etiologies such as renal failure and vitamin D toxicity.
What is the evidence?
Wood, EG, Lynch, RE, Fuhrman, Zimmerman. “Electrolyte management in pediatric critical illness”. 2006.
Geerse, DA, Bindels, AJ, Kuiper, MA. “Treatment of hypophosphatemia in the intensive care unit: a review”. Critical Care. vol. 14. 2010. pp. R147
Razzaue, MS. “Osteo-renal regulation of systemic phosphate metabolism”. Life. vol. 63. 2011. pp. 240-247.
Lee, R, Weber, TJ. “Disorders of phosphorus homeostasis”. Curr Opin Endocrinol Diabetes Obes. vol. 17. 2010. pp. 1561-1567.
Shroff, R. “Dysregulation of mineral metabolism in children with chronic kidney disease”. Curr Opin Nephrol Hypertens. vol. 20. 2011. pp. 233-240.
Boateng, AA, Sriram, K, Meguid, MM, Crook, M. “Refeeding syndrome: treatment considerations based on collective analysis of case reports”. Nutrition. vol. 26. 2010. pp. 156-167.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has a disorder of phosphorus? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Confirming the diagnosis
- If you are able to confirm that the patient has a disorder of phosphorus, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of disorders of phosphorus?
- Are additional laboratory studies available; even some that are not widely available?
- How can disorders of phosphorus be prevented?
- What is the evidence?