Hypophosphatemia Clinical Presentation

Updated: Jan 23, 2018
  • Author: Eleanor Lederer, MD, FASN; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Presentation

History

Most patients with hypophosphatemia are asymptomatic. The history alone rarely alerts the physician to the possibility of hypophosphatemia. In cases of oncogenic osteomalacia or in some of the genetic causes of phosphate wasting, patients complain of bone pain and fractures. Otherwise, physicians must have a high index of suspicion and must be aware of the clinical conditions that might be complicated by hypophosphatemia. [29]

Symptoms of hypophosphatemia are nonspecific and highly dependent on cause, duration, and severity. Mild hypophosphatemia (ie, 2-2.5 mg/dL), whether acute or chronic, is generally asymptomatic. Patients with severe and/or chronic hypophosphatemia are more likely to be symptomatic. Weakness, bone pain, rhabdomyolysis, and altered mental status are the most common presenting features of persons with symptomatic hypophosphatemia.

Occasionally, patients with mild hypophosphatemia may complain of weakness. Whether the weakness is secondary to hypophosphatemia or is due to the underlying disorder causing the hypophosphatemia is not clear, however.

Acute mild hypophosphatemia commonly occurs with the treatment of diabetic ketoacidosis because of the sudden large doses of insulin used to treat the uncontrolled diabetes. However, mild hypophosphatemia is asymptomatic and rapidly reversed.

Mild hypophosphatemia can also occur after renal transplantation and can last years without any discernible symptoms.

Primary hyperparathyroidism is also associated with mild hypophosphatemia; however, the symptoms of hypercalcemia appear to be more prominent than those of mild hypophosphatemia.

Moderate degrees of hypophosphatemia are commonly observed in patients with the refeeding syndromes. Most commonly, these individuals have a history of long-standing alcohol use and chronic malnutrition, resulting in the development of total body phosphate depletion. When these patients are admitted to the hospital, their serum phosphate level is most often within the reference range. However, feeding stimulates insulin release, leading to a shift of phosphate from the extracellular to the intracellular compartment.

At times, the ensuing hypophosphatemia can be profound. Depending on the severity of the hypophosphatemia, the patient may complain of muscle weakness and generalized weakness or may develop the full-blown hypophosphatemic syndrome. In this particular clinical situation, if the practitioner does not have a high index of suspicion, the delirious state can be misinterpreted as delirium tremens.

The acute hypophosphatemic syndrome occurs most commonly in persons with chronic alcoholism, but it can also be observed in refeeding of patients who have eating disorders, [30] patients who have been starved for any reason, or patients who are receiving parenteral nutrition with inadequate quantities of phosphate replacement. [31]

Hypophosphatemia has been reported as a presenting feature in some patients with cannabinoid hyperemesis syndrome. [32]

Patients with chronic phosphate wasting syndromes frequently present with bone pain, muscle weakness, and skeletal disorders. In the genetic syndromes of renal phosphate wasting or acquired oncogenic osteomalacia, the serum phosphate level is generally moderately depressed. Symptoms are predominantly muscle weakness and bone pain or fractures. [33]

In short, symptoms alone rarely alert the physician to the possibility of hypophosphatemia. Recognizing that hypophosphatemia can complicate specific clinical conditions allows the physician to make this diagnosis. If considering the diagnosis of hypophosphatemia, the physician should attempt to elicit the following clinical clues to conditions associated with hypophosphatemia:

  • Poor nutrition
  • Symptoms of malabsorption
  • Excessive antacid use
  • Bone pain or fractures
  • Symptoms suggestive of multiple myeloma or other paraproteinemia
  • Treatment with parenteral nutrition
  • Exposure to heavy metals
  • Use of drugs such as glucocorticoids, cisplatin, or pamidronate
  • Treatment of diabetic ketoacidosis
  • Extensive burns
  • Treatment with growth factors
  • Treatment with parenteral iron (eg, ferric carboxymaltose) [34, 35]
  • Bone marrow transplant
  • Intensive care unit (ICU) setting
  • Treatment of HIV infection
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Physical

No physical signs are specific for hypophosphatemia. In fact, physical signs of mild hypophosphatemia are generally absent.

Chronic hypophosphatemia can be associated with short stature and evidence of rickets, with bowing of the legs, when caused by one of the genetically transmitted phosphate wasting disorders. In adults, chronic hypophosphatemia is more commonly associated with bone pain upon palpation.

Severe acute hypophosphatemia can have a variety of signs, including the following:

  • Disorientation
  • Seizures
  • Focal neurologic findings
  • Evidence of heart failure
  • Muscle pain

Myocardial contractility may be impaired from depletion of adenosine triphosphate (ATP), and respiratory failure due to weakness of the diaphragm has been described. The reduction in cardiac output may become clinically significant, leading to congestive heart failure, when the plasma phosphate concentration falls to 1.0 mg/dL (0.32 mmol/L). [36]

Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion can lead to rhabdomyolysis. Although creatine phosphokinase elevations are fairly common in hypophosphatemia, clinically significant rhabdomyolysis has been described almost exclusively in alcoholics and in patients receiving hyperalimentation without phosphate supplementation.

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Causes

The differential diagnosis of hypophosphatemia is most easily considered according to pathogenetic mechanisms. The following discussion conforms to this approach, but note that hypophosphatemia is frequently the result of more than one mechanism.

Inadequate intake

Inadequate ingestion can result from phosphate deficiency in the diet or from poor intestinal absorption. Hypophosphatemia due to inadequate intake is uncommon but should be strongly considered in certain patient populations, as follows:

  • Individuals who have had prolonged poor intake of phosphate develop true phosphate deficiency
  • Persons with alcoholism who ingest an inadequate diet comprise one population at risk for this clinical scenario; serum phosphate levels may be within reference ranges upon admission to the hospital, but refeeding stimulates cellular uptake and results in profound hypophosphatemia
  • Similarly, critically ill patients receiving a parenteral diet deficient in phosphate may suddenly become hypophosphatemic as their catabolic condition resolves and they become more anabolic
  • People with eating disorders or dietary deficiencies due to socioeconomic, dental, or swallowing difficulties may also become hypophosphatemic when fed an adequate diet
  • Malabsorption of intestinal phosphate can be severe enough to produce phosphate deficiency and hypophosphatemia
  • Individuals who ingest large quantities of antacids can become hypophosphatemic because of phosphate binding by the antacids, resulting in poor intestinal absorption
  • Primary intestinal disorders, such as Crohn disease or celiac sprue, can limit phosphate absorption, leading to hypophosphatemia
  • Similarly, steatorrhea or chronic diarrhea can cause mild-to-moderate hypophosphatemia due to decreased phosphate absorption from the gut and renal phosphate wasting; the latter is caused by secondary hyperparathyroidism induced by concomitant vitamin D deficiency
  • Vitamin D deficiency causes hypophosphatemia by limiting intestinal and renal phosphate absorption

Excessive losses

Phosphate wasting can result from genetic or acquired renal disorders. The genetic disorders generally manifest in infancy, when the children exhibit short stature and bone deformities.

Genetic disorders

Genetic disorders that cause phosphate wasting include the following:

  • X-linked hypophosphatemia [37]
  • Autosomal dominant hypophosphatemic rickets
  • Hereditary hypophosphatemic rickets with hypercalciuria [38]
  • Vitamin D–resistant rickets
  • Mutations in the type 2a sodium-phosphate cotransporter [2]
  • Fibrous dysplasia/McCune-Albright syndrome

X-linked hypophosphatemic rickets is characterized by short stature, radiographic evidence of rickets, and bone pain. Patients with this condition also may have calcification of tendons, cranial abnormalities, and spinal stenosis. In addition to hypophosphatemia, these patients have relatively low levels of 1,25 dihydroxyvitamin D-3, levels that are inappropriately low for the degree of hypophosphatemia.

The defective gene is PHEX, which encodes for a membrane-bound neutral endopeptidase. [39, 40] Present understanding of this disorder is that the inactive neutral endopeptidase is unable to cleave a circulating phosphaturic substance. Data suggest that this circulating substance might be FGF23. This results in impaired phosphate reabsorption by decreasing the sodium-phosphate cotransporter in the kidneys.

Autosomal dominant hypophosphatemic rickets has similar manifestations, with hypophosphatemia, clinical rickets, and inappropriately low levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is thought to be mutations of FGF23 that result in resistance to degradation, persistently high circulating levels of FGF23, and subsequent phosphaturia.

Hereditary hypophosphatemic rickets with hypercalciuria is a rare disorder characterized by hypophosphatemia, phosphate wasting, hypercalciuria, bone pain, muscle weakness, and high levels of 1,25 dihydroxyvitamin D-3. The cause of this disorder is an inactivating mutation in the type 2c sodium-phosphate cotransporter.

Vitamin D–resistant rickets is an autosomal recessive disorder. In type I, the defect is in renal 1-alpha-hydroxylation. Type II is characterized by end organ resistance to the effects of 1,25 dihydroxyvitamin D-3. These patients present in childhood with hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, bone pain, muscle weakness, and alopecia. The disease is caused by mutations in the vitamin D receptor that prevent normal responsiveness to circulating vitamin D-3.

Mutations in the type 2a sodium-phosphate cotransporter have been reported in some patients with hypophosphatemia and inappropriate urinary phosphate wasting associated with nephrolithiasis and/or osteoporosis. [1, 41]

Rarely, significant renal phosphate wasting is observed in patients with fibrous dysplasia/McCune-Albright syndrome, disorders that result from mutations in the alpha subunit of the stimulatory G protein. Excess production of FGF23 has been found in some of these patients. [42]

Acquired phosphate-wasting syndromes

Acquired phosphate wasting syndromes are of diverse etiologies, as follows:

  • Simple vitamin D deficiency results in hypophosphatemia, at least in part, from renal wasting. Vitamin D deficiency can result from several mechanisms, including poor oral intake, lack of sun exposure, drug-induced hypermetabolism of vitamin D precursors in the liver, or loss of vitamin D binding protein in the urine in persons with nephrotic syndrome. The loss of normal bone mineralization produces rickets in children and osteomalacia in adults.
  • Primary hyperparathyroidism is another cause of renal phosphate wasting.
  • Heavy metal intoxication and paraproteinemias can cause global proximal renal tubule dysfunction. These patients have hypophosphatemia along with type II renal tubular acidosis, renal glycosuria, aminoaciduria, and hypouricemia, ie, the condition referred to as Fanconi syndrome. Serum calcitriol concentrations can be either low or inappropriately normal. In children, cystinosis, Wilson disease, and hereditary fructose intolerance are the most common of the syndrome.
  • Drugs that can produce renal phosphate wasting include loop diuretics; acetazolamide; bisphosphonates, including pamidronate and zoledronate [43] ; and multiple chemotherapeutic and biologic agents, including cisplatinum; bevacizumab plus irinotecan [44] ; everolimus plus octreotide LAR [45] ; imatinib mesylate, a drug used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors [46, 47] ; sorafenib [48] ; carmustine [49] ; and ifosfamide. [50] In some circumstances, renal phosphate wasting is part of a more generalized, drug-induced Fanconi syndrome. [51]
  • Extracellular volume expansion or the administration of bicarbonate can cause loss of phosphate through the kidneys.
  • Oncogenic osteomalacia is a paraneoplastic syndrome characterized by osteomalacia, hypophosphatemia, renal phosphate wasting, bone pain, and muscle weakness. Several tumors that cause this syndrome have been described, most of which are benign tumors of mesenchymal origin. [52]
  • Other factors that can increase urinary phosphate excretion are osmotic diuresis (most often due to glucosuria), proximally acting diuretics (acetazolamide and some thiazide diuretics that also have carbonic anhydrase inhibitory activity, such as metolazone), and acute volume expansion (which diminishes proximal sodium reabsorption).

Intracellular shift of phosphate

Several physiologic agents stimulate phosphate uptake from the extracellular environment into the cell. This phenomenon can exacerbate the hypophosphatemia caused by the previously described mechanisms and can result in profound hypophosphatemia. However, in some circumstances, the shift alone may be enough to produce hypophosphatemia, albeit of a milder degree.

Acute respiratory alkalosis or hyperventilation produces hypophosphatemia by stimulating a shift of phosphate into the cells. This mechanism is responsible for the hypophosphatemia observed with salicylate overdose, panic attacks, and sepsis. Extreme hyperventilation in normal subjects can lower serum phosphate concentrations to below 1.0 mg/dL (0.32 mmol/L), and it is probably the most common cause of marked hypophosphatemia in hospitalized patients. Less pronounced hypophosphatemia may occur during the increase in ventilation after the successful treatment of severe asthma. [53]

The effects of respiratory alkalosis are exacerbated by concomitant glucose infusions and may persist after hyperventilation ceases. Respiratory alkalosis also may be the precipitating factor in the hypophosphatemia-induced acute rhabdomyolysis that can occur in alcoholic patients. [54]

Other mechanisms are as follows:

  • Insulin increases cell phosphate uptake and causes hypophosphatemia during treatment of diabetic ketoacidosis, refeeding, and parenteral nutrition therapy
  • Exogenous epinephrine also stimulates cellular phosphate uptake
  • Several cytokines reportedly stimulate intracellular phosphate shifts; this mechanism is perhaps responsible for the hypophosphatemia observed in the ICU setting of trauma, extensive burns, and bone marrow transplantation
  • In hungry bone syndrome, rapid uptake of phosphate into bone occurs after the initial treatment of osteomalacia or rickets or postparathyroidectomy [55]
  • Kidney transplantation

Kidney transplantation

Hypophosphatemia is a common complication of kidney transplantation. [56] Tertiary hyperparathyroidism has long been thought to be the etiology, but hypophosphatemia can occur in patients with low parathyroid hormone (PTH) levels and can persist after high PTH levels normalize. Furthermore, even in the setting of normal allograft function, hypophosphatemia, and hyperparathyroidism, calcitriol levels remain inappropriately low following transplantation, suggesting that mechanisms other than PTH contribute to phosphate homeostasis.

FGF23 induces phosphaturia, inhibits calcitriol synthesis, and accumulates in chronic kidney disease. This factor has been suggested as a possible mediator of posttransplantation hypophosphatemia. [57] Dipyridamole enhances renal tubular phosphate reabsorption and has been shown to be effective in posttransplant hypophosphatemia in small studies.

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