Hypophosphatemia - Background

Phosphate is the most abundant intracellular anion and is essential for membrane structure, energy storage, and transport in all cells. In particular, phosphate is necessary to produce ATP, which provides energy for nearly all cell functions. Phosphate is an essential component of DNA and RNA. Phosphate is also necessary in red blood cells for production of 2,3diphosphoglycerate (2,3-DPG), which facilitates release of oxygen from hemoglobin. Hypophosphatemia is defined as a phosphate level of less than 2.5 mg/dL (0.8 mmol/L). Phosphate is critical for an incredible array of cellular processes. It is one of the major components of the skeleton, providing mineral strength to bone. Phosphate is an integral component of the nucleic acids that comprise DNA and RNA. Phosphate bonds of ATP carry the energy required for all cellular functions. It also functions as a buffer in bone, serum, and urine. The addition and deletion of phosphate groups to enzymes and proteins are common mechanisms for the regulation of their activity. In view of the sheer breadth of influence of this mineral, the fact that phosphate homeostasis is a highly regulated process is not surprising. Approximately 85% of the body's phosphorus is in bone as hydroxyapatite, while most of the remainder (15%) is present in soft tissue. Only 0.1% of phosphorus is present in extracellular fluid, and it is this fraction that is measured with a serum phosphorus level. Reducing available phosphate may compromise any organ system, alone or in combination. The critical role phosphate plays in every cell, tissue, and organ explains the systemic nature of injury caused by phosphate deficiency. Serum phosphate or phosphorus normally ranges from 2.5-4.5 mg/dL (0.81-1.45 mmol/L) in adults. Hypophosphatemia is defined as mild (2-2.5 mg/dL, or 0.65-0.81 mmol/L), moderate (12 mg/dL, or 0.32-0.65 mmol/L), or severe (< 1 mg/dL, or 0.32 mmol/L). Mild to moderately severe hypophosphatemia is usually asymptomatic. Major clinical sequelae usually occur only in severe hypophosphatemia. As in the case of other intracellular ions (eg, potassium, magnesium), a decrease in the level of serum phosphate (hypophosphatemia) should be distinguished from a decrease in total body storage of phosphate (phosphate deficiency).

Pathophysiology
Phosphorus homeostasis is complex and regulated by the actions of several hormones. Parathyroid hormone causes phosphate to be released from bone and inhibits renal reabsorption of phosphorus, resulting in phosphaturia. Vitamin D aids in the intestinal reabsorption of phosphorus. Thyroid hormone and growth hormone act to increase renal reabsorption of phosphate. Finally, a new class of phosphate-regulating factors, the so-called phosphatonins, have been shown to be important in phosphate-wasting diseases, such as oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia, and tumoral calcinosis.[1]

Hypophosphatemia is caused by the intracellular shift of phosphate from serum, increased urinary excretion of phosphate, decreased intestinal absorption of phosphate, or decreased dietary intake. Hypophosphatemia may be transient, reflecting intracellular shift with minimal clinical consequences. The disease also may reflect a deeper state of total body phosphate depletion with significant sequelae.

Intracellular shift
Respiratory alkalosis moves phosphate into cells by activating phosphofructokinase, which stimulates intracellular glycolysis. Glycolysis leads to phosphate consumption as phosphorylated glucose precursors are produced. Any cause of hyperventilation (eg, sepsis, anxiety, pain, heatstroke, alcohol withdrawal, diabetic ketoacidosis [DKA], hepatic encephalopathy, salicylate toxicity) can precipitate hypophosphatemia. Since respiratory alkalosis is one of the most common causes of hypophosphatemia, discovery of hypophosphatemia should prompt a search for the serious causes of hyperventilation, when clinically appropriate.[2] Administering carbohydrate lowers serum phosphate by stimulating the release of insulin, which moves phosphate and glucose into cells. This so-called refeeding syndrome occurs when starving or chronically malnourished patients are refed or given intravenous (IV) glucose, and typically produces a hypophosphatemic state by treatment day 3 or 4. In addition, during refeeding, cells switch to an anabolic state, resulting in further phosphate depletion as this essential substrate is incorporated into cells and cell products.[3] Diabetic ketoacidosis is also an important cause of hypophosphatemia. Metabolic acidosis and insulin deficiency will mobilize intracellular phosphate stores, causing them to shift to the extracellular space and leading to urinary losses.[4] Treatment of DKA with insulin causes phosphate to move back into cells resulting in a decrease of serum phosphate levels. Routine replacement of phosphate in the setting of DKA is not proven to decrease morbidity or mortality. However, because patients in DKA are often hypokalemic and hypophosphatemic, some clinicians replete these losses with potassium phosphate salts. Catecholamines and beta-receptor agonists also stimulate phosphate uptake into cells. Certain rapidly growing malignancies (eg, acute leukemia, lymphomas) may consume phosphate preferentially, leading to hypophosphatemia. In most cases of intracellular phosphate shift, serum phosphate normalizes once the precipitating cause is removed.

Increased urinary excretion

Since parathyroid hormone stimulates the kidneys to excrete phosphate, hypophosphatemia is a common sequela of primary and secondary hyperparathyroidism. Urinary loss of phosphate also occurs with acute volume expansion due to a dilution of serum calcium, which, in turn, triggers an increase in the release of parathyroid hormone. Osmotic diuresis, such as seen in hyperosmolar hyperglycemic syndrome (HHS), also produces increased urinary excretion of phosphorus. Diuretics, including loop diuretics, thiazides, and carbonic anhydrase inhibitors (eg, acetazolamide) interfere with the ability of the proximal tubule to reabsorb phosphorus, thus producing hyperphosphaturia and potentially leading to hypophosphatemia. Patients with transplanted kidneys, congenital defects (X-linked hypophosphatemia [XLH] and autosomal dominant hypophosphatemic rickets [ADHR]), or Fanconi syndrome (proximal tubule dysfunction) also may excrete excess urinary phosphate.[5] There is also evidence that shows estrogen to be a downregulator of a renal sodium phosphate cotransporter, causing significant hypophosphatemia in patients.[6]

Decreased intestinal absorption

Phosphate may be lost via the gut, as in chronic diarrhea, malabsorption syndromes, severe vomiting, or NG suctioning. Phosphate may also be bound in the gut, thereby preventing absorption (eg, chronic use of sucralfate, or phosphate-binding antacids, including aluminum hydroxide, aluminum carbonate, and calcium carbonate). Also, the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.[7]

Decreased dietary intake

Decreased dietary intake of phosphate is a rare cause of hypophosphatemia because of the ubiquity of phosphate in foods. Dietary sources of phosphate include fruits, vegetables, meats, and dairy products. Vitamin D enhances the absorption of both phosphate and calcium. Certain conditions such as anorexia nervosa or chronic alcoholism may lead to hypophosphatemia in part due to this mechanism, as well as increased renal excretion.

Manifestations of phosphate deficiency

Weakness of skeletal or smooth muscle is the most common clinical manifestation of phosphate deficiency. It can involve any muscle group, alone or in combination, ranging from ophthalmoplegia to proximal myopathy to dysphagia or ileus. Hypophosphatemia also causes rhabdomyolysis via ATP depletion and the consequent inability of muscle cells to maintain membrane integrity. Patients undergoing acute alcohol withdrawal are especially vulnerable to rhabdomyolysis secondary to hypophosphatemia, which is caused by the rapid uptake of phosphate into muscle cells. Rhabdomyolysis occurs more rarely in patients being treated for DKA or being refed after starvation. Respiratory insufficiency may occur in some patients with severe hypophosphatemia, particularly when the underlying cause is malnourishment. Impaired cardiac contractility occurs, leading to generalized signs of myocardial depression. Blood pressure and stroke volume have been shown to improve when serum phosphorus is corrected. The hypophosphatemic myocardium also has a reduced threshold for ventricular arrhythmias. Phosphate deficiency commonly impairs neurologic function, which may be manifested by confusion, seizures, and coma. Peripheral neuropathy and ascending motor paralysis, similar to Guillain-Barr syndrome, may occur.[8] Extrapontine myelinolysis has also been reported. Hematologic function may be impaired. The hemolytic anemia associated with severe hypophosphatemia has been attributed to the inability of erythrocytes to maintain integrity of cell membranes in the face of ATP depletion, leading to their destruction in the spleen. Phosphate deficiency also compromises oxygen delivery to the tissues due to decreases in erythrocyte 2,3-DPG and the resulting leftward shift in the oxygen-hemoglobin dissociation curve. Diminished oxygen delivery to the brain may be the cause of some of the neurologic manifestations mentioned above. Leukocyte function is affected, which results in impaired chemotaxis and phagocytosis. Manifestations of phosphate deficiency may occur singly or simultaneously.

Epidemiology
Frequency
United States Hypophosphatemia may occur in as many as 2-3% of hospitalized patients and in as many as 30% of patients admitted to ICUs. Certain subgroups, including HIV-positive patients and patients with falciparum malaria, have higher rates of hypophosphatemia than the general public (17% and 38.5%, respectively, in 2 separate studies), although the significance of this is unknown. Fortunately, severe hypophosphatemia is rare, occurring in no more than 0.5% of hospitalized patients.

Sex

No predilection is known.

Age

Hypophosphatemia can affect people of all ages.

History

Weakness is the most common symptom suggesting hypophosphatemia and may involve any muscular system to any extent. o Diplopia o Dysarthria o Dysphagia o Weakness of trunk or extremities, particularly the large muscle groups Symptoms of respiratory insufficiency or myocardial depression may indicate hypophosphatemia. Neurologic symptoms may vary, ranging from simple paresthesias to profound alterations in mental status.

Laboratory Studies

Serum calcium, magnesium, and potassium o In addition to serum phosphate studies, calcium and magnesium studies can be helpful. High calcium levels coupled with low phosphate levels suggest primary hyperparathyroidism, while low calcium levels suggest vitamin D deficiency or malabsorption. Because of the many factors that regulate calcium independently of phosphate, serum calcium concentrations may be within reference ranges in either of these circumstances and thus cannot be used for a definitive diagnosis. o Low magnesium levels are also suggestive of poor nutrition. o Serum potassium derangements, especially hypokalemia, may occur with certain hypophosphatemic conditions, such as DKA and alcoholism. Serum albumin o Because almost half of serum albumin is bound to serum calcium, changes in serum albumin levels affect the total calcium concentration. o Thus, in hypoalbuminemia, a decrease in albumin of 1 g/dL causes a fall in total calcium of approximately 0.8 mg/dL. Intact PTH and vitamin D levels

Primary hyperparathyroidism is very common, especially in elderly persons. Vitamin D deficiency is also very common, especially in geriatric or chronically ill persons. o The excellent assays available for evaluation of PTH and vitamin D levels have simplified confirmation of the diagnosis of PTH and vitamin D disorders. o A high PTH level in the presence of high calcium and low phosphate levels is very suggestive of primary hyperparathyroidism. If the PTH level is high and the calcium and phosphate levels are low, secondary hyperparathyroidism is probable, perhaps due to intestinal malabsorption. The intestinal malabsorption could be due to isolated vitamin D deficiency or to a primary gastrointestinal disorder. Arterial blood gas: An arterial blood gas study should be ordered if respiratory alkalosis is under consideration as a cause of hypophosphatemia. Serum lactate, CBC with differential, and serum ammonia level, may be useful in selected patients to investigate some of the common causes of hypophosphatemia, such as sepsis and hepatic encephalopathy, which can cause respiratory alkalosis with subsequent hypophosphatemia. Urinary phosphorus determination o A 24-hour urine collection for phosphate can be performed if the question of phosphate wasting is unresolved. o A fractional excretion of phosphate of greater than 15% in the presence of hypophosphatemia confirms the presence of renal phosphate wasting. Urinalysis - Phosphate wasting and subsequent hypophosphatemia can be due to proximal tubule disorders, such as Fanconi syndrome. To determine if the patient has a generalized proximal renal tubule disorder, urinalysis should be performed and serum bicarbonate, serum glucose, and serum uric acid levels should be measured. Full-blown Fanconi syndrome consists of renal glycosuria, aminoaciduria, type II renal tubular acidosis, hypouricemia due to hyperuricosuria, and hypophosphatemia due to phosphate wasting. When Fanconi syndrome is present, the urinalysis demonstrates the presence of amino acids (proteinuria) and glucose. If the urine dipstick is positive for glucose at a time when the serum glucose concentration is less than 180 mg/dL, then renal glycosuria or renal glucose wasting is also present. Uric acid levels are also low, often less than 2 mg/dL. Evidence of mild nonanion gap metabolic acidosis is observed on the renal profile.

Imaging Studies

If a phosphate wasting syndrome is suggested, then bone films to evaluate for osteopenia, osteomalacia, or hyperparathyroidism are indicated. Although plain bone films cannot yield histologic data, looser zones are very suggestive of osteomalacia. Erosions of the distal phalanges and clavicles and circular punched-out lesions in the long bones are highly typical of primary hyperparathyroidism. Ultrasonographic images of the neck can help, at times, identify a parathyroid adenoma. A technetium Tc 99m sestamibi scan may be more useful. Uptake of the radioactive tracer has the advantage of being able to pick up ectopic parathyroid tissue. Bone densitometry is also useful for assessing the chronicity and the severity of phosphate wasting. Chronic phosphate deficiencies result in significant decreases in bone density, while mild transient hypophosphatemia does not. Mesenchymal tumors that can cause oncogenic osteomalacia have been discovered with the use of indium In 111 octreotide scanning, CT scanning, or MRI.

Procedures

Bone biopsy is the only method for defining bone pathology. Hyperparathyroidism and osteomalacia may both have classic radiologic findings, but when the radiograph shows only osteopenia, bone biopsy findings help distinguish between these pathologies. The finding of osteomalacia directs the diagnostic studies toward vitamin D deficiency, malabsorption, or oncogenic osteomalacia. On the other hand, classic findings of hyperparathyroidism prompt the search for parathyroid disease.

Histologic Findings
Most parathyroid lesions are adenomas. Occasionally, a carcinoma is found. Most of the tumors causing oncogenic osteomalacia are benign (eg, hemangiopericytoma).

Emergency Department Care

Treatment of hypophosphatemia is twofold. o Correct any precipitating causes of hypophosphatemia. o Replace total body phosphates. Depending on the clinical situation, replacement options include dietary phosphate, oral phosphate preparations, and IV phosphate. Hypophosphatemia and hypokalemia can coexist in certain disorders like diabetic ketoacidosis and alcoholism, so replacement with the potassium salt is most appropriate. The most important consideration in choosing replacement therapy is whether the patient has signs or symptoms of phosphate depletion. Mild to moderately severe, asymptomatic hypophosphatemia o Mild to moderately severe, asymptomatic hypophosphatemia may require oral phosphate replacement; however, correcting factors that led to the hypophosphatemia usually is sufficient. o In most asymptomatic patients, the serum phosphate level spontaneously normalizes over several days when factors inducing hypophosphatemia are corrected. o In patients with minimal symptoms or moderate hypophosphatemia (serum phosphate 1-2 mg/dL), providing oral phosphate replacement may be desirable. o The average adult consumes 1 gram of phosphorus daily. A quart of cow's milk provides this amount of phosphorus (1 mg phosphorus/mL). Dairy products have an additional advantage of supplying absorbable calcium, which can help avoid the hypocalcemia that may result with more aggressive replacement regimens. o Phosphorus preparations with sodium and potassium are available, but they have disadvantages, including causing osmotic diarrhea, volume overload, or hyperkalemia. o Usual starting doses are 2-3 grams of elemental phosphorus in divided doses.

Severe/symptomatic hypophosphatemia o Patients with symptoms of hypophosphatemia or with serum phosphate levels less than 1 mg/dL require IV phosphate replacement.

o o

The intracellular nature of phosphate makes interpreting a low serum phosphate level difficult and predicting the amount required to replenish cellular stores nearly impossible. Accordingly, recommendations for IV phosphate in the literature are varied and based on therapeutic experiences with limited numbers of patients. Avoid hyperphosphatemia when replacing phosphorus intravenously, as this can lead to hypocalcemia (leading to tetany) and calcium-phosphate deposition in tissues (eye, heart, kidney, lung).

Further Inpatient Care

Patients with severe or symptomatic hypophosphatemia should be admitted for IV replacement therapy. Since isolated phosphate deficiency is extremely unlikely, these patients invariably have a comorbid reason for admission. Equilibration of IV with intracellular phosphate usually leads to recurrence of hypophosphatemia, making periodic monitoring and replacement necessary over the ensuing 2 days. A rational approach to IV phosphate replacement is to administer a predefined amount of phosphate, then reevaluate the resulting serum phosphate level every 6 hours to guide further treatment.