Disorders of phosphorus metabolism

Normal phosphorus physiology

1. What is the difference between phosphate and phosphorus and how are they measured in clinical medicine?

Phosphorus is a critical element in physiology. Phosphorus is an essential component of bone (hydroxyapatite), DNA, lipid membranes (phospholipids), signal molecules (phosphorylation activates numerous enzymes), and chemical energy storage (adenosine triphosphate and creatine phosphate). In the serum, phosphorus circulates as phosphate, PO 4 −3 usually with one or two protons, H 2 PO 4 or HPO 4 2− ( Fig. 76.1 ).

Figure 76.1.

There are four forms of phosphate, with two found in the body. Hydrogen phosphate is the dominant form in the extracellular compartment, while dihydrogen phosphate is more common in the intracellular compartment. The other forms are essentially nonexistent in the body.

The atomic weight of phosphorus is 31 g/mole and the average valence (pH 7.4) is 1.8. Normal serum phosphorus is 2.5 to 4.5 mg/dL. This converts to 0.8 to 1.45 mmol/L or 1.45 to 2.61 mEq/L.

2. Where is phosphorus found in the body?

There is 780 mg in a typical 70 kg man. Almost all of it (80% to 85%) is found in teeth and bones as hydroxyapatite. Only 0.1% is found in the extracellular fluid.

3. Tell me about dietary phosphorus intake.

Organic phosphorus is found in meat, fish, dairy, whole grains, and nuts. However, most of the phosphorus we encounter in our diet is in the form of inorganic phosphorus added during food processing to enhance flavor and to improve color, and it serves as a preservative. Between 40% and 80% of dietary phosphorus is absorbed. The variability is largely due to the type of phosphorus consumed. Organic phosphorus is typically bound to proteins and must be metabolized to phosphate prior to absorption. Only about 40% to 60% of organic phosphorus is absorbed. Phosphate from animal protein is better absorbed than plant phosphate (phytate). Inorganic phosphate is more bioavailable, with as high as 90% absorption. The institute of medicine recommends 750 mg of phosphorus per day, with larger requirements (1250 mg/day) for children and pregnant women.

Food tables that list the phosphorus content do not include the phosphorus used as preservatives and so tend to underestimate daily phosphorus intake by as much as 272 to 350 mg.

Phosphate absorption in the gastrointestinal (GI) tract is largely unregulated, so increased dietary phosphate ingestion increases phosphate absorption. Active (1,25-OH) vitamin D also increases phosphate absorption.

4. How is phosphorus handled by the kidney?

The kidney filters between 3700 and 6100 mg of phosphate a day. Phosphate excretion is about 600 to 1500 mg/day, so about 75% to 85% of filtered phosphate is reabsorbed by the kidney. The proximal tubule reabsorbs about 85% of the filtered load via a triad of sodium-phosphate cotransporters (NaPi-2a, NaPi-2c, PiT-2). Phosphate reabsorption is regulated by numerous dietary, metabolic, and hormonal factors. Calculating the tubular reabsorption of phosphorous (TRphos) can provide insight into renal phosphorus handling. See Equation 76.1 .

Equation 76.1.

The tubular reabsorption of phosphorus is the percentage of filtered phosphorus, which is subsequently reabsorbed. It is one minus the fractional excretion of phosphorus. It is generally between 75% and 85%.

Factors that lead to increased renal phosphate absorption include a low phosphate diet, 1,25-OH vitamin D, and thyroid hormone. On the other hand, parathyroid hormone (PTH), fibroblast growth factor (FGF)23, a high phosphate diet, metabolic acidosis, potassium deficiency, glucocorticoids, dopamine, hypertension, and estrogen lower phosphate absorption.

5. What is FGF-23?

FGF-23 is classified as a phosphotonin—a hormone that increases urinary phosphorus. It is produced and released by osteocytes in response to increased serum phosphorus. When FGF-23 binds its receptor and the receptor’s co-factor, Klotho, it decreases phosphorus reabsorption in the proximal tubule. It also decreases 1-alpha hydroxylase, lowering 1,25-OH D levels. FGF-23 also can directly suppress PTH. Increases in FGF-23 are found early in chronic kidney disease (CKD) and is responsible for the decreased 1,25-OH D levels found in CKD. It helps maintain normal phosphate levels despite compromised glomerular filtration rate (GFR).


6. What is the difference between phosphate depletion and hypophosphatemia?

Phosphate depletion is a decrease in the total body soluble phosphate. Hypophosphatemia is a low serum phosphate level. Hypophosphatemia can be due to a decreased total phosphate level or to altered transcellular distribution of phosphorus into the intracellular compartment. Often, patients with phosphate depletion can maintain normal phosphate levels for a while, but are predisposed to sudden and acute drops in phosphate levels from events that shift phosphate into cells.

7. What is the definition of hypophosphatemia and how common is it?

Hypophosphatemia is defined as serum phosphate level less than 2.5 mg/dL (0.8 mmol/L). In unselected hospitalized patients, hypophosphatemia has a prevalence of 2% to 3%. However, that increases dramatically in selected populations: 34% for intensive care unit patients, 65% to 80% for patients with sepsis.

8. What are the causes of hypophosphatemia?

The causes of hypophosphatemia should be organized by decreased intake and GI losses, transcellular shift, and increased renal phosphate wasting. Since phosphorus is a common constituent of food, decreased dietary intake is a rare cause of hypophosphatemia. However, malabsorption or increased colonic secretion from diarrhea can result in hypophosphatemia. Some cases of hypophosphatemia occur with chronic overuse of phosphorus binders or calcium-, magnesium-, or aluminum-containing antacids that block phosphorus absorption. Pharmaceutical niacin causes a modest reduction in serum phosphorus (0.3 mg/dL, 0.1 mmol/L), which is thought to be due to decreased GI absorption.

Increased renal phosphate excretion is a common cause of hypophosphatemia. Since PTH decreases renal phosphorus absorption by decreasing sodium-phosphate cotransporter activity in the proximal tubule, primary hyperparathyroidism is the prototypical example of renal phosphorous wasting. A unique form of hyperparathyroidism can occur after a kidney transplant. Patients with significant secondary hyperparathyroidism prior to transplant often have prolonged hypophosphatemia because they are unable to adequately suppress PTH following the transplant. In others, the hypophosphatemia persists despite normal PTH. In a series of 27 living donor transplants, FGF-23 was found to correlate best with post-transplant phosphorus levels.

Vitamin D deficiency can lead to hypocalcemia. This causes secondary hyperparathyroidism, which decreases serum phosphorus. This is made worse by decreased dietary phosphorus absorption from the lack of vitamin D.

Generalized dysfunction in the proximal tubule, Fanconi syndrome, is characterized by hypophosphatemia, in addition to glucosuria, proximal renal tubular acidosis, hypokalemia, and aminoaciduria.

Autosomal dominant hypophosphatemic rickets causes renal wasting of phosphorus. Patients are unable to mineralize bones so they end up with soft bones. It is due to an inability to inactivate FGF-23, which results in increased renal phosphorus wasting. A similar phenotype is seen in X-linked hypophosphatemic rickets ; however, in this condition, there is an inactivating mutation of PHEX, which normally decreases the expression of FGF-23.

The last major cause of hypophosphatemia is transcellular shift, where phosphorus is either shifted into cells or taken up by bones. The former occurs with increases in insulin. Refeeding syndrome occurs in patients with total body phosphorus depletion, who then undergo a fast of 2 to 3 days. When they resume eating, the sudden increase in carbohydrates causes a release of insulin which shifts glucose, potassium, and phosphorus into cells. Phosphorus, which is already somewhat depleted, is rapidly consumed with the conversion of glucose to glucose 6-phosphate.

Respiratory alkalosis reliably causes a shift of phosphorus into cells.

The other sudden cause of hypophosphatemia is hungry bone syndrome, which occurs in patients with significant secondary or tertiary hyperparathyroidism, which is then corrected by surgical removal of the parathyroid glands. This triggers a sudden drop in PTH and rapid remineralization of osteoid throughout the skeleton, causing sudden drops in serum calcium, phosphorus, magnesium, and potassium.

9. How does hypophosphatemia present?

Since phosphorus is a key ingredient to the cellular energy molecule, adenosine triphosphate (ATP), hypophosphatemia causes symptoms related to the lack of ATP. Symptoms are rare until the phosphorus falls below 1 mg/dL (0.32 mmol/L). The most severe hypophosphatemia can cause hemolysis from decreased red blood cell deformability due to ATP depletion. Hypophosphatemia can also cause rhabdomyolysis. Hemolysis and rhabdomyolysis both release intracellular phosphorus covering the tracks of the inciting hypophosphatemia.

A number of studies have associated hypophosphatemia with increased hospital mortality; however, the lack of randomized, interventional trials keeps the question open of whether the hypophosphatemia causes or is associated with the increased mortality.

Hypophosphatemia has been associated with decreased respiratory muscle strength resulting in increased duration of mechanical ventilation. Others have reported decreased myocardial contractility, and improved left ventricular performance was documented with the correction of severe (<1 mg/dL or 0.3 mmol/L) but not moderate hypophosphatemia. Decreased phosphorus can result in central nervous system (CNS) symptoms ranging from paresthesias (perioral numbness) to irritability, delirium, seizures, and coma.

10. How should one approach evaluating the cause of hypophosphatemia?

Generally, the cause of the hypophosphatemia can be elucidated from the patient’s history, focusing on diet, nutritional status, social habits, and medication use. In situations where it is not clear, a 24-hour urinary phosphate or calculating the TRphos can distinguish renal wasting from GI loss or cellular redistribution. A 24-hour urinary phosphate excretion <100 mg or TRphos >95% is indicative of appropriate renal phosphate retention in the setting of hypophosphatemia.

11. How should hypophosphatemia be treated?

Moderate hypophosphatemia (phosphorus >1 mg/dL, 0.32 mmol/L) and asymptomatic patients can be treated with oral phosphate. Cow’s milk is a good source of phosphate. Typical oral dosing is 40 to 80 mmol (124 to 248 mg) divided into four doses over 24 hours. Severe hypophosphatemia (<1 mg/dL, 0.32 mmol/L) and patients who cannot tolerate oral replacement need intravenous (IV) replacement. IV phosphorus can cause hypocalcemia, kidney failure, hypotension, hyperphosphatemia, and electrocardiogram (ECG) abnormalities. These complications can be avoided with moderate doses. A safe dose is considered to be 15 mmol over 2 hours; however, doses graded by weight and phosphorus level were shown to be more effective and just as safe in a prospective trial.

This protocol ( Table 76.1 ) corrected 78% of patients with hypophosphatemia with a single dose administered over 6 hours (compared to 47% prior to the protocol) and resulted in no cases of hyperphosphatemia (compared to 16 episodes prior to the protocol).

Table 76.1.

Phosphorus Treatment Protocol

From Taylor, B. E., Huey, W. Y., Buchman, T. G., Boyle, W. A., & Coopersmith, C. M. (2004). Treatment of hypophosphatemia using a protocol based on patient weight and serum phosphorus level in a surgical intensive care unit. Journal of the American College of Surgeons, 198 (2), 198–204.

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Jul 23, 2019 | Posted by in NEPHROLOGY | Comments Off on Disorders of phosphorus metabolism
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