Hyperphosphatemia

I. Problem/Condition.

Hyperphosphatemia is a common laboratory finding that arises from a host of differing causes. Phosphorus is found in bone, soft tissue and within the extracellular fluid. Intracellularly, phosphorus is the substrate for making compounds such as adenosine triphosphate, or ATP. The average person ingests roughly 800 to 1,200 mg per day, and phosphorus is primarily extracted from foods such as: red meat, dairy products, fish, poultry and legumes.

Normal serum phosphorus levels range from 3.0 to 4.5 mg per dL, and in the normal subject it is largely absorbed in the intestines from diet and its excretion is determined primarily by the kidneys. The recommended daily allowance is 800mg/day, however the average American consumes close to 1000-1400mg/day, and roughly two thirds of this is excreted in the urine, the remaining in stool. In the normal functioning kidney, intakes as high as 4,000mg per day will cause only minimal elevations in serum phosphate.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The clinical condition of hyperphosphatemia should be initially organized into one of the following catagories: increased phosphorus load, decreased excretion, increased renal reabsorption of phosphorus, and pseudohyperphosphatemia.

Increased phosphorus load

Hyperphosphatemia as a result of increased phosphorus load occurs in such conditions as tumor lysis syndrome, rhabdomyolysis, lactic acidosis and ingestion of a high phosphorus containing products (found in laxatives).

Decreased phosphorus excretion

Hyperphosphatemia may also result from acute or chronic renal failure, whereby the reduction in glomerular filtration rate (GFR) will reduce the phosphorus filtered and excreted in the renal tubule. In a normal nephron, approximately 70-80% of the filtered phosphorus is reabsorbed in the proximal tubule; the remaining phosphorus (20-30%) is reabsorbed in the distal tubule. In the presence of hyperphosphatemia, the kidneys respond rather quickly, so that sustained elevated phosphorus levels are not seen without renal disease.

Increased phosphorus reabsorption

Increased renal reabsorption gives rise to hyperphosphatemia and occurs in conditions such as hypoparathyroidism, hyperthyroidism, acromegaly, bisphosphonate use, vitamin D toxicity, tumoral calcinosis, and other conditions.

Pseudohyperphosphatemia

Finally, pseudohyperphosphatemia may be a cause for a spurious elevation in phosphorus, and occurs when blood samples are hemolyzed or in conditions such as hyperlipidemia, hyperbilirubinemia, dysproteinemia, and hemolysis.

B. Describe a diagnostic approach/method to the patient with this problem

The diagnosis of hyperphosphatemia is made on laboratory evidence. A serum phosphorus of greater than 4.5mg per dL indicates an elevation beyond a normal value. It is always important to take into account the patient’s GFR as well as serum calcium level. By doing so, quick evidence is obtained to support whether or not renal failure or hypoparathyroidism may be playing a role.

In addition, it remains important to review the patient’s metabolic panal, paying close attention to the patient’s serum bicarbonate, calculated anion gap, transaminasis and urinalysis. If hyperthyroidism is suspected, it is then prudent to follow up with a thyroid stimulating hormone (TSH) and free T4 level. Serum ionized calcium levels and an intact parathyroid hormone (PTH) should be requested if the diagnosis of hypoparathyroidism be in question. These laboratory values will help determine the underlying pathophysiological reason for the hyperphosphatemia.

1. Historical information important in the diagnosis of this problem.

When assessing the patient for hyperphosphatemia, which is a diagnosis grounded in laboratory evidence, it remains important to fit the laboratory data into the context of the patient. Questions should be aimed at asking whether or not the patient has had a history of chronic kidney disease as well as asking about uremic sxs (weight loss, decreased appetite, nausea, fatigue, generalized malaise).

One should ask about previously diagnosed bone disorders or symptoms that may hint to the underlying condition such as bone pain, change in ring size/hat size, vertebral fractures or other long bone fractures. Questions regarding thyroid disorders include asking about weight loss, feeling unusually hot, having more energy, hair and skin changes, etc. It is important to ask about all previous or current malignancies or chemotherapeutic regimens recently used.

Certain medications such as Vitamin D, bisphosphonates and colonic preparations may lead to hyperphosphatemia, so it would be recommended to ask specifically about treatment of osteoporosis or bone fractures, as well as recent use of enemas and colonic purgatives. Likewise, it is important to ask the patient about risk factors for rhabdomyolysis – prolonged immobility, recent trauma or crush type injuries and burns, although this typically is readily available information.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Depending on the etiology of the hyperphosphatemia, there may be very little on physical exam that will be useful in pointing to the underlying condition giving rise to elevated phosphorus levels. The physician should perform a thorough skin and soft tissue exam, evaluating for evidence of trauma that may give rise to soft tissue and muscular injury and in turn, rhabdomyolysis.

One should also palpate over long bones and boney prominences to evaluate for “bone pain” that may be a red flag for malignancy states. Along with assessing bone pain, one should pay close attention to subtle evidence for enlarged hands, frontal bossing which may be present with acromegalics. One should closely examine the skin for evidence of renal “frost” or calcium deposition of the soft tissue from chronically elevated calcium-phosphorus product. Also, an exam of the thyroid gland is recommended.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

It is helpful to first try to catagorize why the serum phosphorus is elevated with a few biochemical markers and then ordering more tests to confirm each diagnosis. The easiest way to do this is to look broadly at very basic tests – taking into account your patient’s complaints and past medical history and medications.

Lab data that will be helpful: serum calcium levels, blood urea nitrogen (BUN), Creatinine, intact PTH, Liver Function studies, thyroid stimulating hormone, urinalysis, urine myoglobin, creatinine kinase, PTHrP, lipids, 1,25-OH-VitD.

Certainly any plain films on hand would be of use to glance at for evidence of lytic bone lesions or evidence of Paget’s disease.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Basic tests include looking for renal failure with BUN/Cr ratios, assessing the PTH-calcium-phosphorus axis by looking at the serum calcium or ionized calcium levels. If the calcium is low, one should check an intact PTH to help determine hypoparathyroidism (low serum calcium and low iPTH) from pseudohypoparathyroidism and chronic kidney disease (CKD – low serum calcium and high iPTH).

If the diagnosis supports pseudohypoparathyroidism, then one should first ensure the sample of blood was not hemolyzed (repeat phosphorus if blood hemolyzed), and consider checking serum lipids as well as liver function tests (LFTs) for dysproteinemia and hyperbilirubinemia. If the calcium is elevated (in the presence of hyperphosphatemia), one should send off 1,25-(OH)vitamin D, which would be elevated in vitamin D intoxication and granulomatous disease.

If rhabdomyolysis is considered, checking a urinalysis for presence of blood present in midst of near absence or disproportionately low red blood cell (RBC) count. A serum CPK and urine myoglobin will help confirm the diagnosis. Liver function tests with an increase in globulin fraction support a diagnosis of dysproteinemia or malignancy states, and an isolated elevated alkaline phosphatase could point toward an infiltrative process in the bone marrow – if it is not coming from the hepatobiliary system.

If there is evidence to support that the hyperphosphatemia is from increased bone turnover, then thyroid studies (TSH) would be indicated, as well as a chest x-ray/skull x-ray to help support making a diagnosis of Paget’s disease of the bone. Also, a parathyroid-related-peptide may be useful if labs seem to suggest that the process is from increased bone turnover with a low intact PTH, elevated serum calcium and elevated serum phosphorus.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

None

III. Management while the Diagnostic Process is Proceeding

A. Management of hyperphosphatemia.

The management should be broken down into the acute and chronic phases of treatment. The acute phase being focused on the rapid reduction of serum phosphorus levels in the short-term, while tackling the long-term treatment should be treating the underlying etiology of hyperphosphatemia.

The acute issue at hand is symptomatic hyperphosphatemia due to it’s effects on serum calcium, PTH and soft tissue.

This typically occurs if the elevation in phosphorus is very abrupt and may lead to symptomatic hypocalcemia marked by tentany, QTc prolongation, and even seizures. When the calcium-phosphorus product nears 60mg2 per dL2, precipitation of calcium-phosphate salts may occur. Once the product exceeds 70mg2 per dL2, metastatic calcification is likely, and is common to occur in the heart, blood vessels, lungs, kidneys, gastric mucosa and cornea.

The goal of treatment for symptomatic hyperphosphatemia should be aimed at forced diuresis. Normal saline infusion is the initial treatment of choice to volume expand and lessen the ability of the proximal tubule to reabsorb the filtered load of phosphorus as well as increase volume in the distal tubule, again limiting the reabsorption and promoting phosphaturia. Loop diuretics may be used for forceful diuresis in conjunction with continued IV fluid hydration once volume expansion has been adequately achieved. This may however also transiently worsen the hypocalcemia with forced diuresis, which needs monitoring and replacement.

Should there be an abrupt increase in phosphorus levels in the setting of renal failure, hemodialysis may be required, although its effects are transient given the equilibration of intracellular and extracellular stores that will ensue promptly after discontinuation of dialysis.

When renal function is intact, managing hyperphosphatemia with intravascular volume expansion and diuresis will result in resolution of hyperphosphatemic state within 6-12 hours. Therefore, for many of the conditions that lead to hyperphosphatemia, prompt recognition, cessation of offending agents and parenteral fluids with forced diuresis will essentially be the cure.

In the setting of chronic kidney disease, restricting dietary phosphorus to 600-900mg per day in patients with sCr of over 30ml/minute will help to maintain near normal levels of sPhos. The goal of therapy should be aimed at trying to keep a near normal calcium-phosphorus product (normal is 40mg2 per dL2). Once the GFR is less than 25ml/min, phosphorus binders are necessary. Phosphate binders should be taken at mealtime to stop further absorption of phosphorus from the diet.

Calcium carbonate or calcium acetate both bind dietary phosphate in the intestine, impairing its absorption in the insoluble calcium phosphate form. Calcium may be absorbed additionally, which may help decrease PTH levels, however can also lead to hypercalcemia when a patient is concomitantly receiving a vitamin D metabolite.

In patients whom hypercalcemia is an issue, a non-absorbable compound such as sevelamer should be used. Vitamin D deficiency should also be corrected to help to reduce secondary hyperparathyroidism and its effects on the skeletal system. Calcitriol should not be given however unless the hyperphosphatemia has been corrected as it will increase the intestinal phosphate absorption.

In patients with tumoral calcinosis, limitation of intestinal absorption of phosphorus along with phosphate binders is typically the treatment of choice.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

One of the most common pitfalls to managing hyperphosphatemia is first of all recognizing the condition and not ignoring the elevation of phosphorus. Often, this may be a subtle clue to underlying problems and warrants a work-up. Also, given the prevelance of renal failure, simply blaming the kidneys for the elevated phosphorus is another common pitfall.

A thorough work-up of the hyperphosphatemia should be performed, so as not to miss an underlying process.

Another common mistake seen in patients with hyperphosphatemia secondary to CKD is simply that patients forget to take their phosphate binders with food. These medications, whether in form of calcium salts or non-absorbable compounds, must be taken prior to all meals in addition to snacks that are high in phosphorus. Simply ensuring that this is done is one step that is absolutely necessary.

All patients undergoing treatment for hyperphosphatemia, especially those with severely elevated levels, need to be monitored for hypocalcemic effects. Hypocalcemia may worsen as the phosphorus level is reduced in the acute phase, which may also lower the calcium to levels that prolong the QTc, cause or worsen tetany. Correcting the serum calcium may be necessary in the short-term.

What's the evidence?

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“clinical practice guidelines for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)”. Kidney Int. vol. 76. 2009. pp. S1

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Moe, S. “Disorders Involving Calcium, Phosphorus, and Magnesium”. Prim Care. vol. 32. 2008. pp. 215-vi.

Murer, H. “Homer Smith Award. Cellular mechanisms in proximal tubular Pi reabsorption: some answers and more questions”. J Am Soc Nephrol. vol. 2. 1992. pp. 1649

Murer, H, Lotscher, M, Kaissling, B. “Renal brush border membrane Na/Pi-cotransport: molectular aspects in PTH-dependent and dietary regulation”. Kidney Int. vol. 49. 1996. pp. 1769

O’Connor, LR, Klein, KL, Bethune, JE. “Hyperphosphatemia in lactic acidosis”. N Engl J Med. vol. 297. 1977. pp. 707

Yu, GC, Lee, DB. “Clinical Disorders of Phosphorus Metabolism”. West J Med. vol. 147. 1987. pp. 569-76.

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