Amy Barton Pai
Severe acute hypercalcemia can result in cardiac arrhythmias, whereas chronic hypercalcemia can lead to calcium deposition in soft tissues including blood vessels and the kidney.
The correction of hypercalcemia can include multiple pharmacotherapeutic modalities such as hydration, diuretics, bisphosphonates, and steroids, depending on the etiology and acuity of the hypercalcemia.
Hypocalcemia is typically associated with an insidious onset; however, some drugs such as cinacalcet are associated with rapid decreases in serum calcium.
Acute treatment of hypocalcemia requires calcium supplementation whereas chronic management may require other therapies such as vitamin D to maintain serum calcium values.
Hyperphosphatemia occurs most frequently in patients with chronic kidney disease (CKD).
Treatment of nonemergent hyperphosphatemia includes the use of phosphate binders to decrease absorption of phosphorus from the GI tract.
Hypophosphatemia is a relatively common complication among critically ill patients.
Treatment of acute hypophosphatemia usually requires IV supplementation of phosphorous salts.
Disorders of calcium and phosphorus are common complications of multiple acute and chronic diseases. These disorders are frequently seen in the acute care setting; however, they are also often present in ambulatory patients, usually in a less severe state. The consequences of electrolyte disorders can range from asymptomatic to life-threatening, requiring hospitalization and emergent treatment. The maintenance of fluid and electrolyte homeostasis requires adequate functioning and modulation by multiple hormones on tissues of multiple organ systems.
There are many common drug therapies that can disturb the normal homeostatic mechanisms that maintain calcium and phosphorous balance. In addition, with some drug therapies, toxicity is enhanced when underlying electrolyte disorders are present. Drug-induced disorders typically respond well to discontinuation of the offending agent(s); however, additional therapies are sometimes required to correct the disorder. This chapter reviews the etiology, classification, clinical presentation, and therapy for the most common disorders of calcium and phosphorus homeostasis.
DISORDERS OF CALCIUM HOMEOSTASIS
The maintenance of physiologic calcium concentrations in the intracellular and extracellular spaces is vital for the preservation and function of cell membranes; propagation of neuromuscular activity; regulation of endocrine and exocrine secretory functions; blood coagulation cascade; platelet adhesion process; bone metabolism; muscle cell excitation/contraction coupling; and mediation of the electrophysiologic slow-channel response in cardiac and smooth-muscle tissue.
The disorders of calcium homeostasis are related to the calcium content of the extracellular fluid (ECF), which is tightly regulated and comprises less than 0.5% of the total body stores of calcium. Skeletal bone contains more than 99% of total body stores of calcium.1 ECF calcium is moderately bound to plasma proteins (46%), primarily albumin.2 Ionized or free calcium is the physiologically active form and is the fraction that is homeostatically regulated.3 Extracellular calcium, however, is most commonly measured as the total serum calcium level, which includes both bound and unbound calcium.2 The normal total calcium serum concentration range is 8.5 to 10.5 mg/dL (2.13 to 2.63 mmol/L).3
Proper assessment of total serum calcium concentrations includes measurement of the patient’s serum albumin concentration. Hypoalbuminemia, which can be associated with many chronic disease states, is probably the most common cause of “laboratory hypocalcemia.” Patients remain asymptomatic because the unbound or ionized fraction of serum calcium remains normal (normal range, 4.4 to 5.4 mg/dL [1.10 to 1.35 mmol/L]). A corrected total serum calcium (Sca) concentration can be calculated based on the measured total serum calcium and the difference between a patient’s measured albumin concentration and the normative value of 4 g/dL (40 g/L) by the following equations:
The concentration of ionized calcium is closely regulated by the interactions of parathyroid hormone (PTH), phosphorus, vitamin D, and calcitonin (Fig. 35-1). PTH increases serum calcium concentrations by stimulating calcium release from bone, increasing renal tubular reabsorption, and enhancing absorption in the GI tract secondary to increased renal production of 1,25-dihydroxy vitamin D3. Vitamin D directly increases serum calcium, as well as phosphorus concentrations, by increasing GI absorption. Indirectly, it can also lead to calcium release from bone and reduced renal excretion. Calcitonin inhibits osteoclastic bone resorption. Its plasma concentrations are increased when ionized calcium concentrations are high as the body attempts to return the calcium level to the normal range. Disruption of these homeostatic mechanisms results in the clinical manifestations of hypercalcemia or hypocalcemia.
FIGURE 35-1 Homeostatic mechanisms to maintain serum calcium concentrations.
Alteration of the concentration of albumin or its binding of calcium can be expected to change the unbound fraction of total serum calcium. The most significant cause of changes in calcium binding to albumin is a change in ECF pH. In the presence of acute metabolic alkalosis the fraction of calcium bound to albumin is increased, thus reducing the plasma concentration of ionized calcium. This can result in symptomatic hypocalcemia; that is, paresthesia, muscle cramping and spasms, memory loss, and seizures.1 Conversely, metabolic acidosis decreases calcium binding to albumin and results in increased ionized calcium. Hypoalbuminemic states are probably the most common cause of “laboratory hypocalcemia.” When the albumin level is decreased, the ionized calcium concentration can be normal, although total serum calcium concentration is low. Each 1 g/dL (10 g/L) drop in the serum albumin concentration below 4 g/dL (40 g/L) will result in a decrease of total serum calcium concentration by 0.8 mg/dL (0.20 mmol/L).1,2 This approach of calculating an albumin-adjusted calcium concentration has been found to overestimate the degree of hypercalcemia and usually fails to identify hypocalcemia in critically ill patients; therefore, ionized calcium values should be used to assess calcium status in these patients.4,5
There are multiple and diverse causes of hypercalcemia (total serum calcium >10.5 mg/dL [>2.62 mmol/L]) (Table 35-1). The most common causes of hypercalcemia are cancer and primary hyperparathyroidism.
TABLE 35-1 Etiologies of Hypercalcemia
Epidemiology and Etiology
The reported incidence of primary hyperparathyroidism in the United States ranges from 10 to 30 cases per 100,000 people.6 Hypercalcemia of cancer occurs in approximately 20% to 40% of cancer patients at some time during the course of their disease.7 Cancer-associated hypercalcemia is predominantly encountered in hospitalized patients, whereas primary hyperparathyroidism accounts for the vast majority of cases in the outpatient setting.8,9
Hypercalcemia is the result of one or a combination of three primary mechanisms: increased bone resorption, increased GI absorption, or increased tubular reabsorption by the kidneys (see Fig. 35-1).
Many tumors secrete PTH-related protein (PTHrP), which binds to the PTH receptors in bone and renal tissues, leading to increased bone resorption and renal tubular reabsorption.11 Tumors can also secrete substances such as vitamin D, transforming growth factor, interleukins, prostaglandins, interferon, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor, which are associated with the development of hypercalcemia.7Hypercalcemia of malignancy is a common complication of squamous cell carcinomas of the lung, head, and neck, hematologic malignancies such as multiple myeloma and T-cell lymphomas, and carcinomas of ovary, kidney, bladder, and breast. The most frequent types of malignancy associated with hypercalcemia are carcinomas of the lung and breast.7 Breast and squamous cell lung carcinomas secrete PTHrP which binds to the type I PTH receptor (PTHR1) and enhances bone resorption.10,11 In contrast, up to 40% of patients with multiple myeloma develop hypercalcemia principally as the result of osteoclast-mediated bone destruction.7
Primary hyperparathyroidism is the most common cause of chronic hypercalcemia in the general population. Benign parathyroid adenomas account for 80% to 85% of these cases of hyperparathyroidism, parathyroid hyperplasia accounts for 15%, and parathyroid carcinoma is the cause in less than 1% of cases.9
Other causes of chronic hypercalcemia include medications, endocrine and granulomatous disorders, physical immobilization, high bone-turnover states (adolescence and Paget’s disease), and rhabdomyolysis. Increased GI absorption can be the result of excessive ingestion of vitamin D analogs, calcium supplements, and lithium. Lithium and vitamin A therapy can increase bone resorption, whereas increased renal tubular reabsorption of calcium can occur with thiazide and lithium therapy. The exact mechanism of lithium-induced hypercalcemia is not known but may include competitive inhibition of calcium influx into cells, increasing the threshold sensitivity of the calcium-sensing receptor (CaSr) and subsequent inhibition of PTH gene transcription.8 Addison’s disease, acromegaly, and thyrotoxicosis are endocrine disorders that can lead to hypercalcemia because of increased renal tubular reabsorption and increased bone resorption. Finally, the granulomatous disorders (sarcoidosis, tuberculosis, histoplasmosis, and leprosy) are associated with hypercalcemia caused by an increase in GI and renal tubular absorption secondary to granuloma production of 1,25-dihydroxy vitamin D2.12 Milk-alkali syndrome is the term applied to those situations where an individual develops hypercalcemia following the ingestion of calcium and absorbable alkali (e.g., calcium carbonate) and is an important cause of hypercalcemia in patients who are not on dialysis.13,14
CLINICAL PRESENTATION Hypercalcemia
• The signs and symptoms of hypercalcemia depend on the severity and on the rapidity of onset
• Symptoms include fatigue, weakness, anorexia, depression, anxiety, cognitive dysfunction, vague abdominal pain, and constipation. Renal symptoms can include polyuria, polydipsia, and nocturia. Rarely, severe hypercalcemia leads to acute pancreatitis
• Renal: Nephrolithiasis; renal tubular dysfunction, particularly decreased concentrating ability; and acute and chronic renal insufficiency
• Cardiovascular: Hypercalcemia also directly shortens the myocardial action potential, which is reflected in a shortened QT interval and coving of the ST–T wave. Spontaneous ventricular tachyarrhythmias and elevations in blood pressure have also been reported. Chronic hypercalcemia can lead to cardiac calcification
• Musculoskeletal: Rheumatologic complaints related to hyperparathyroidism include gout, pseudogout, and chondrocalcinosis
• Serum calcium concentrations of >10.5 mg/dL (>2.63 mmol/L) are considered to represent hypercalcemia. Patients with values up to 13 mg/dL (3.25 mmol/L) are generally considered to have mild or moderate hypercalcemia, whereas those with values greater than this indicate the presence of severe hypercalcemia
Patients with mild-to-moderate hypercalcemia, that is, total serum calcium concentrations above the upper threshold of normal but less than 13 mg/dL (<3.25 mmol/L) or ionized calcium concentrations less than 6 mg/dL (<1.50 mmol/L) can often be asymptomatic. This is typically the case for the vast majority of patients who have drug-induced hypercalcemia or primary hyperparathyroidism.8,15,16 In fact, one study noted normocalcemia in approximately 20% of patients with a diagnosis of primary hyperparathyroidism, suggesting target tissue resistance to PTH.16
The presenting signs and symptoms of severe hypercalcemia that occur if the total serum calcium concentration is >13 mg/dL (>3.25 mmol/L) may differ depending on the acuity of onset.2Hypercalcemia of malignancy usually develops quickly and is accompanied by a classic symptom complex of anorexia, nausea and vomiting, constipation, polyuria, polydipsia, and nocturia.15 Polyuria and nocturia secondary to a urinary-concentrating defect constitute some of the most frequent renal effects of hypercalcemia.15 Hypercalcemic crisis is characterized by an acute elevation of total serum calcium to a value >15 mg/dL (>3.75 mmol/L), acute renal insufficiency, and obtundation (inability to arouse).15 If untreated, hypercalcemic crisis can progress to oliguric renal failure, coma, and life-threatening ventricular arrhythmias.15 The primary complications associated with chronic hypercalcemia (hyperparathyroidism) include metastatic calcification, hypercalciuria, and chronic renal insufficiency secondary to interstitial nephrocalcinosis.15
Calcium and/or calcium–phosphorus complex deposition in blood vessels and multiple organs is a complication of chronic hypercalcemia and/or concomitant hyperphosphatemia and hyperparathyroidism. Calcium deposits in atherosclerotic lesions contribute to cardiac disease.17 Intracardiac and arterial calcifications have been found in patients with Paget’s disease who have normal renal function. It is hypothesized that similar calcification processes occur in both bone and vascular tissue, leading to cardiovascular diseases including heart failure, systolic hypertension, and ischemic heart disease.18
The electrocardiographic changes associated with hypercalcemia include shortening of the QT interval and coving of the ST-T wave.15 Very high serum calcium concentrations can cause T-wave widening, indicating a repolarization defect that may be associated with spontaneous ventricular tachyarrhythmias.15 Hypertension and arrhythmias have occurred in the setting of hypercalcemia. The effects of digoxin on cardiac conduction including lowering of the excitation threshold, shortening of the effective refractory period, and increased atrioventricular refractoriness can be potentiated by hypercalcemia.19
Nephrolithiasis (kidney stones) and nephrocalcinosis (calcium deposits in the kidney) are the primary renal complications arising from long-standing hypercalcemia, as the result of primary hyperparathyroidism. Stone formation is dependent on a favorable milieu within the kidney or urinary tract, such as oversaturation of the urine and/or reduced concentrations of endogenous inhibitors of crystal formation (e.g., citrate or pyrophosphate). It is estimated that hyperparathyroidism accounts for 2% to 8% of all patients with calcium stones.20,21 Of note, in those patients with low glomerular filtration rates (GFRs), the 24-hour urinary calcium will actually diminish secondary to decreased production of 1,25-dihydroxy vitamin D2. However, the fractional excretion of calcium might increase.21 Sarcoidosis is the other hypercalcemic condition frequently associated with calcium stones.20 Other causes of nephrolithiasis with calcium-containing stones include hypocitraturia, renal tubular acidosis, hyperoxaluria, and hyperuricosuria.22,23 Stone formers who have primary hyperparathyroidism are more likely to be female, older than 50 years of age, and have a family history of multiple endocrine disorders.20 High dietary sodium intake can also raise urinary calcium concentrations, perhaps due to a reduction in calcium reabsorption in the kidney, thus predisposing patients to calcium stones. Although chronic renal failure can be the ultimate result of persistent stones, it is the primary cause of renal disease in <2% of the end-stage renal disease population.
The indications for the treatment of acute hypercalcemia are dependent on the severity of hypercalcemia, acuity of its development, and presence or absence of symptoms requiring emergent treatment (e.g., necrotizing pancreatitis). The therapeutic intervention plan should be crafted to reverse signs and symptoms, restore normocalcemia, and correct or manage the underlying cause of hypercalcemia.
General Approach to Treatment
Chronic hypercalcemia is usually caused by an underlying medical condition or prescribed pharmacotherapies that can be resolved by successful treatment of the condition or withdrawal of the offending agent. Acute hypercalcemic episodes induced by malignancies may be mitigated by chemotherapy and/or radiation treatment. Effective surgical or drug treatment of primary hyperparathyroidism should reduce serum calcium concentrations as well as reduce the development of long-term complications such as vascular complications, chronic kidney disease (CKD), and kidney stones.
Hypercalcemic crisis and acute symptomatic severe hypercalcemia should be considered medical emergencies and treated immediately (Fig. 35-2).
FIGURE 35-2 Pharmacotherapeutic options for the acutely hypercalcemic patient. Serum calcium of 12 mg/dL is equivalent to 3 mmol/L.
These patients may require immediate-acting interventions to promptly reduce the serum calcium concentration if they are experiencing ECG changes, neurologic manifestations, or pancreatitis. Pharmacologic therapy consisting of volume expansion and enhancement of urinary calcium excretion with loop diuretics is usually the initial management strategy. Hemodialysis against a zero- or low-calcium dialysate solution should be considered for patients with severely impaired renal function (CKD stage 4 or 5) who cannot tolerate large fluid loads and in whom diuretics have limited efficacy.22
Effective treatment of moderate to severe hypercalcemia in the absence of life-threatening symptoms begins with attention to the underlying disorder and correction of associated fluid and electrolyte abnormalities. Patients with primary hyperparathyroidism may require surgery, particularly if they have systemic manifestations.
For patients with primary hyperparathyroidism, emerging data suggest that treatment with cinacalcet may be appropriate as a first-line intervention over parathyroidectomy.
Patients with malignancy often require surgical or chemotherapeutic reduction of tumor load to control the exogenous supply of cytokines and hormones (e.g., PTHrP) that cause hypercalcemia. In contrast, patients with drug-induced hypercalcemia generally respond to discontinuation of the offending agent.23
For those patients with normal to moderately impaired renal function (CKD stages 3 and 4), the cornerstone of initial treatment of severe hypercalcemia or hypercalcemic crisis is volume expansion with normal saline to increase natriuresis and ultimately urinary calcium excretion (see Table 35-2). Patients with symptomatic hypercalcemia are often extracellular volume depleted secondary to vomiting and polyuria; thus rehydration with saline-containing fluids is necessary to interrupt the stimulus for sodium and calcium reabsorption in the renal tubule.24 Rehydration can be accomplished by the infusion of normal saline at rates of 200 to 300 mL/h, until the patient is fluid resuscitated and serum calcium approaches the upper limit of the normal range. The precise rate depends on concomitant conditions (primarily cardiovascular and renal) and magnitude of hypercalcemia. The saline infusion rate can be decreased to a rate that approximates the patient’s intake of oral or IV fluids. (see Chap. 34 for a thorough discussion of how to calculate water deficit.) Adequacy of hydration is assessed by measuring fluid intake and output or by central venous pressure monitoring.9 Loop diuretics such as furosemide (40 to 80 mg IV every 1 to 4 hours) or ethacrynic acid (for patients with sulfa allergies) can also be instituted to increase urinary calcium excretion and to minimize the development of volume overload from the administration of saline9 (Fig. 35-2 and Table 35-2). Loop diuretics such as furosemide block calcium (and sodium) reabsorption in the thick ascending limb of the loop of Henle and augment the calciuric effect of saline alone. The importance of rehydration prior to loop diuretic use is critical because if dehydration persists or becomes worse, the serum calcium can actually increase because of enhanced proximal tubule calcium reabsorption.2 Potassium chloride, 10 to 20 mEq/L (10 to 20 mmol/L), should be added to the saline solution after rehydration is accomplished to maintain normokalemia in the presence of diuretic therapy. Serum magnesium levels should also be monitored, and magnesium replacement instituted if magnesium levels fall below 1.8 mg/dL (0.74 mmol/L) (Table 35-3). Rehydration with saline and administration of furosemide can result in a decrease of 2 to 3 mg/dL (0.50 to 0.75 mmol/L) in total serum calcium within 24 to 48 hours.9
TABLE 35-2 Drug Dosing Table for Hypercalcemia
TABLE 35-3 Hypercalcemia Drug Monitoring Table
Alternative Drug Treatments
In those patients in whom saline hydration therapy is contraindicated (e.g., those with severe chronic heart failure [CHF] or moderate-to-severe renal dysfunction), short-term therapy with calcitonin is a viable alternative agent to initiate reduction of serum calcium levels within 24 to 48 hours. Calcitonin has a rapid onset of action (within 1 to 2 hours); however, the degree and extent of serum calcium level reduction are often unpredictable.2
Subcutaneous administration of salmon calcitonin, 50 to 100 international units daily or three times weekly, has been used to manage mild hypercalcemia in patients with Paget’s disease.25 The intranasal formulation of calcitonin has been used in doses of 200 to 400 international units daily; unfortunately, this has resulted in only mild decreases in serum calcium. The lack of significant efficacy of the synthetic intranasal formulation is the result of the lower potency and shorter duration of action as compared to salmon calcitonin. Patients who develop nephrolithiasis from hypercalciuria are most often treated with sodium citrate to prevent stone formation, thiazide diuretics to decrease urinary calcium excretion, or shock wave lithotripsy (Table 35-4).
TABLE 35-4 Treatment of Nephrolithiasis Associated with Chronic Hypercalcemia and Hypercalciuria
Pharmacology Calcitonin decreases serum calcium concentrations, primarily by inhibiting bone resorption. It can also reduce renal tubular reabsorption of calcium, thus promoting calciuresis.26 Recently, the calcitonin receptor has been shown to play an important role in calcium homeostasis, particularly in states of calcium stress (e.g., vitamin D toxicity).26 Calcitonin from salmon sources is most commonly administered subcutaneously or intramuscularly (for larger volumes) in a starting dose of 4 units/kg every 12 hours.
Adverse Effects The side effects from IV administered calcitonin (facial flushing, nausea, and vomiting) limit patient acceptability. Allergic reactions, although rare, do occur; therefore, a test dose (intradermal injection of 0.1 mL of a 10 units/mL solution) is recommended prior to starting therapy. If marked erythema and/or wheal formation does not occur within 15 minutes after administration, therapy can begin. Salmon calcitonin therapy is associated with tachyphylaxis caused by antibody formation to foreign proteins or molecules resembling the calcitonin polypeptide.26 Tachyphylaxis has been primarily documented in patients receiving therapy for more than 4 months and thus might not be clinically significant in the acute care setting. The addition of corticosteroid therapy or conversion to human calcitonin increases effectiveness.2
Bisphosphonates block bone resorption very efficiently, render the hydroxyapatite crystal of bone mineral resistant to hydrolysis by phosphatases, and also inhibit osteoclast precursors from attaching to the mineralized matrix, thus blocking their transformation into mature functioning osteoclasts.15,27 The antiresorptive properties of this class of agents can provide long-term control of serum calcium and are the first-line therapy for cancer-associated hypercalcemia.
Pharmacology and Dosing Pamidronate is very effective in controlling hypercalcemia associated with malignancy and slightly more effective than etidronate.7 The usual dose of pamidronate is 30 to 90 mg as an IV infusion given over 2 to 24 hours. Pamidronate also has the advantage of single-day therapy.9 Etidronate, when administered in doses of 7.5 mg/kg per day by slow IV infusion over at least 2 hours for 3 days, is effective in the therapy of hypercalcemia of malignancy.9 Zoledronate and ibandronate are newer, high-potency bisphosphonates with demonstrated effectiveness in the treatment of hypercalcemia of malignancy. Complete response has been reported in 88.4% to 86.7% of zoledronate- versus 69.7% of pamidronate-treated patients.28,29 Zoledronate IV doses of 4 to 8 mg given over 5 minutes have resulted in normalization of serum calcium concentrations.29 IV infusions of 0.02 or 0.04 mg/kg diluted in 5% dextrose (given over 20 to 50 minutes) have also been effective.30 A similar hypocalcemic response has been noted with ibandronate in comparison with pamidronate (76.5% vs. 75.8%); however, the time period to a relapse of hypercalcemia was longer with ibandronate (14 vs. 4 days), suggesting a therapeutic advantage for ibandronate.31 In contrast to other bisphosphonates, ibandronate can be administered by bolus injection. Single doses of 4 to 6 mg when administered every 3 to 4 weeks have been effective in managing hypercalcemia of malignancy.32 The onset of serum calcium concentration decline is slower with bisphosphonate therapy (concentrations begin to decline in 2 days and reach a nadir in 7 days); thus calcitonin therapy can be necessary if rapid serum level reduction is required.9,32 Duration of normocalcemia varies, but usually does not exceed 2 to 3 weeks. It appears to be dependent on the severity and treatment response of the underlying malignancy.2 The duration of response has been suggested to be longer with zoledronate (4 to 5 weeks), although the data are sparse.30
Adverse Effects Fever is a common side effect of IV bisphosphonate therapy. Although oral bisphosphonates are useful for the treatment of bone turnover in Paget’s disease, there are insufficient data to suggest their use for the initial treatment of hypercalcemia. The use of oral bisphosphonates for maintenance therapy in patients predisposed to hypercalcemia (malignancy) has been successful in some cases.33 The safety of continuous bisphosphonate therapy in patients with moderate-to-severe renal insufficiency is currently unknown. Renal function monitoring (serum creatinine) is advised with the use of bisphosphonates, as cases of acute tubular necrosis have been reported.34,35 Although there are no published guidelines for frequency of serum creatinine monitoring, it is advisable to evaluate serum creatinine within a week after the infusion and just prior to the next scheduled dose.
Denosumab is a monoclonal antibody that inhibits the receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) ligand (RANKL), a principal mediator of osteoclast survival. Denosumab is FDA approved for the treatment of osteoporosis.
Denosumab has been investigated in patients with malignancies and bone metastases (without hypocalcemia) who were either bisphosphonate naïve or who had previous exposure to bisphosphonates. Patients were randomized to receive an IV bisphosphonate every 4 weeks (91% received zoledronic acid) or a fixed dose of denosumab every 4 weeks (30, 120, and 180 mg) or every 12 weeks (60 and 180 mg) to investigate the effect on the primary outcome measure of urinary-N-telopeptide, a marker for bone turnover. Patients who were bisphosphonate naïve had similar decline in markers of bone turnover. In patients with previous exposure to bisphosphonates, treatment with denosumab produced significantly greater reductions in bone turnover compared with an IV bisphosphonate.36 A recent clinical trial in breast cancer patients that were randomized to subcutaneous denosumab 120 mg or IV zolendronic acid 4 mg and placebo every 4 weeks showed that denosumab therapy prolonged time to first skeletal-related event or hypercalcemia by 18%.37 These data indicate utility of denosumab in hypercalcemia of malignancy, particularly in patients who do not have an optimal response to bisphosphonates.38Denosumab has also been reported to successfully treat hypercalcemia after successful stem cell transplantation and restitution of osteoclast function in patients with osteopetrosis, a heritable disorder associated with defective osteoclast function.39
Gallium nitrate is indicated for the treatment of symptomatic hypercalcemia of malignancy not responsive to hydration therapy.40 However, because of its adverse side-effect profile, it is generally reserved for those who fail to respond to less toxic agents. Gallium nitrate inhibits bone resorption, and may be superior to calcitonin in inducing normocalcemia. The initial dose is usually a continuous IV infusion of 200 mg/m2 per day for five consecutive days. Gallium nitrate can be more effective in achieving normocalcemia in patients with epidermoid (squamous) cancers.41 Because gallium nitrate is nephrotoxic, the initial dose should be conservative and the patient’s renal function should be closely monitored.
Mithramycin (plicamycin) is a potent cytotoxic antibiotic that inhibits osteoclast-mediated bone resorption and thereby reduces hypercalcemia. Mithramycin can be administered via IV infusion (25 mcg/kg) over 4 to 6 hours in saline or 5% dextrose solutions. This therapy can be repeated daily for 3 to 4 days or on alternating days for three to eight doses.9,42 Serum calcium levels begin to fall within 12 hours of a mithramycin dose, with the peak effect generally occurring over 48 to 96 hours.2,9 Common dose-related adverse effects of mithramycin include nausea, vomiting, stomatitis, thrombocytopenia, inhibition of platelet function, and renal and hepatotoxicity.
Prednisone or an equivalent agent is usually effective in the treatment of hypercalcemia resulting from multiple myeloma, leukemia, lymphoma, sarcoidosis, and hypervitaminoses A and D.2,27,42 These agents are effective because they reduce GI calcium absorption.42 Corticosteroids may also prevent tachyphylaxis to salmon calcitonin.26 Daily doses of 40 to 60 mg of prednisone or the equivalent are effective at reducing serum calcium within 3 to 5 days followed by a reduction in urinary calcium excretion within 7 to 10 days. The disadvantages of corticosteroid therapy are its relatively slow onset of action and the potential for diabetes mellitus, osteoporosis, and increased susceptibility to infection.43
The calcimimetic agent cinacalcet HCl is approved for management of parathyroid carcinoma.44,45 It binds to the CaSr, and increases the sensitivity for receptor activation by extracellular calcium. This results in reduced PTH and serum calcium concentrations.44,45 Cinacalcet HCl administered at a starting dose of 30 mg orally twice daily has been used for the treatment of hypercalcemia secondary to parathyroid carcinoma. The dosage is titrated every 2 to 4 weeks in 30-mg increments until the desired serum calcium level is achieved. The maximum approved dosage is 90 mg three to four times daily. Patients should have serum calcium measured within 1 week after starting or increasing the dose of this agent.46
Hypocalcemia occurs infrequently in the outpatient setting and is most common in elderly, malnourished patients and those who have received sodium phosphate as a bowel preparation agent.
The incidence of hypocalcemia in intensive care unit patients ranges from 70% to 90% based on total serum calcium values less than 8.5 mg/dL (<2.13 mmol/L) to 15% to 50% based on the observation of ionized calcium concentrations less than 4.4 mg/dL (<1.10 mmol/L).3 Emergent treatment of hypocalcemia is rarely warranted unless life-threatening symptoms are present (e.g., frank tetany or seizures).
Hypocalcemia is the result of alterations in the effect of PTH and vitamin D on the bone, gut, and kidney (see Fig. 35-1). The primary causes of hypocalcemia are postoperative hypoparathyroidism and vitamin D deficiency. Other causes include magnesium deficiency, thyroid surgery, medications, hypoalbuminemia, blood transfusions, peripheral blood progenitor cell harvesting, tumor lysis syndrome, and mutations in the CaSr.47–52 PTH concentrations are elevated in conditions of hypocalcemia, with the exception of hypoparathyroidism and hypomagnesemia.53
Vitamin D Deficiency
Vitamin D and its metabolites play an important role in the maintenance of extracellular calcium concentrations and in normal skeletal structure and mineralization. Vitamin D is necessary for the optimal absorption of calcium and phosphorus. On a worldwide basis, the most common cause of chronic hypocalcemia is nutritional vitamin D deficiency. In malnourished populations, manifestations include rickets and osteomalacia. Nutritional vitamin D deficiency is uncommon in Western societies because of the fortification of milk with ergocalciferol. The most common cause of vitamin D deficiency in Western societies is GI disease.15 Gastric surgery, chronic pancreatitis, small-bowel disease, intestinal resection, and bypass surgery are associated with decreased concentrations of vitamin D and its metabolites.15Vitamin D replacement therapy might need to be administered by the IV route if poor oral bioavailability is noted. Decreased production of 1,25-dihydroxyvitamin D3 can occur as a result of a hereditary defect resulting in vitamin D-dependent rickets.53 Recently, polymorphisms of the vitamin D receptor have been identified, and these genetic variations can contribute to increased risk of rickets associated with vitamin D and calcium deficient diets, especially in certain African and East Asian populations.54 It also can occur secondary to CKD if there is insufficient production of the 1-α-hydroxylase enzyme for the production of the most active metabolite, 1,25-dihydroxy vitamin D3. Treatment of hypocalcemia associated with CKD is reviewed in Chapter 29.
Hypomagnesemia of any cause can be associated with severe symptomatic hypocalcemia that is unresponsive to calcium replacement therapy (see Chap. 36). Reduced serum magnesium concentrations can impair PTH secretion and induce resistance of target organs to the actions of PTH.15 Normalization of serum calcium concentrations in these patients is thus dependent on appropriate replacement of magnesium.
Hungry Bone Syndrome
An acute, symptomatic rapid fall in total serum calcium concentration (to values <7 mg/dL [<1.75 mmol/L]) is common in patients who have recently had a parathyroidectomy or thyroidectomy. Hypocalcemia in these postsurgical patients is generally transient in nature.53 The “hungry bone syndrome” is a condition of profound hypocalcemia whereby the bone avidly incorporates calcium and phosphorus from the blood in an attempt to recalcify bone.55 Serum calcium concentrations should be monitored every 6 hours during the 24 to 48 hours following such surgeries, and pharmacologic doses of calcium can be necessary to prevent or minimize the drop in serum calcium. Additionally, mild-to-moderate hypocalcemia can be a long-term consequence of parathyroidectomy in hemodialysis patients.53
Drug-induced hypocalcemia has been reported in patients receiving furosemide, calcitonin, bisphosphonates, gallium nitrate, mithramycin, cinacalcet, fluoride, ketoconazole, and pentamidine.46,56
Some data have shown that animal source vitamin D3 (cholecalciferol) is more efficacious at raising serum 25(OH) D concentrations compared with plant source vitamin D2 (ergocalciferol).
Oral phosphorus therapy, commonly used to treat patients with malabsorption syndromes caused by GI diseases, can also result in hypocalcemia. The anticonvulsants phenobarbital and phenytoin cause hypocalcemia by increasing catabolism of vitamin D and thereby impairing calcium release from bone and reducing intestinal calcium absorption.47 Drugs that cause hypomagnesemia (aminoglycosides, amphotericin B, cyclosporine, diuretics, foscarnet, and cisplatin) are also associated with an increased risk of hypocalcemia. Chelating agents in blood (citrate) and in radiographic contrast media (ethylenediaminetetraacetate) can also cause transient hypocalcemia.47,48,57Concentrated citrate is increasingly being used in hemodialysis catheter locks and to anticoagulate the dialysis circuit during continuous renal replacement therapy. Symptomatic hypocalcemia (ionized calcium <2.4 mg/dL [<0.60 mmol/L]) has been reported in patients exposed to citrate solutions, which appears to be related to the concentration of the citrate solution.58 Injection of citrate solutions greater than the volume of the dead space of the catheter lumen or accidental injection of citrate catheter lock solutions that are not intended for systemic administration have been associated with serious cardiovascular problems such as hypotension or cardiac arrest.59
Hypoparathyroidism can be caused by autoimmune disease, congenital defects, or iatrogenically by inadvertent removal during thyroidectomy or from damage with radiation therapy. Chronic hypothyroidism produces an insidious development of hypocalcemia and thus most patients remain asympotomatic. The chronic hypocalcemia may ultimately present as visual impairment secondary to cataracts.60
The clinical manifestations of hypocalcemia are quite variable. The more acute the drop in ionized calcium concentration, the more likely the patient will develop symptoms.51 Increases in plasma pH enhance the binding of calcium to albumin and thus alkalosis can result in rapid decreases in ionized calcium. Concomitant hypomagnesemia, hypokalemia, hyponatremia, and additive side effects from prescribed medications also increase the likelihood of symptomatic presentation.
Hypocalcemia can manifest as neuromuscular, CNS, dermatologic, and cardiac sequelae.15 Acute hypocalcemia is more likely to manifest as neuromuscular (paresthesia, muscle cramps, tetany, and laryngeal spasm) and cardiovascular symptoms, whereas chronic hypocalcemia often presents as CNS (e.g., depression, anxiety, memory loss, confusion, hallucinations, and tonic–clonic seizures) and dermatologic symptoms (hair loss, grooved and brittle nails, and eczema).47 The hallmark sign of acute hypocalcemia is tetany caused by enhanced peripheral neuromuscular irritability.15 Tetany manifests as paresthesia around the mouth and in the extremities, muscle spasms and cramps, carpopedal (hands and feet) spasms, and rarely as laryngospasm and bronchospasm.15 Chvostek’s and/or Trousseau’s signs can be elicited during physical examination.47 Chvostek’s sign is elicited by tapping the facial nerve anterior to the ear and eliciting twitching of facial muscles. Trousseau’s sign is elicited by inflating a blood pressure cuff above systolic blood pressure for 3 minutes and observing whether a carpal spasm is induced.
CLINICAL PRESENTATION Hypocalcemia
• Acute hypocalcemia may result in rapid decreases in serum ionized calcium. Parathyroidectomy and thyroidectomy are also associated with a rapid reduction in serum calcium. In chronic hypocalcemia vitamin D deficiency should be considered
• The symptoms of hypocalcemia include tetany, paresthesia, muscle cramps, and laryngeal spasms. Chronic hypocalcemia is usually associated with depression, anxiety, memory loss, and confusion
• Neurologic: The hallmark of acute hypocalcemia is tetany, which is characterized by neuromuscular irritability including seizure potential. Extrapyramidal disorders, mainly parkinsonism but also dystonia, hemiballismus, choreoathetosis, and oculogyric crises occur in 5% to 10% of patients with idiopathic hypoparathyroidism. Chvostek’s and/or Trousseau’s signs can be elicited during physical examination
• Dermatologic: The skin can be dry, puffy, and coarse. Other dermatologic manifestations can include hyperpigmentation, dermatitis, eczema, and psoriasis. Hair and skin signs including coarse, brittle, and sparse hair with patchy alopecia and brittle nails can also appear
• Ophthalmologic: Cataract development has been reported to occur with hypocalcemia
• Dental manifestations: These are usually associated with the presence of chronic hypocalcemia in early development. Signs include dental hypoplasia, failure of tooth eruption, defective enamel and root formation, and abraded carious teeth
• Cardiovascular: Hypotension, decreased myocardial performance, and CHF have been reported. A prolonged QT interval, arrhythmias, and bradycardia can also occur but are more common with acute or very severe hypocalcemia
• GI: Steatorrhea can be associated with chronic hypocalcemia
• Musculoskeletal: Myopathy has been reported
• Endocrine: Hypocalcemia alone can impair insulin release. In addition, idiopathic hypoparathyroidism can be associated with polyglandular autoimmune syndromes
• Serum calcium levels of less than 8.5 mg/dL (<2.13 mmol/L) are considered to represent hypocalcemia if ionized calcium values are also less than 4.4 mg/dL (<1.1 mmol/L)
The cardiovascular manifestations of hypocalcemia result in electrocardiographic changes characterized by a prolonged QT interval and symptoms of decreased myocardial contractility often associated with congestive heart failure (CHF).47 Both acute and chronic hypocalcemia can result in a reversible syndrome characterized by acute myocardial failure or refractory CHF. Other cardiovascular manifestations include arrhythmias, bradycardia, and hypotension that are unresponsive to fluid and pressor administration.47
The goals of therapy for patients with normal renal function are the resolution of signs and symptoms of hypocalcemia, restoration of normocalcemia, management of associated electrolyte abnormalities, and treatment of the underlying cause of hypocalcemia. The goals for patients with CKD are different and are discussed in detail in Chapter 29. Asymptomatic hypocalcemia associated with hypoalbuminemia requires no treatment because ionized (physiologically active) plasma calcium concentrations are normal. Treatment of hypocalcemia is dependent on identification of the pathogenesis of the underlying disorder, acuteness of onset, and presence and severity of symptoms. Acute symptomatic hypocalcemia requires parenteral administration of soluble calcium salts (Fig. 35-3).
FIGURE 35-3 Hypocalcemia diagnostic and treatment algorithm. Serum calcium of 8.5 mg/dL is equivalent to 2.13 mmol/L.
The initial therapeutic intervention for patients with acute symptomatic hypocalcemia is to administer 100 to 300 mg of elemental calcium IV over 5 to 10 minutes.61 This can be accomplished by the administration of 1 g of calcium chloride (27% elemental calcium) or 2 to 3 g of calcium gluconate (9% elemental calcium). Calcium gluconate is generally preferred over calcium chloride for peripheral venous administration because calcium gluconate is less irritating to veins. The use of calcium gluconate provides a less predictable and slightly smaller increase in plasma ionic calcium compared with calcium chloride. Calcium should not be infused at a rate greater than 60 mg of elemental calcium per minute because severe cardiac dysfunction, including ventricular fibrillation, can result.61 IV calcium administration should be used with caution in patients receiving digitalis glycosides because of the possibility of bradycardia or atrioventricular (A-V) block.3 The bolus dose of calcium is only effective for 1 to 2 hours and should be followed by a continuous infusion of elemental calcium at a rate of 0.5 to 2 mg/kg per hour.3 The calcium concentrations should be monitored every 4 to 6 hours during the IV infusions. The ionized calcium concentration usually normalizes within 4 hours, and the maintenance infusion rate of elemental calcium can then be decreased to 0.3 to 0.5 mg/kg per hour to maintain the desired calcium concentration.1 Calcium should not be added to bicarbonate- or phosphate-containing solutions because of the possibility of precipitation.
Once acute hypocalcemia is corrected by parenteral administration, further treatment modalities should be individualized according to the cause of hypocalcemia. If hypomagnesemia is present, magnesium supplementation is indicated (see Chap. 36). Hypocalcemia secondary to hungry bone syndrome following parathyroidectomy has been attenuated by pretreatment with bisphosphonates.62 Asymptomatic and chronic hypocalcemia associated with hypoparathyroidism and vitamin D-deficient states can be managed by oral calcium and vitamin D supplementation (see Chap. 29). Therapy is begun with 1 to 3 g/day of elemental calcium.1 Average maintenance doses range from 2 to 8 g of elemental calcium per day in divided doses. If serum calcium does not normalize, a vitamin D preparation may need to be added.
Treatment of hypocalcemia associated with vitamin D-deficient states should be individualized. In patients with malabsorption, vitamin D requirements vary markedly, and large doses can be required. In contrast, vitamin D deficiency associated with anticonvulsant medication can be corrected with smaller doses of vitamin D. Oral doses of 1,25-dihydroxy vitamin D3 usually range from 0.5 to 3 mcg daily. The usual initial oral dose of ergocalciferol is 50,000 international units daily.61 Vitamin D doses are usually adjusted approximately every 4 weeks. Vitamin D deficiency is highly prevalent especially in areas of low sun exposure and limited dietary sources of vitamin D.63 New data suggest that current dietary recommendations are not sufficient to maintain 25-hydroxy vitamin D3 concentrations at or above 32 mcg/L (80 nmol/L).63 The treatment of vitamin D deficiency associated with CKD generally requires the administration of 1,25-dihydroxy vitamin D3 or another synthetic vitamin D2 analog such as paricalcitol or doxercalciferol. Patients who have reduced 25-hydroxylase activity (e.g., hepatic disease) can also require treatment with calcitriol (1,25-dihydroxy vitamin D3). The newer vitamin D2 analogs (paricalcitol and doxercalciferol) were developed to preferentially suppress PTH secretion with less effect on serum calcium concentration and thus their efficacy for the management of hypocalcemia may be minimal. In selected cases, increasing calcium ingestion can be required if vitamin D replacement alone is ineffective in returning calcium concentrations to normal.
Several single nucleotide polymorphisms have been identified in the CaSr gene. The effect of these polymorphisms on the pharmacodynamic profile and the risk of hypocalcemia associated with cinacalcet and other calcimimetics remains to be elucidated.
Adverse effects of oral calcium and vitamin D supplementation include hypercalcemia and hypercalciuria, especially in the hypoparathyroid patient, in whom the renal calcium-sparing effect of PTH is absent. Hypercalciuria can increase the risk of calcium stone formation and nephrolithiasis in susceptible patients. One maneuver to help prevent calcium stones is to maintain the urine calcium excretion below 300 mg per day. Intermittently monitoring 24-hour urine collections for total calcium excretion can help to minimize the occurrence of hypercalciuria. The addition of thiazide diuretics for patients at risk for stone formation can result in an increase in tubular calcium reabsorption and reduction of vitamin D requirements.61
DISORDERS OF PHOSPHORUS HOMEOSTASIS
Inorganic phosphorus in the form of phosphate is an essential element in phospholipid cell membranes, nucleic acids, and phosphoproteins, which are required for mitochondrial function.64 Phosphorus regulates the intermediary metabolism of carbohydrates, fats, and proteins. Phosphorus also regulates enzymatic reactions including glycolysis, ammoniagenesis, and the 1-hydroxylation of 25-hydroxyvitamin D3.64 In addition, phosphorus is required for the generation of 2,3-diphosphoglycerate (2,3-DPG) in red blood cells, which is required for normal oxygen–hemoglobin dissociation and delivery of oxygen to the tissues.65 Phosphorus is the source of the high-energy bonds of adenosine triphosphate (ATP), thus fueling a wide variety of physiologic processes, including muscle contractility, electrolyte transport, neurologic function, and other important biochemical reactions.64 Considering its diverse biologic importance, it is not difficult to appreciate the clinical implications of disorders of phosphorus homeostasis.
Phosphate, the major intracellular anion, is present in living organisms mainly as organic phosphate esters such as 2,3-DPG, adenosine, guanosine triphosphate, and fructose 1,6-diphosphate.64 Only a small fraction of intracellular phosphorus exists as inorganic phosphate; however, this fraction is critical because it is the source from which ATP is resynthesized.64 The majority of inorganic phosphate is located in the extracellular space where it is the prime determinant of intracellular phosphate; thus, small increments in the organic phosphate levels can profoundly alter both the extracellular and intracellular phosphate levels. Metabolic disturbances (acidosis, alkalosis, and ketoacidosis), hydrogen ion shifts, and hormones (PTH, calcitonin, cortisol, and vitamin D) all can cause transcellular shifts in phosphorus concentrations. Because of these phenomena, the serum phosphorus level does not accurately reflect total body stores.65
The typical Western diet provides a daily intake of 800 to 1,600 mg of phosphorus. Approximately 60% to 80% of this is absorbed in the GI tract by passive and active transport (vitamin D mediated). PTH, 1,25-dihydroxy vitamin D3, and low-phosphate diets mediate increased absorption. Decreased absorption occurs under conditions of increased dietary intake of phosphorus and magnesium, glucocorticoid therapy, and hypothyroidism. The normal serum phosphorus concentration in adults is 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L) and for children younger than 12 years old it is 4 to 5.6 mg/dL (1.29 to 1.81 mmol/L). Influx via the GI tract and bone and tubular reabsorption by the kidney are the most important regulators of steady-state serum phosphorus concentrations. Renal excretion of phosphorus is a two-step process: glomerular filtration and proximal tubular reabsorption by passive transport coupled to sodium. Under normal conditions, 85% to 90% of filtered phosphate is reabsorbed, the majority in the early proximal tubule. Renal tubular reabsorption of phosphate is inhibited by PTH and 1,25-dihydroxy vitamin D3.64 There are increasing data in the literature that indicate fibroblast growth factor 23 (FGF23) is a key regulator of phosphate homeostasis.66,67 FGF23 acts principally to decrease tubular reabsorption of phosphate and inhibit 1-α-hydroxylase, thereby reducing the concentration of active vitamin D. FGF23-mediated receptor activation requires klotho, a transmembrane protein. The tissue specificity for FGF23 effects appears to be defined by klotho–FGF23 coexpression. Conversely, phosphate reabsorption in the renal tubule is increased by growth hormone, insulin, and insulin-like growth factor 1.64 Internal phosphorus balance (transcellular phosphate distribution) is also of importance in the maintenance of normal serum phosphate. The serum phosphate level can vary by as much as 2 mg/dL (0.65 mmol/L) throughout the day, primarily as the result of changes in carbohydrate intake, insulin secretion, and diurnal variation.64
Hyperphosphatemia typically results from either renal failure or endogenous intracellular phosphate release. Hyperphosphatemia occurs frequently in patients with acute renal failure and is a nearly universal finding in those with advanced stages of CKD (e.g., stages 4 and 5). Tumor lysis syndrome is a complication of chemotherapy associated with massive lysis of cells and release of intracellular contents. The incidence of tumor lysis syndrome has been reported to be as high as 40% in patients treated for non-Hodgkin’s lymphoma.64 Other causes of hyperphosphatemia include hemolysis and rhabdomyolysis.
The most common cause of hyperphosphatemia is a failure of renal tubular reabsorption to maintain serum phosphate when GFR is markedly inpaired (e.g., GFR <25 mL/min/1.73 m2 [<0.24 mL/s/m2]).64 Retention of phosphate decreases vitamin D synthesis and induces hypocalcemia, which leads to an increase in PTH, a finding that can be seen in those with stage 2 to 3 CKD. This physiologic response inhibits further tubular reabsorption of phosphorus as the kidney attempts to correct hyperphosphatemia and normalize serum calcium concentrations. Patients with excessive exogenous phosphate administration or who experience massive tissue breakdown or cell lysis in the setting of acute renal failure can rapidly develop moderate-to-severe hyperphosphatemia (serum phosphate >6.5 mg/dL [>2.10 mmol/L]).64 Severe hyperphosphatemia (serum phosphate >7 mg/dL [>2.26 mmol/L]) is commonly encountered in patients with CKD, especially those with GFRs less than 15 mL/min per 1.73 m2 (0.14 mL/s/m2) (see Chap. 29).
Hyperphosphatemia caused by an increase in renal tubular reabsorption associated with hypoparathyroidism and associated decreases in PTH is usually less severe than that observed in patients with severe renal failure or excessive exogenous or endogenous introduction of phosphate into the ECF. Acromegaly (mediated by growth hormone) and thyrotoxicosis (mediated by catecholamines) can also cause hyperphosphatemia by increasing tubular phosphate reabsorption.
Exogenous Phosphate Loads Iatrogenic causes of hyperphosphatemia have been widely reported, and clinicians should be aware of the phosphorus content of IV, oral, and rectally administered products. Large doses of phosphate administered IV to treat hypercalcemia can ultimately result in severe life-threatening hyperphosphatemia. Although less-well recognized, oral and rectal administration of phosphate-containing solutions such as sodium phosphate (Fleet Phospho-Soda) can also result in severe and life-threatening hyperphosphatemia, especially in patients with moderate and severe renal insufficiency.68,69The risk of mortality is dependent on the amount of phosphorus absorbed from the administered product; however, fatalities have occurred at lower phosphate concentrations.68 Acute phosphate nephropathy and renal failure have also been reported with the use of oral sodium phosphate bowel preparations. Recently the FDA issued a safety warning regarding the use of these products in patients at risk (the elderly, those with CKD) or on medications known to effect renal hemodynamics (e.g., diuretics, nonsteroidal antiinflammatory drugs [NSAIDs], or renin–angiotensin–aldosterone system inhibitors).70 IV or oral vitamin D therapy can increase absorption of phosphorus in the GI tract by up to 50%. Acute phosphorus poisoning as a result of ingestion of laundry detergents is a rare and often unrecognized cause of elevated phosphate concentrations.
Rapid Tissue Catabolism Any disorder that results in necrosis of skeletal muscle (i.e., rhabdomyolysis) can generate the release of large amounts of intracellular phosphate into the systemic circulation. This condition is frequently associated with acute kidney injury (see Chap. 28) and thus severe hyperphosphatemia can develop because of increased endogenous phosphate release coupled with the impaired proximal tubule reabsorption such that phosphaturic hormones (e.g., PTH, FGF23) become ineffective. Bowel infarction, malignant hyperthermia, and severe hemolysis are also conditions that can increase endogenous release of phosphate.
Moderate hyperphosphatemia is also commonly observed in patients undergoing treatment for acute leukemia and lymphomas.50 Chemotherapeutic treatment of acute lymphoblastic leukemia can result in the release of large amounts of phosphate into the systemic circulation secondary to lysis of lymphoblasts. Initiation of chemotherapy for Burkitt’s lymphoma results in tumor lysis syndrome, a rapid lysis of malignant cells that results in hyperphosphatemia, hyperuricemia, hyperkalemia, and hypocalcemia.50
Acid-Base Disorders Lactic acidosis and diabetic ketoacidosis can trigger the transcellular shift of endogenous intracellular phosphate into the extracellular space and thereby dramatically increases serum phosphorous concentrations. In one study, hyperphosphatemia was present in more than 90% of patients with diabetic ketoacidosis prior to the initiation of treatment.74 After the institution of treatment, serum phosphate levels should be checked hourly as they can decrease rapidly, and patients can ultimately develop hypophosphatemia.
The severe acute onset of hyperphosphatemia can result in calcium and phosphate complexation and lead to the precipitation of calcium phosphate into soft tissues, intrarenal calcification, nephrolithiasis, or obstructive uropathy. Other symptoms associated with moderate-to-severe hyperphosphatemia include nausea, vomiting, diarrhea, lethargy, and seizures. The major effects of long-term hyperphosphatemia are related to the development of hypocalcemia (caused by phosphate inhibition of renal 1-õ-hydroxylase) and its related consequences, as well as vascular and organ damage resulting from the deposition of calcium-phosphate crystals. Extravascular calcification can result in band keratopathy, “red eye,” pruritus, and periarticular calcification, especially in CKD patients. In addition, soft-tissue calcifications in the conjunctiva, skin, heart, cornea, lung, gastric mucosa, and kidney have been observed, primarily in CKD patients with chronic disordered mineral metabolism.65 Hyperphosphatemia associated with CKD can result in renal osteodystrophy because of overproduction of PTH. This condition is discussed in detail in Chapter 29.
CLINICAL PRESENTATION Hyperphosphatemia
• Serum phosphate concentration is primarily determined by the ability of the kidneys to reabsorb phosphate; therefore, hyperphosphatemia is uncommon in patients with normal kidney function
• Acute symptoms include GI disturbances, lethargy, obstruction of the urinary tract, and rarely seizures. Symptoms associated with chronic hyperphosphatemia are associated with deposition of calcium-phosphate crystals and include “red eye” and pruritus
• The elevated calcium-phosphate product results in precipitation in arteries, joints, soft tissues, and the viscera. This can result in tissue necrosis, termed calciphylaxis or calcemic uremic arteriopathy
• Serum phosphate levels >4.5 mg/dL (>1.45 mmol/L) represent hyperphosphatemia
Management of patients with acutely elevated serum phosphate should be directed at avoiding GI and neurologic symptoms and preventing deposition in the urinary tract to avoid the development of acute renal failure. The treatment of hyperphosphatemia is focused on returning serum phosphate concentrations to the normal or near normal (for those with CKD) range, with the hope that one can minimize the long-term cardiovascular consequences of calcium-phosphate crystal deposition in the vasculature. Calcium-phosphate crystals are likely to form in vivo when the product of the serum calcium and phosphate concentrations exceeds 50 to 60 mg2/dL2 (4 to 4.8 mmol2/L2). Serum phosphate concentrations greater than 6.5 mg/dL (2.10 mmol/L) have been independently associated with increased morbidity and mortality in patients on maintenance hemodialysis.71 The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines suggest that for patients with CKD stages 3 to 5, serum phosphorus should be maintained in the normal range. In dialysis-dependent patients with stage 5 CKD, KDIGO suggests lowering elevated phosphorus levels toward the normal range.72
Severe symptomatic hyperphosphatemia manifesting as hypocalcemia and tetany should be treated by the IV administration of calcium salts. Although this can seem counterintuitive in a patient with a phosphate of 16 mg/dL (5.17 mmol/L) and a calcium of 7 mg/dL (1.75 mmol/L) (the calcium–phosphorus product is 112 mg2/dL2 [9 mmol2/L2]), correction of severe hypocalcemia is of primary importance because of the critical nature of this disorder. If calcium concentrations are not critically low, the initial management strategy should include limitation of all exogenous sources of phosphate and efforts to block further absorption should be initiated. Dialysis can be initiated if the patient remains symptomatic despite these interventions.
Drug Treatments of First Choice
In general, the most effective way to treat nonemergent hyperphosphatemia is to decrease phosphate absorption from the GI tract by the use of phosphate-binding agents.64 Antacids containing divalent and trivalent cations (calcium, lanthanum, magnesium, and aluminum), or sevelamer are the agents most frequently used in the prevention and treatment of hyperphosphatemia (see Table 29-13).73 Long-term treatment with aluminum hydroxide and aluminum carbonate should be discouraged because the use of these agents has been associated with anemia, CNS disorders, and bone disease.73 Short-term therapy with these agents is effective and safe. Aluminum and calcium are available in oral suspension formulations, which can aid administration in acutely ill patients with G-tubes. The most frequent adverse effect from phosphate-binding agents (especially calcium) is constipation. Calcium salts are the preferred phosphate-binding agents except when there is concomitant hypercalcemia. Therapy with the polymer agent (sevelamer) or lanthanum carbonate might avoid the detrimental effects associated with aluminum, magnesium, or calcium therapy.
Mild-to-moderate hypophosphatemia is usually asymptomatic and associated with serum phosphate concentrations of 1 to 2 mg/dL (0.32 to 0.65 mmol/L), whereas severe hypophosphatemia that is frequently symptomatic is correlated with serum phosphorus concentrations of less than 1 mg/dL (0.32 mmol/L).65 Hypophosphatemia has been observed in approximately 1% to 3% of the laboratory screening panels of patients who have been admitted to a hospital.65 The incidence in hospitalized critically ill patients is 18% to 28%.64 Unlike its severe form, mild or moderate hypophosphatemia seldom causes recognizable signs and symptoms.73
Hypophosphatemia can be the result of decreased GI absorption, reduced tubular reabsorption, or extracellular to intracellular redistribution.64 Although mild-to-moderate hypophosphatemia is common and can occur in inpatients and outpatients, severe hypophosphatemia is predominantly encountered in the acute care setting and can be associated with life-threatening symptoms, including seizures, coma, and rhabdomyolysis (Table 35-5).
TABLE 35-5 Conditions Associated with the Development of Hypophosphatemia
Decreased GI absorption
Decreased dietary phosphorus intake
Vitamin D deficiency/resistance
Reduced tubular reabsorption
Hyperparathyroidism (primary and secondary)
Recovery from burns
Acute volume expansion
Vitamin D deficiency and/or resistance
Parathyroidectomy (hungry bone syndrome)
Diabetic ketoacidosis (correction)
Decreased GI Absorption Phosphate-binding substances such as sucralfate, calcium carbonate, sevelamer, lanthanum carbonate, and aluminum- or magnesium-containing antacids have the potential to bind large amounts of phosphorus in the gut, thereby preventing absorption. If phosphate-binding agents are ingested on a chronic basis in conjunction with a dietary phosphorus deficiency, hypophosphatemia can result.74 Patients who are receiving long-term phosphate-binding agents, those with peptic ulcer disease or CKD, and those who may be predisposed to moderate hypophosphatemia (alcoholics) are at highest risk for the development of severe hypophosphatemia. Hyperparathyroidism can cause hypophosphatemia as a result of decreased GI absorption of dietary phosphorus.
Decreased Tubular Reabsorption Reduced tubular reabsorption of phosphate can occur in hyperparathyroid (primary and secondary) patients with normal renal function and those with vitamin D deficiency or elevated FGF23 concentrations. Elevated PTH levels lead to an increase in serum calcium concentrations and decreased serum phosphate concentrations. Serum phosphorus is decreased as the result of a reduction in renal tubular reabsorption.75Recovery from extensive third degree burns is associated with development of an anabolic state as stress levels decrease and nutritional therapies take effect as well as a marked diuretic phase associated with an impressive renal loss of phosphate.75 Because phosphate is rapidly incorporated into the new cells, this can contribute to the severity of the hypophosphatemia. Drugs that cause increased renal elimination of phosphate include diuretics (acetazolamide and osmotic diuretics), glucocorticoids, and sodium bicarbonate.74
Cellular Shifts Rapid refeeding of malnourished patients with high-carbohydrate, high-calorie diets with inadequate amounts of supplemental phosphate can result in severe symptomatic hypophosphatemia. This phenomenon is especially prevalent in patients with other underlying risk factors for the development of hypophosphatemia, such as alcoholism.75 The etiology of severe hypophosphatemia associated with hyperalimentation and nutritional recovery can be separated into two phases: acute, rapid hypophosphatemia secondary to intracellular shifts of phosphate resulting from glucose-induced insulin secretion; and the gradual decrease in serum phosphate concentration over 5 to 10 days secondary to tissue repair in the presence of phosphate deprivation.76 The development of severe hypophosphatemia secondary to hyperalimentation can be prevented by the administration of 12 to 15 mmol of phosphate per liter of hyperalimentation solution or 15 mmol per 1,000 calories (4.2 kJ) of dextrose.76 Transcellular shifts in phosphate also occur after parathyroidectomy, causing severe hypocalcemia and hypophosphatemia because of hungry bone syndrome (deposition of phosphate and calcium in the bone).
Severe and prolonged respiratory alkalosis (a result of hyperventilation, pain, anxiety, and sepsis) can cause hypophosphatemia.65 Respiratory alkalosis is thought to contribute significantly to the hypophosphatemia observed during alcohol withdrawal.68 Although patients with diabetic ketoacidosis may present with hyperphosphatemia, the institution of therapy to correct it can cause serum phosphate concentrations to decrease rapidly as phosphate shifts back into the intracellular compartment. In addition, the acidosis associated with the diabetic ketoacidotic state can cause a decomposition of organic compounds inside the cell and a release of inorganic phosphate into the plasma and subsequently into the urine.64 The combination of intracellular phosphate breakdown and the shift of phosphate into cells on initiation of treatment can lead to severe hypophosphatemia. Drugs associated with transcellular shifts in phosphate include dextrose solutions, glucagon, insulin, catecholamines, calcitonin, erythropoietic agents, and anabolic steroids.
Chronic ethanol abusers are prone to a variety of serum electrolyte disorders including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. The etiology of hypophosphatemia in the alcoholic patient is multifactorial. Malnutrition, poor dietary intake, diarrhea, vomiting, and the use of phosphate-binding antacids can all contribute to the hypophosphatemia of alcoholism.64 In addition, serum phosphate concentrations may decrease after hospitalization in the alcoholic patient with the institution of dextrose-containing IV fluids as a result of an intracellular shift of phosphate.64,76Hyperventilation associated with the alcohol withdrawal syndrome can also contribute to the development of hypophosphatemia.76 Alcoholic patients are particularly susceptible to the complications of hypophosphatemia such as rhabdomyolysis, which is often seen during withdrawal or refeeding.76 Thus, serum phosphate concentrations should be routinely monitored in alcoholic patients.
The clinical manifestations of severe hypophosphatemia are diverse and many organ systems can be affected. It is likely that two primary biochemical abnormalities are responsible for most of the clinical manifestations of severe hypophosphatemia.64 First, intracellular energy stores may be decreased secondary to depletion of intracellular ATP. This can result in disruptions in cellular function. Second, reduced red blood cell 2,3-DPG concentrations are associated with a shift to the left of the oxyhemoglobin saturation curve. This shift is associated with a decrease in the release of oxygen to peripheral tissues (increased oxygen affinity for hemoglobin) and may result in tissue hypoxia.65 These metabolic disorders can be seen in a wide variety of organ systems.
Neurologic (CNS) manifestations of severe hypophosphatemia result in a metabolic encephalopathy syndrome. This progressive syndrome of irritability, apprehension, weakness, numbness, paresthesia, dysarthria, confusion, obtundation, seizures, and coma has been described in patients with severe hypophosphatemia.75,76 Neuropsychiatric disturbances include apathy, delirium, hallucinations, and paranoia. Peripheral neuropathy and symptoms resembling Guillain-Barrése syndrome have also been reported.76
Severe hypophosphatemia can result in significant dysfunction of skeletal muscle ranging from myalgia, bone pain, and weakness, with chronic hypophosphatemia, to potentially fatal rhabdomyolysis with severe acute hypophosphatemia.75 Laboratory evaluations can help to distinguish between chronic and acute on chronic hypophosphatemia. Elevated alkaline phosphatase, normal creatine phosphokinase, and normal to low phosphate and calcium are present in cases of chronic hypophosphatemia. In contrast, hyperkalemia, hyperuricemia, elevated blood urea nitrogen and creatinine, hypercalcemia, and myoglobinuria are often present in cases in which rhabdomyolysis complicates the acute or chronic hypophosphatemia.75 Hypophosphatemia can result in acute respiratory failure secondary to respiratory muscle weakness and diaphragmatic contractile dysfunction. Thus, frequent assessment of serum phosphate concentration is indicated in patients at risk for respiratory failure. Likewise, adequate treatment of hypophosphatemia in respiratory failure can aid in successful weaning from the ventilator.65Dysphagia and ileus have also been attributed to hypophosphatemia.65
Myocardial dysfunction has been reported to be impaired in the setting of hypophosphatemia and has resulted in congestive cardiomyopathy. This has been reported in alcoholics, and postoperative and intensive care patients. Depletion of cardiac ATP stores has been hypothesized as the cause of this syndrome.72 Arrhythmias have also been reported in patients with hypophosphatemia. Because hypophosphatemia is a potentially reversible cause of heart failure, it should be considered in patients who experience an acute deterioration in ventricular function.
CLINICAL PRESENTATION Hypophosphatemia
• Major conditions associated with symptomatic hypophosphatemia are chronic alcoholism, IV hyperalimentation without adequate phosphate supplementation, and the chronic ingestion of antacids. Severe hypophosphatemia can also be seen during treatment of diabetic ketoacidosis and with prolonged hyperventilation
• Except for the effects on mineral metabolism, the symptoms of hypophosphatemia are caused by two consequences (reduction of red cell 2,3-DPG and reduction of intracellular ATP levels), and can impact virtually all organ systems. The symptoms are predominantly neurological and can include irritability, apprehension, weakness, numbness, paresthesia, and confusion. Severe acute development of hypophosphatemia can result in seizures or coma
• The initial response of bone to hypophosphatemia contributes to hypercalcemia and hypercalciuria. Prolonged hypophosphatemia can also result in rickets and osteomalacia
• Neurologic: Severe hypophosphatemia can lead to a metabolic encephalopathy
• Cardiopulmonary: Impaired myocardial contractility, respiratory failure secondary to ATP depletion, CHF, new onset or worsening of an existing condition
• Musculoskeletal: Proximal myopathy, dysphagia, and ileus have been reported. Acute hypophosphatemia superimposed on preexisting severe phosphate depletion can lead to rhabdomyolysis
• Hematologic: Alterations in the hematopoietic system can also occur, resulting in hemolysis, reduction in phagocytotic and granulocyte chemotactic ability, as well as defective clot retraction and thrombocytopenia
• Serum phosphate levels <2.4 mg/dL (<0.78 mmol/L) are indicative of hypophosphatemia; however, symptomatic hypophosphatemia typically is not evident until serum phosphate <1 mg/dL (<0.32 mmol/L)
Hematologic manifestations of hypophosphatemia include decreased levels of 2,3-DPG, decreased red blood cell ATP, and membrane rigidity.64 When red blood cell ATP decreases to below 15% of normal, cells become spherocytic and rigid, and are trapped and destroyed in the spleen.65 Therefore, hemolysis can be a manifestation of severe hypophosphatemia. Reduction in ATP content of white blood cells can result in mobility, chemotaxis, phagocytosis, and bactericidal dysfunction.76 These changes can contribute to an increased risk of infection in hypophosphatemic patients.
Finally, prolonged hypophosphatemia may result in osteopenia and osteomalacia because of enhanced osteoclastic resorption of bone and limited crystallization constituents (phosphate), respectively. Glucose intolerance from hypophosphatemia caused by tissue insensitivity to insulin has also been described.
The goals of therapy are the reversal of signs and symptoms of hypophosphatemia, normalization of serum phosphate concentrations, and management of underlying conditions. Awareness of the clinical situations in which hypophosphatemia is anticipated (alcoholism, diabetic ketoacidosis, and parenteral nutrition) is of vital importance in preventing iatrogenic hypophosphatemia. The routine addition of phosphate (12 to 15 mmol/L) to IV hyperalimentation solutions is of utmost importance for the prevention of severe hypophosphatemia in hospitalized patients.
Severe (<1 mg/dL [<0.32 mmol/L]) or symptomatic hypophosphatemia should be treated with parenteral phosphate replacement. Oral phosphate supplementation is usually reserved for patients who are asymptomatic or who exhibit mild-to-moderate hypophosphatemia. Estimation of total body phosphate deficit is difficult because phosphate is an intracellular electrolyte. Dosage and infusion recommendations, as well as response to parenteral phosphate replacement, are highly variable.77 The infusion of 15 mmol of phosphate in 250 mL of 5% dextrose or 0.9% sodium chloride over 3 hours is a safe and effective treatment for severe hypophosphatemia.77 Mean increases in serum phosphate of 0.5 to 0.8 mg/dL (0.16 to 0.26 mmol/L) have been reported. Doses of 15 to 30 mmol of phosphate can be given over 1 to 3 hours in patients without hypercalcemia (serum calcium >10.5 mg/dL [>2.63 mmol/L]).78Other authors recommend a wider dosage range of 0.08 to 0.64 mmol/kg body weight (5 to 45 mmol in a 70-kg [154 lb] patient) given over 4 to 12 hours.79 IV phosphate therapy produces the desired increase in serum phosphate at 24 hours in 20% to 80% of patients. Response is dependent on the degree of phosphate depletion and replacement dose administered.65 Furthermore, the initial success is often followed in 48 to 72 hours by recurrent hypophosphatemia, necessitating close monitoring of serum phosphate and repeated administration of phosphate products as warranted.
Adverse Effects of Parenteral Phosphate Parenteral phosphate supplementation is associated with risks of hyperphosphatemia, metastatic soft tissue deposition of calcium-phosphate product, hypomagnesemia, hypocalcemia, and hyperkalemia or hypernatremia (caused by IV phosphate salt). Inappropriate administration of large doses of parenteral phosphate over relatively short time periods has resulted in symptomatic hypocalcemia and soft-tissue calcification.64 The rate of infusion and choice of initial dosage should therefore be based on severity of hypophosphatemia, presence of symptoms, and coexistent medical conditions. Patients should be closely monitored with frequent (every 6 hours) serum phosphate determinations for 48 to 72 hours after starting IV therapy. It can be necessary to continue administration of IV phosphate for several days in some patients, although other patients may be able to tolerate an oral maintenance regimen. Monitoring should also include assessment of serum potassium, calcium, and magnesium concentrations. Hypomagnesemia secondary to intracellular shifts occurs frequently (27% to 80%) in severely hypophosphatemic patients.77 Therapy with parenteral phosphate should be undertaken with great caution and at reduced dosage for patients with hypercalcemia or renal dysfunction.76
Mild-to-moderate or asymptomatic hypophosphatemia can be treated by the administration of oral phosphate salts in doses of 1.5 to 2 g (50 to 60 mmol) daily in divided doses (see Table 35-6). Phosphate concentrations should be monitored daily, with the goal of correcting the reduced phosphate concentration in approximately 7 to 10 days. The primary dose-limiting adverse effect associated with oral phosphate replacement is the development of osmotic diarrhea. Patients with mild-to-moderate hypophosphatemia and moderate-to-severe renal insufficiency should receive reduced daily oral doses (i.e., 1 g or approximately 30 mmol of phosphate) with careful monitoring of serum phosphate concentration because they are predisposed to phosphate retention. In addition to phosphate supplementation for hypophosphatemia, dipyridamole can decrease renal phosphate leaking and increase serum phosphate. Doses of 75 mg four times daily have resulted in increases in serum 1,25-dihydroxy vitamin D3 and decreases in serum calcium and urolithiasis events.80
TABLE 35-6 Phosphorus Replacement Therapy
CLINICAL BOTTOM LINE
Clinicians play an integral part in the management of fluid and electrolyte abnormalities. Initial treatment strategy should be based on acuity of onset and severity of symptoms. Because the etiologies of calcium and phosphate disorders are diverse, it is important to integrate the known or anticipated pathophysiologic disease course into the treatment strategy. The patient’s medication history should be comprehensively assessed to determine whether the electrolyte abnormality may be drug induced. After resolution or treatment of the calcium or phosphate disorder, the medication regimen should be evaluated periodically. This proactive interventional approach will facilitate the management of mild disorders in the community and can reduce the need for hospitalization.
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