Harold E. Carlson
I. HYPERCALCEMIA
A. Mechanisms. Cancer is the most common cause of hypercalcemia in hospitalized patients. Hypercalcemia usually results from excessive bone resorption relative to bone formation.
1. Bone metastases. Most tumors capable of bone metastasis (see Chapter 33, Section I) can also produce hypercalcemia. Local production of various substances by tumor cells may stimulate osteoclastic bone resorption.
2. Ectopic parathyroid hormone (PTH) secretion appears to be rare.
3. Humoral hypercalcemia of malignancy is caused by production of a PTH-like substance called PTH-related peptide (PTH-RP) by a variety of carcinomas (squamous tumors of many organs, hypernephroma, parotid gland tumors). PTH-RP has bone-resorbing activity and interacts with the renal PTH receptor to stimulate renal calcium resorption. PTH-RP is not measured in serum PTH assays.
4. Vitamin D metabolites (e.g., 1,25-dihydroxyvitamin D) may be produced by some lymphomas; these metabolites promote intestinal calcium absorption.
5. Prostaglandins and interleukin-1 produced by various tumors may occasionally cause hypercalcemia, perhaps by enhancing bone resorption.
6. Tumors rarely or never associated with hypercalcemia despite high frequencies of bone metastases:
a. Small cell lung cancer
b. Prostate cancer
c. Colorectal cancer
B. Diagnosis
1. Symptoms of hypercalcemia depend both on the serum level of ionized calcium and on how fast the level rises. Rapidly rising serum calcium levels tend to produce obtundation and coma with only moderately elevated serum calcium levels (e.g., 13 mg/dL). Slowly rising serum calcium levels may produce only mild symptoms, even with serum levels exceeding 15 mg/dL.
a. Early symptoms
(1) Polyuria, nocturia, polydipsia
(2) Anorexia
(3) Easy fatigability
(4) Weakness
b. Late symptoms
(1) Apathy, irritability, depression, decreased ability to concentrate, mental obtundation, coma
(2) Profound muscle weakness
(3) Nausea, vomiting, vague abdominal pain, constipation, obstipation
(4) Pruritus
(5) Abnormalities of vision
2. Differential diagnosis of hypercalcemia. Idiopathic hypercalcemia is not a tenable diagnosis in adult patients. More and more often, benign causes of hypercalcemia are recognized to occur in patients with cancer. The possible etiologies of hypercalcemia include the following:
a. Malignancy
(1) Metastases to bone
(2) Secretion of PTH-like or other humoral factors
(3) Production of vitamin D metabolites
b. Primary hyperparathyroidism
c. Thiazide diuretic therapy
d. Vitamin D or vitamin A intoxication
e. Milk–alkali syndrome
f. Familial benign hypocalciuric hypercalcemia
g. Others
(1) Immobilization of patients with accelerated bone turnover (e.g., Paget disease or myeloma)
(2) Sarcoidosis, tuberculosis, and other granulomatous diseases
(3) Hyperthyroidism
(4) Lithium administration
(5) Adrenal insufficiency
(6) Diuretic phase of acute renal failure
(7) Severe liver disease
(8) Theophylline intoxication
3. Laboratory studies. All patients with cancer and polyuria, mental status changes, or gastrointestinal symptoms should be evaluated for hypercalcemia.
a. Routine studies
(1) Serum calcium, phosphorus, and albumin levels
(a) Ionized calcium constitutes about 47% of the serum calcium and is in equilibrium with calcium bound to proteins, especially to albumin. Roughly 0.8 mg of calcium is bound by 1 g of serum albumin. An alkaline pH (e.g., resulting from repeated vomiting because of hypercalcemia) tends to decrease the fraction of ionized calcium. When serum albumin is low, the measured serum calcium can be corrected (to a normal albumin concentration of 4 g/dL) using the following formula:
Corrected serum calcium (mg/dL) =
measured calcium + 0.8(4.0 − measured albumin)
(b) Long-standing hypercalcemia with hypophosphatemia suggests primary hyperparathyroidism.
(2) Serum alkaline phosphatase. Elevated levels may be due to either hyperparathyroidism or metastatic disease to the bone or liver. Normal levels are typical in cases of hypercalcemia produced by myeloma.
(3) Serum electrolytes. Serum chloride concentrations are frequently elevated in primary hyperparathyroidism. Renal tubular acidosis may complicate chronic hypercalcemia.
(4) Blood urea nitrogen (BUN) and serum creatinine. The direct effect of hypercalcemia on the kidneys can result in nephrogenic diabetes insipidus with defective renal tubular water conservation (i.e., symptoms of polyuria) leading to dehydration and azotemia.
(5) Electrocardiogram (ECG). Hypercalcemia results in relative shortening of the QT interval and prolongation of the PR interval. The T wave widens at blood levels above 16 mg/dL, paradoxically lengthening the QT interval.
(6) Radiographs of the abdomen and bones
(a) Nephrolithiasis is rare in hypercalcemia caused by malignancy and suggests hyperparathyroidism.
(b) Nephrocalcinosis and other ectopic calcifications are common in long-standing hypercalcemia.
(c) Subperiosteal bone resorption is pathognomonic of hyperparathyroidism, but diffuse osteopenia is the most common radiologic finding in this condition.
b. Further studies. Results from preliminary evaluation may indicate the need for measuring serum PTH levels or for performing other tests.
(1) Evidence for concomitant primary hyperparathyroidism
(a) Documented long history of hypercalcemia or renal stones
(b) Radiographic evidence of hyperparathyroid bone disease (subperiosteal reabsorption, osteitis fibrosa cystica, or salt-and-pepper skull)
(c) Hyperchloremic acidosis, particularly with a serum chloride-to phosphate ratio ≥34
(d) Elevated serum PTH level in the presence of hypercalcemia
(e) Absence of hypocalciuria; if the ratio of calcium clearance to creatinine clearance in a 24-hour urine specimen is <0.01, the patient probably has familial hypocalciuric hypercalcemia, which can otherwise mimic primary hyperparathyroidism. Note, however, that vitamin D deficiency must first be corrected in order to accurately assess urinary calcium excretion.
(2) Evidence for humoral hypercalcemia of malignancy
(a) Low or low-normal serum PTH levels in the presence of hypercalcemia
(b) Elevated serum level of PTH-RP
(c) Metabolic alkalosis
(d) Low serum level of 1,25-dihydroxyvitamin D
4. When should neck surgery for primary hyperparathyroidism be considered? Both primary hyperparathyroidism and humoral hypercalcemia of malignancy are characterized by hypercalcemia and, with many cancers, elevated urinary excretion of cyclic adenosine monophosphate. Parathyroid surgery is justified if all of the following apply:
a. Clinical and laboratory findings (see earlier) suggest hyperparathyroidism.
b. The malignancy is under control, and the patient’s expected survival is reasonably long.
c. The general condition of the patient makes the surgical risk acceptable.
d. The hypercalcemia is severe enough to warrant treatment. Mild hypercalcemia (e.g., ≤11.5 mg/dL) caused by primary hyperparathyroidism may remain stable and asymptomatic for many years and may never produce clinically significant complications during the patient’s remaining life span.
e. Parathyroid scanning with technetium-99m sestamibi or neck sonography demonstrates a probable parathyroid adenoma. Neck exploration may also be undertaken in patients with negative radiologic studies but convincing biochemical findings of primary hyperparathyroidism; however, in such cases, one must carefully weigh the possible benefits of surgery against the possibility of greater surgical morbidity and resultant chronic hypocalcemia.
C. Management
1. Acute, symptomatic hypercalcemia should be treated as an emergency.
a. Hydration and saline diuresis. Achieving and maintaining normal intravascular volume and hydration are the cornerstones of promoting urinary calcium excretion. Normal saline containing potassium chloride (KCl; 10 mEq/L) is given at a dosage of 2 to 3 L per day IV.
(1) Fluid intake and output and body weight are carefully monitored. Patients are evaluated for evidence of congestive heart failure two or three times daily. Patients with a history of congestive heart failure or renal insufficiency should be monitored with central venous pressure (CVP) measurements. If necessary, furosemide may be given to treat volume overload.
(2) Blood levels of calcium, potassium, and magnesium are measured every 8 to 12 hours, and concentrations of cations in the IV solutions are adjusted.
(3) Treatment is continued until the blood calcium concentration is below 12 mg/dL. Central nervous system manifestations in elderly or comatose patients may not improve until normal blood calcium levels are maintained for several days.
(4) More vigorous administration of fluids (e.g., 12 to 14 L over 24 hours) and diuretics (e.g., every 1 to 2 hours) requires excellent cardiac and renal function and necessitates close monitoring in an intensive care unit. Treatment at this intensity is rarely necessary for patients with malignancies.
b. Bisphosphonates are potent inhibitors of osteoclast activity and are effective in the treatment of hypercalcemia of malignancy. These drugs are relatively free of significant adverse effects. Zoledronate (Zometa) is the most effective of the available drugs; it is given as a single IV infusion of 4 mg in 100 mL of normal saline over 15 minutes. Pamidronate (Aredia) is slightly less effective; it is given as a single IV infusion of 60 to 90 mg in 250 to 500 mL of normal saline over 2 to 4 hours. With either drug, significant reductions in serum calcium occur in 1 to 2 days and generally persist for several weeks. Common side effects of both drugs include fever, nausea, and constipation; both drugs may also cause hypocalcemia, hypophosphatemia, and increased serum creatinine. Patients should be well hydrated both before and after administration of IV bisphosphonates. Doses may be repeated every 7 to 30 days.
A potential adverse effect of bisphosphonates is osteonecrosis of the jaw. In this condition, patients typically develop a painful area of exposed, necrotic bone, usually on the medial aspect of the mandible. The majority of cases have occurred after repeated IV administration of potent bisphosphonates for malignancy and may be precipitated by dental surgery; poor oral hygiene may also play a role. Although prospective data are scanty, some authorities have recommended that patients about to begin IV bisphosphonate therapy have routine dental care performed before treatment starts and biannually thereafter; patients who have already received >3 months of drug therapy have been cautioned to avoid or postpone extensive dental surgery, if possible. Treatment of osteonecrosis of the jaw usually consists of antibiotics and oral rinses; it is not yet clear if discontinuation of bisphosphonates is beneficial.
c. Gallium nitrate (Ganite), a potent inhibitor of bone resorption, is given intravenously in a dose of 200 mg/m2 daily for 5 days. Serum calcium levels fall within a few days and remain normal for about 1 week. Renal function may worsen during gallium nitrate therapy, and the drug should not be given if the serum creatinine level is higher than 2.5 mg/dL.
d. Mithramycin (plicamycin). This drug inhibits bone resorption by reversibly poisoning osteoclasts. Mithramycin, 25 μg/kg, is given by rapid infusion into a well-established IV line; serum calcium levels are lowered in 24 to 48 hours. The dose may be repeated every 3 to 4 days. Hypocalcemia is averted by measuring blood calcium levels every 1 or 2 days or when mental status changes or tetany develops. Other important toxicities of mithramycin are discussed in Chapter 4, Section III.I. The drug is contraindicated in the presence of severe thrombocytopenia or severe hepatocellular dysfunction. In patients with renal failure, mithramycin may be given in lower doses (10 μg/kg), but calcitonin is preferred in these cases.
e. Calcitonin is useful for rapid reduction of blood calcium levels. Calcitonin can be given when diuresis or other drugs are contraindicated or ineffective (e.g., in severe thrombocytopenia, renal failure, congestive heart failure). The drug inhibits bone resorption and increases renal calcium clearance. Blood calcium levels are decreased within 2 to 3 hours of administration. The effect is transient but may be prolonged to 4 or more days by concurrent administration of prednisone, 10 to 20 mg given three times daily. Allergy is the only important complication of therapy. Synthetic salmon calcitonin is given in a dose of 4 U/kg (Medical Research Council Units) SC or IM every 8 to 12 hours; the dose may be increased to 8 U/kg every 8 to 12 hours if needed.
f. Dialysis. Peritoneal dialysis and hemodialysis rapidly lower blood calcium levels but are rarely used.
g. Dangerous therapies that have little clinical usefulness and are not recommended:
(1) Intravenous phosphates (extraosseous calcification)
(2) Intravenous sodium sulfate (hypernatremia, heart failure)
(3) Calcium-chelating agents (severe renal damage)
2. Chronic hypercalcemia. Ambulation is encouraged to minimize bone resorption that accompanies immobilization. Liberal fluid intake (2 to 3 L/d) is prescribed. Foods containing large amounts of calcium, such as milk products, are avoided. Thiazide diuretics aggravate hypercalcemia and should not be taken. Treatment of the underlying malignancy may be beneficial.
a. Glucocorticoids. Prednisone, 20 to 40 mg PO daily, or hydrocortisone, 100 to 150 mg IV every 12 hours, may be used for patients with tumors that are sensitive to glucocorticoids (e.g., lymphoma, multiple myeloma). Glucocorticoids also increase renal calcium excretion.
b. Bisphosphonates. Zoledronate (4 mg IV) or pamidronate (60 to 90 mg IV) may be given every 7 to 30 days as needed to control hypercalcemia (see Section I.C.1).
c. Phosphates given orally lower blood levels by binding calcium in the gut. Because this may compromise renal function, effects of therapy should be monitored. Diarrhea nearly always accompanies phosphate therapy and is treated with diphenoxylate (Lomotil), 2 to 5 mg PO, with each dose of phosphate. Diarrhea may also be reduced by diluting the liquid or powder forms. The daily dose is 1 to 6 g of phosphate. One gram of inorganic phosphate is supplied by the following preparations:
(1) Fleet Phospho-soda, liquid, 6.7 mL
(2) Neutra-Phos, four capsules or 1 teaspoon of powder (Neutra-Phos-K contains no sodium)
(3) K-Phos Original Formula, six tablets (contains no sodium)
d. Prostaglandin inhibitors, such as aspirin and indomethacin, produce variable and inconsistent lowering of calcium levels but may be tried in patients with refractory hypercalcemia.
II. HYPOCALCEMIA
A. Mechanisms
1. Paraneoplasia. Hypocalcemia is an extremely rare paraneoplastic syndrome.
a. Rapid uptake of calcium. Patients with osteoblastic bone metastases may occasionally develop hypocalcemia due to uptake of calcium in the bone lesions. In addition, patients with bone metastases from prostate or breast cancer who are treated with hormonal agents may develop hypocalcemia, supposedly because of rapid bone healing. Calcifying chondrosarcoma is a rare tumor that has been associated with hypocalcemia.
b. Calcitonin production by medullary carcinoma of the thyroid rarely causes hypocalcemia.
2. Magnesium deficiency. Magnesium is necessary both for the secretion of PTH and for its peripheral action. Hypomagnesemia results in hypocalcemia that does not respond to calcium replacement therapy. Magnesium deficiency occurs in the following circumstances:
a. Patients who have prolonged nasogastric drainage
b. Patients who receive parenteral hyperalimentation without magnesium replacement
c. Cisplatin therapy–induced renal tubular dysfunction with urinary magnesium loss
d. Chronic diuretic therapy or diuresis due to glycosuria
e. Chronic alcoholism (alcohol interferes with renal conservation of magnesium)
f. Chronic diarrhea
3. Other causes of hypocalcemia
a. Therapy for hypercalcemia, especially if using IV bisphosphonates or mithramycin
b. Hypoalbuminemia
c. Hyperphosphatemia (see Section III)
d. Pancreatitis
e. Renal disease
f. Hypoparathyroidism
g. Pseudohypoparathyroidism
h. Rickets and osteomalacia
i. Sepsis
B. Diagnosis
1. Symptoms and signs are aggravated by hyperventilation or other causes of alkalosis.
a. Tetany is the most prominent symptom of hypocalcemia and is manifested by paresthesias (especially numbness and tingling of the face, hands, and feet), muscle cramps, laryngospasms, or seizures. Other problems include diarrhea, headache, lethargy, irritability, and loss of recent memory. Chronic hypocalcemia may be well tolerated, however, with few symptoms.
b. Dry skin, abnormal nails, cataracts, and papilledema may develop in longstanding cases.
c. Chvostek sign: twitching of muscles around the mouth, nose, or eyes after tapping the facial nerve.
d. Trousseau sign: spasm of the hand during 3 to 4 minutes of exercise while a blood pressure cuff on the arm is inflated midway between systolic and diastolic pressures.
2. Laboratory studies. Serum levels of calcium, phosphorus, magnesium, electrolytes, BUN, creatinine, albumin, intact PTH, and 25-hydroxy-vitamin D should be obtained. The ECG may show a prolonged QT interval; the ECG is monitored during therapy.
3. Differential diagnosis of hypocalcemia
a. Severe alkalosis resulting from prolonged nasogastric suction, vomiting, or hyperventilation
b. Severe muscle cramps resulting from vincristine or procarbazine therapy
C. Management
1. Severe, acute, symptomatic hypocalcemia (blood calcium ≤6 mg/dL) is generally managed in an intensive care setting with ECG monitoring.
a. Calcium gluconate or calcium chloride, 1 g, diluted in 50 mL of either D5W or normal saline, is given every 15 to 20 minutes as long as tetany persists.
b. Magnesium sulfate, 1 g IV or IM every 8 to 12 hours, is also administered if the blood magnesium level is unknown or <1.5 mg/dL until the calcium or magnesium blood levels have normalized.
c. Hyperventilating patients should breathe into a paper bag to decrease respiratory alkalosis.
d. Serum calcium levels are obtained every 1 to 2 hours until the serum calcium level exceeds 7 mg/dL.
2. Moderate hypocalcemia (blood calcium between 7 and 8 mg/dL)
a. Calcium may be given either PO or, if the patient is severely symptomatic, IV.
(1) Calcium carbonate, 2.5 g/d, or calcium citrate, 4 to 5 g/d PO; either form will provide about 1,000 mg of elemental calcium daily.
(2) Calcium gluconate, 2 g IV in 500 mL of 5% dextrose in water, is given every 8 hours.
b. Hypomagnesemia (<1.5 mg/dL) is treated with magnesium sulfate, 1 g IM or IV once or twice daily, until the blood level is normal.
c. Patients recovering from hypercalcemia who were treated with IV bisphosphonates or mithramycin are in jeopardy of recurrent life-threatening hypocalcemia for as long as 4 days after treatment is stopped.
d. Patients with postthyroidectomy hypoparathyroidism are discussed in Chapter 15, Section III.F.1.a.
III. HYPERPHOSPHATEMIA
A. Mechanisms. Hyperphosphatemia (>4.5 mg/dL) is a rare complication of treatment of certain tumors, notably leukemia and lymphoma (especially Burkitt lymphoma). Rapid tumor lysis releases large amounts of potassium, phosphate, and nucleic acids (which are metabolized to uric acid). Elevated blood phosphate levels may not be observed until 2 days after beginning tumor therapy; elevations may persist for 4 to 5 days and can exceed 20 mg/dL.
B. Diagnosis. The serum phosphate level itself does not cause symptoms. Renal damage or acute renal failure results from precipitation of calcium phosphate in the kidneys. Tetany and seizures may develop if the ionized calcium concentration becomes inordinately reduced (e.g., with alkalosis from bicarbonate administration or vomiting).
1. Laboratory studies. Serum phosphate, calcium, and other electrolyte levels should be measured regularly in susceptible patients during the initial course of antitumor therapy.
2. Differential diagnosis
a. Hypoparathyroidism
b. Renal failure
c. Rapid tissue breakdown after muscle trauma or burn
d. Tumor lysis syndrome (see Section XIII)
e. Large oral or rectal doses of phosphates
C. Management. High phosphate levels must be lowered rapidly to avoid or reverse renal damage. Serum chemistries are monitored every 4 to 6 hours. The following methods are used simultaneously until the phosphate concentration reaches 5 mg/dL:
1. An IV infusion of 20% dextrose containing 10 U/L of regular insulin is administered at a rate of 50 to 100 mL/h until the blood phosphate level falls below 7 mg/dL. When insulin drives glucose into cells, it moves phosphorus along with it; as soon as glucose enters a cell, it is phosphorylated to glucose-6-phosphate. The extracellular volume is expanded by infusing half-normal saline at 100 to 200 mL/h. Potassium is added to the solution if the serum level is <4 mEq/L.
2. Oral phosphate binders are given to bind phosphate in the intestine.
a. An aluminum hydroxide gel preparation (e.g., Amphojel), 30 to 60 mL PO, every 2 to 6 hours
b. Sevelamer hydrochloride (Renagel), 800 to 1,600 mg orally t.i.d. with meals
c. Lanthanum carbonate (Fosrenol), 500 to 1,000 mg orally t.i.d. with meals
3. Oral fluids are given at a rate of 2 to 4 L every 24 hours.
4. Dialysis may be necessary for patients with renal failure.
IV. HYPOPHOSPHATEMIA
A. Mechanism. Hypophosphatemia (<3 mg/dL) is occasionally associated with rapidly growing tumors (such as acute leukemia), presumably because tumor cells consume phosphate. Severe hypophosphatemia (<1 mg/dL) may result in rhabdomyolysis or hemolysis. Hypokalemia may be associated with hypophosphatemia, the reasons for which are unclear. In patients with cancer, hypophosphatemia more commonly accompanies marked nutritional deprivation or cachexia.
B. Diagnosis
1. Laboratory studies. Hypophosphatemia is usually recognized by routine serum electrolyte studies in patients with nutritional disturbances.
2. Differential diagnosis of hypophosphatemia
a. Renal phosphate wasting accompanies certain syndromes associated with malignancies, including myeloma (Fanconi syndrome), multiple endocrine neoplasia (hyperparathyroidism), and oncogenic osteomalacia (see later discussion).
b. Therapy with phosphate-binding antacids or other phosphate binders
c. Starvation or malabsorption (decreased phosphate intake)
d. Cachexia
e. Alcoholism
f. Recovery from malnutrition without adequate phosphate supplementation (refeeding syndrome)
g. Massive, rapid tumor growth
h. Alkalosis
i. Treatment of diabetic ketoacidosis
j. Use of IV bisphosphonates
k. Use of imatinib, sunitinib, sorafenib, or temsirolimus
l. Oncogenic osteomalacia appears to be caused by tumor products, primarily fibroblast growth factor-23, that interfere with the production of 1,25-dihydroxycholecalciferol and promote phosphaturia. This entity has been associated with mesenchymal neoplasms (usually benign) and prostate cancer. Oncogenic osteomalacia is characterized by hypophosphatemia, usually normocalcemia, elevated serum alkaline phosphatase, and decreased serum 1,25-dihydroxycholecalciferol. The responsible tumor can sometimes be detected with somatostatin receptor scanning using radioactively labeled octreotide.
C. Management
1. Patients with phosphorus levels <1 mg/dL are given 30 to 40 mmol/L of neutral sodium phosphate or sodium potassium phosphate administered IV at a rate of 50 to 150 mL/h. Doses and precautions are about the same as for IV potassium preparations.
2. Patients with blood phosphorus levels of 1 to 2 mg/dL may be given oral inorganic phosphate supplements (see Section I.C.2.c). One bottle of Neutra-Phos (64 g of phosphorus) is dissolved in 4 L of water, and 2 to 3 ounces of the solution is given four times daily PO.
3. Patients with simultaneous hypokalemia are treated with 20 mEq of KCl in 10% solution three times daily or with potassium-containing phosphate preparations. Neutra-Phos-K and Phos-Tabs both contain 50 to 57 mEq of potassium per gram of phosphate.
4. Oncogenic osteomalacia is treated by completely resecting the responsible tumor. If this is not possible, patients may be treated with a combination of 1,25-dihydroxycholecalciferol (calcitriol) 1.5 to 3.0 μg/d and phosphorus supplementation of 2 to 4 g/d.
V. HYPERNATREMIA
A. Mechanisms. Hypernatremia nearly always is due to a loss of water from the body fluids. Any hypotonic fluid loss (e.g., sweating, hyperventilation, fever, vomiting, nasogastric suction) causes mild hypernatremia if not treated. Extreme elevations of plasma sodium concentrations (>160 mEq/L) are usually encountered in only three clinical situations:
1. Decreased or absent fluid intake is the most common cause of hypernatremia, especially in patients who have disabilities that impair normal fluid intake.
2. Diabetes insipidus (insufficient production of antidiuretic hormone [ADH]) is usually caused by head trauma (accidental or neurosurgical) or pituitary or hypothalamic neoplasms (primary or metastatic). Breast and lung cancers appear to have a special propensity for metastasizing to the hypothalamus. Although there are other rare causes of diabetes insipidus, nearly half of the cases are idiopathic. Diabetes insipidus is an exceptionally rare paraneoplastic syndrome. Nephrogenic diabetes insipidus occurs when the kidney is unable to respond to normal circulating levels of ADH and may be the result of hypercalcemia, hypokalemia, or medications.
3. Osmotic diuresis and often osmotic diarrhea are encountered in obtunded patients who receive a massive urea load from high-protein nasogastric tube feedings. Progressive dehydration develops, and the osmotic diuresis produces an apparently normal urine output. Daily weighing and twice-weekly measuring of serum electrolytes and urea nitrogen are necessary to detect or prevent this problem.
B. Diagnosis
1. Signs and symptoms. Most patients with severe hypernatremia are already seriously ill. The specific contribution of hypertonicity is frequently difficult to distinguish from the underlying disease. Polyuria draws attention to the problem in most cases. If the solute intake is low, however, urine output may not exceed 2 to 3 L/d.
2. Laboratory studies. To make a diagnosis of diabetes insipidus, a water-deprivation test is performed. Baseline body weight, serum sodium concentration, serum osmolality, and urine osmolality are measured. Water intake is completely restricted; however, these patients should never be deprived of water without continuous observation. Beginning in the morning, urine volume and the baseline studies are determined hourly. The test should be terminated if the patient’s weight decreases by >3% or when serum osmolality exceeds 300 mOsm/kg. Pending results of direct measurement, the serum osmolality can be rapidly and accurately estimated from serum concentrations of sodium, urea nitrogen, and glucose by the following formula:
Serum osmolality = 2 (sodium) + BUN/2.8 + glucose/18
a. Criterion for diagnosing diabetes insipidus. Urine osmolality is <600 mOsm/kg when serum osmolality is >300 mOsm/kg.
b. Differentiating pituitary diabetes insipidus. Significant diabetes insipidus is excluded if the urine osmolality is >600 mOsm/kg after water deprivation in the absence of glycosuria or recently injected contrast media. Urine osmolality between 200 and 600 mOsm/kg suggests partial diabetes insipidus. It is necessary to distinguish pituitary (central) diabetes insipidus from nephrogenic diabetes insipidus. To do this, the kidney’s response to ADH is assessed. Desmopressin, 1 μg, is given SC at the conclusion of the water-deprivation test, and hourly urine specimens are collected for an additional 3 hours. After desmopressin injection, urine osmolality exceeds 400 mOsm/kg in patients with ADH deficiency and 800 mOsm/kg in normal persons; values are lower in patients with nephrogenic diabetes insipidus.
C. Management
1. Severe hypernatremia is life-threatening and must be carefully managed. Correcting the water deficit too rapidly may precipitate fatal cerebral edema. Therapy should not lower the serum sodium level by >2 to 4 mEq/h. Emergency therapy for patients in shock consists of plasma volume expansion with normal saline solution (200 to 250 mL boluses IV over 10 minutes until the systolic blood pressure exceeds 90 mm Hg); volume expansion itself induces a saluresis and initiates reduction of the serum sodium level. When the patient is hemodynamically stable, the total volume (in liters) of 5% dextrose in water is given according to the following formula:
2. Therapy for chronic ADH deficiency usually involves administration of desmopressin (desamino-D-arginine vasopressin [DDAVP]), 5 to 10 μg intranasally or 0.5 to 1.0 μg by SC injection, which produces 6 to 18 hours of antidiuresis. To avoid water intoxication, the next dose is not given until thirst and polyuria redevelop. Oral desmopressin is also available for chronic therapy; doses of 0.05 to 1.2 mg/d are given.
VI. HYPONATREMIA: SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE (SIADH)
A. Mechanisms
1. ADH is normally released from the posterior pituitary gland in response to increased osmolality or decreased plasma volume. The release of ADH is normally inhibited by decreased plasma osmolality and increased plasma volume. The hormone acts by increasing water resorption from the renal collecting ducts.
2. SIADH. Unregulated production of ADH results in increased water retention by the kidney, increased total body water, and moderate expansion of plasma volume. Plasma hypotonicity fails to suppress the secretion of ADH. Hyponatremia, plasma hypo-osmolality, and inability to excrete maximally diluted urine are the consequences of SIADH.
3. Associated tumors. Ectopic production of ADH may occur with any malignancy but is most frequently associated with bronchogenic carcinoma, especially the small cell type, and mesothelioma.
a. About half of the patients with small cell lung cancer are unable to excrete an exogenous free water load normally; however, only a small portion of these develop severe hyponatremia (<120 mEq/L).
b. Abnormalities of serum electrolytes, other than hyponatremia and (occasionally) hypouricemia, do not occur in SIADH. Some tumors, however, produce multiple ectopic hormones. Concomitant hypokalemia suggests a complicating ectopic adrenocorticotropic hormone (ACTH) syndrome. Concomitant hypercalcemia suggests the presence of a paraneoplastic disorder of calcium metabolism.
4. Central nervous system disease (e.g., mass lesions, hemorrhage, infection) and pulmonary infection (e.g., pneumonia, tuberculosis, abscess) may result in excessive ADH release from the posterior pituitary.
5. Cerebral salt wasting may occur in patients with intracranial trauma or hemorrhage. This syndrome resembles SIADH and manifests hyponatremia and increased urinary sodium excretion. However, in contrast to SIADH, plasma volume contraction is seen with cerebral salt wasting, and BUN and serum creatinine may be high-normal or mildly decreased. Therapy is directed at salt and volume replacement.
6. Drugs associated with hyponatremia
a. Diuretics commonly produce hyponatremia, particularly in patients with unrestricted fluid intake.
b. Vincristine and vinblastine may produce SIADH and profound hyponatremia. Manifestations develop 1 to 2 weeks after treatment.
c. Cyclophosphamide, when given intravenously, may produce SIADH. Mild hyponatremia develops 4 to 12 hours after a dose, persists for about 20 hours, and is usually asymptomatic.
d. Cisplatin, high-dose melphalan, and thiotepa have been associated with SIADH.
e. Chlorpropamide occasionally causes SIADH; other oral hypoglycemics rarely do so.
f. Carbamazepine and oxcarbazepine induce ADH secretion.
g. Intravenous narcotics have been associated with SIADH.
h. Antidepressants and antipsychotics have occasionally been associated with SIADH.
B. Diagnosis
1. Symptoms and signs. Lethargy, nausea, anorexia, and generalized weakness are common symptoms in patients with hyponatremia; however, the symptoms may be related more to comorbid conditions than to the serum sodium concentration. Confusion, convulsions, coma, and death may ensue if the hyponatremia is severe or rapid in onset.
2. Laboratory studies. Laboratory results in conditions associated with hyponatremia are shown in Table 27.1. Measurements that should be obtained in patients with hyponatremia are as follows:
Table 27.1 Hyponatremia: Differential Diagnosis and Laboratory Results
BUN, blood urea nitrogen; S, serum; U, urine; SIADH, syndrome of inappropriate antidiuretic hormone; D, decreased; N, normal; I, increased; GI, gastrointestinal. Parentheses indicate slight or occasional amount.
a. In all patients with hyponatremia
(1) Serum electrolytes, creatinine, urea nitrogen, calcium, phosphate, glucose, total protein, and triglycerides
(2) Urine sodium
b. In patients with hyponatremia and without an elevated BUN
(1) Serum and urine osmolality
(2) Chest radiograph or CT scan to look for evidence of lung cancer and brain CT or MRI to look for CNS lesions
c. In patients with evidence of endocrine hypofunction
(1) Thyroid function tests
(2) Adrenal function tests
(3) Pituitary gland function tests, as necessary
3. Diagnostic criteria for SIADH include all five of the following:
a. Hyponatremia with a disproportionately low BUN (often <10 mg/dL)
b. Absence of intravascular volume contraction
(1) Volume contraction is a potent stimulus for ADH secretion and overrides the suppressive effect of hypotonicity.
(2) Persistent urinary excretion of sodium constitutes indirect evidence of volume expansion (urine sodium concentration >30 mEq/L; fractional excretion of sodium >1). However, note that urinary sodium may be similarly increased in cerebral salt wasting.
c. Absence of abnormal fluid retention, such as peripheral edema or ascites
d. Normal renal, thyroid, and adrenal function
e. Serum hypotonicity along with urine that is not maximally dilute. A normal adult should be able to dilute urine to an osmolality of 50 to 75 mOsm/kg in the presence of decreased plasma osmolality; higher values are presumptive evidence for ADH activity at the renal tubules. Urine must be less than maximally dilute but need not be hypertonic relative to serum. Urine osmolality >75 to 100 mOsm/kg (or urine specific gravity >1.003) with plasma osmolality <260 mOsm/kg is suggestive of SIADH.
C. Management. Control of the responsible cancer usually corrects the problems associated with ectopic SIADH.
1. Severe, symptomatic hyponatremia (serum sodium <110 mEq/L). Comatose or seizing patients with severe hyponatremia must receive aggressive management, preferably in an intensive care unit. The development of mental status changes or seizures in patients with severe hyponatremia is prima facie evidence of cerebral herniation; dexamethasone, 10 to 20 mg IV, and mannitol, 50 g IV, are given immediately.
a. An IV infusion of 3% NaCl at a rate of 1 L every 6 to 8 hours is started.
b. Furosemide, 40 to 80 mg IV every 6 to 8 hours, is administered simultaneously.
c. The CVP is monitored every 15 to 30 minutes; serum sodium and potassium concentrations are obtained hourly. Give additional doses of furosemide, 20 to 40 mg IV, or decrease the saline infusion rate if the CVP exceeds 18 cm of water or if congestive heart failure becomes evident on physical examination.
d. Furosemide and saline are discontinued when the serum sodium concentration exceeds 110 mEq/L. More rapid treatment increases the risk for osmotic cerebral myelinolysis. The hyponatremia should then be further corrected more slowly as described in Section VI.C.2; serum sodium should rise no >12 mEq/L in the first 24 hours to avoid myelinolysis. Correction to serum sodium values of 125 to 130 mEq/L is usually sufficient.
2. Moderately severe hyponatremia (serum sodium >110 mEq/L)
a. Fluid restriction is of paramount importance in treatment of all patients with SIADH and should result in correction of hyponatremia within 3 to 5 days. Patients with serum sodium levels <125 mEq/L should be restricted to 500 to 700 mL/d. Patients with higher serum sodium levels can be restricted to 1,000 mL/d.
b. Demeclocycline (Declomycin), 150 to 300 mg PO given four times daily, induces renal resistance to ADH and facilitates free water excretion. Although its effects are variable, the drug may be useful in patients who cannot tolerate chronic fluid restriction or who have insufficient improvement of hyponatremia with fluid restriction. The only significant toxicity of the drug is azotemia, which may be a problem in patients who receive the higher doses or simultaneous nephrotoxic agents.
c. Tolvaptan (Samsca) blocks the renal V2-vasopressin receptor, preventing the action of ADH. It has been given to patients with mild or moderate euvolemic or hypervolemic hyponatremia in doses of 15 mg orally daily and doses titrated up to a maximum of 60 mg daily if needed. Fluids are not restricted during tolvaptan therapy. Close monitoring of serum sodium is required to avoid overly rapid correction of hyponatremia, and the drug should be initiated only during hospitalization. Tolvaptan is metabolized by CYP3A and P-glycoprotein and may interact with other drugs that alter these metabolic pathways (see Chapter 4, part VI.A.).
VII. HYPERKALEMIA
A. Mechanisms
1. Hyperkalemia in patients with or without cancer often develops as a consequence of renal failure.
2. Hyperkalemia may result from rapid tumor lysis after therapy, especially in patients with Burkitt lymphoma or acute leukemia.
3. Adrenal metastases are common in patients with many types of cancer, but clinical adrenal insufficiency from metastases is unusual.
4. Pseudohyperkalemia occurs in patients with persistent leukocytosis or thrombocytosis, especially in the myeloproliferative disorders (see Chapter 24, Section II.G.3 in “Comparable Aspects”).
B. Diagnosis
1. Symptoms mostly consist of weakness and other neuromuscular complaints.
2. Laboratory studies
a. Serum potassium concentration
b. The severity of the ECG abnormalities corresponds to the severity of hyperkalemia; as hyperkalemia gets worse, the ECG may show increased T-wave amplitude, decreased R-wave amplitude, and increased S-wave depth; prolongation of PR intervals and widening of the QRS complex; and then a sine wave pattern, eventuating in asystole or ventricular tachyarrhythmias. However, the absence of ECG changes does not exclude hyperkalemia.
3. Differential diagnosis
a. Renal insufficiency
b. Excessive potassium intake, especially with renal insufficiency
c. Potassium-sparing diuretics
d. Adrenal insufficiency
e. Acidosis
f. Cell destruction (e.g., tumor lysis, rhabdomyolysis)
g. Angiotensin-converting enzyme inhibitors
h. Angiotensin receptor blockers
C. Management
1. In patients with significant ECG abnormalities, IV calcium gluconate (10 mL of 10% solution) may be given to antagonize the effect of hyperkalemia on cardiac cell membranes.
2. Immediate lowering of the potassium is achieved by IV administration of 10 units of regular insulin plus 50 to 100 mL of 50% dextrose solution. If the patient is acidotic, 150 to 300 mEq (one to two ampules) of sodium bicarbonate is given IV. Note that bicarbonate cannot be simultaneously given via the same IV line as calcium because of the precipitation of calcium carbonate.
3. Beta-adrenergic agonists also shift potassium from serum into cells. Albuterol or salbutamol can be given by nebulizer in doses of 10 to 20 mg (these doses are much larger than those used for treating asthma).
4. Removal of potassium from the body can be achieved with cation exchange resins like Kayexalate, 15 to 30 g every 6 hours. Sorbitol, 20 mL of 70% solution PO four times daily, or 100 g in a water-retention enema, is given to expel the resin from the bowel.
5. If renal function is adequate and the patient is not dehydrated, a loop diuretic, such as furosemide 40 to 80 mg, may be given intravenously to increase urinary potassium excretion.
6. Hemodialysis is necessary for management of chronic or refractory hyperkalemia.
7. Hyperkalemia due to adrenal insufficiency may be corrected with the synthetic mineralocorticoid, fludrocortisone, 0.05 to 0.20 mg/d.
VIII. HYPOKALEMIA: ECTOPIC SECRETION OF ACTH
A. Mechanism. A variety of tumors may ectopically synthesize ACTH and produce Cushing syndrome. Biologically active ACTH is secreted in varying proportions with biologically inactive prohormone and preprohormone. All of these substances possess antigenic activity for ACTH. Thus, assays based on ACTH antigenic activity do not prove the presence of Cushing syndrome. Although hypokalemia may occur in Cushing syndrome due to any cause, it is particularly common (>50%) in patients with Cushing syndrome due to ectopic ACTH secretion.
1. Tumors commonly producing ectopic ACTH syndrome
a. Small cell lung cancer
b. Malignant thymoma
c. Pancreatic cancer, especially islet cell tumors
d. Bronchial carcinoids
2. Tumors uncommonly or rarely producing ectopic ACTH syndrome
a. Ovarian cancer
b. Thyroid cancer (except medullary)
c. Colon cancer
d. Prostate cancer
e. Renal cancer
f. Sarcomas
g. Hematologic malignancies
B. Diagnosis
1. Symptoms and signs. The most common malignant causes of ectopic ACTH syndrome are rapidly fatal. The typical features of adrenal or pituitary Cushing syndrome are often absent. Presenting signs usually are cachexia, weakness, and hypertension. Slower-growing cancers and benign tumors give rise to the characteristic rounded facies, truncal obesity, purple striae in skin stretch areas, and overt diabetes mellitus.
2. Laboratory studies
a. Cancer patients who complain of weakness should have serum electrolytes measured. Hypokalemia and metabolic alkalosis may be severe (serum potassium as low as 1 mEq/L, bicarbonate >30 mEq/L) in patients with ectopic ACTH syndrome.
b. The diagnosis of ectopic ACTH syndrome may be quickly made by demonstrating the failure of high-dose dexamethasone to suppress ACTH levels in most cases (see Chapter 15, Section V.C.2).
3. Differential diagnosis of hypokalemia
a. Gastrointestinal losses associated with alkalosis (vomiting, prolonged nasogastric suctioning, colonic neoplasms [villous adenoma], chronic laxative abuse)
b. Gastrointestinal losses associated with acidosis (chronic diarrhea, ureterosigmoidostomy, Zollinger-Ellison syndrome)
c. Potassium-wasting drugs (e.g., diuretics, cisplatin, corticosteroids)
d. Hyperaldosteronism
e. Hypercortisolism
f. Licorice ingestion
g. Renal tubular acidosis
h. Hypercalcemia, hypomagnesemia
i. Hypophosphatemia in anabolic states (e.g., rapid tumor growth)
j. Respiratory therapy resulting in alkalosis in patients with chronic carbon dioxide retention
k. Correction of nutritional anemias
C. Management of ectopic ACTH syndrome. Control of the underlying tumor is the most effective method. Hypokalemia is often difficult to correct. Potassium replacement consists of PO or IV doses of 80 to 150 mEq/d. Severe symptoms may occasionally improve with the use of adrenal suppressant medications, such as various combinations of mitotane, metyrapone, ketoconazole, and aminoglutethimide. The toxicity of these drugs may be worse than the symptoms from the underlying disease. Spironolactone, 100 to 400 mg daily, may be useful. Adrenalectomy is a consideration in the rare patient with an indolent, unresectable tumor that causes the ectopic ACTH syndrome.
IX. HYPERURICEMIA
A. Mechanisms. Hyperuricemia and hyperuricosuria pose a major problem for patients with myeloproliferative disorders, lymphomas, myeloma, or leukemias but usually not for patients with solid tumors.
1. Hyperuricosuria. Urinary uric acid excretion is increased in untreated patients who have myeloproliferative disorders, acute or chronic myelocytic leukemia, or acute lymphoblastic leukemia. Patients with lymphoma have normal or slightly increased uric acid excretion. During treatment with either cytotoxic agents or radiation, massive tumor lysis releases nucleic acids and results in excess production of uric acid, especially in patients with lymphoma or leukemia.
2. Uric acid nephropathy results from the precipitation of uric acid crystals in the concentrated, acidic urine of the renal medulla, distal tubules, and collecting ducts. The resultant sludge leads to intrarenal obstructive nephropathy and distinct inflammatory interstitial changes. Four types of renal disease comprise hyperuricemic nephropathy.
a. Acute hyperuricemic nephropathy is seen in patients treated for hematologic malignancies. It is characterized by acute renal failure with a rapidly rising serum creatinine concentration. Blood uric acid levels of >20 mg/dL are consistently associated with acute renal functional impairment or failure. Lower levels may acutely compromise renal function if the patient is dehydrated or acidotic.
b. Gouty nephropathy is usually mild to moderate and is characterized by the deposition of uric acid crystals (tophi) in the medulla or pyramids and a surrounding giant cell reaction.
c. Uric acid nephrolithiasis develops in gouty and nongouty patients with or without hyperuricemia. Symptomatic uric acid calculi are usually manifested by renal colic. Acute or chronic renal failure may develop secondary to obstructive uropathy.
d. Interstitial nephritis of hyperuricemia may lead to chronic renal failure after 20 to 30 years. This condition is almost always associated with hypertension and is questioned as an isolated cause of renal failure.
3. Xanthine stones, resulting from the inhibition of xanthine oxidase by allopurinol in the setting of purine hypermetabolism, rarely complicates malignancies.
4. Oxypurinol stones have rarely developed after therapy with massive doses of allopurinol.
B. Diagnosis is established by measurement of serum and urine uric acid concentrations. The normal excretory rate for uric acid is 300 to 500 mg/d.
C. Management
1. Prevention is the cornerstone of management.
a. Vigorous hydration is essential for increasing uric acid clearance and diluting the concentration of uric acid in the renal tubules. Urinary flow should be at least 100 mL/h.
b. Alkalinization of the urine. Traditionally, the urine pH is maintained between 7.0 and 7.5 (checked by dipstick). Recently, routine alkalinization of the urine has been questioned because it increases the risk of forming crystals of calcium phosphate and xanthine within the renal tubules, since these are both less soluble in an alkaline urine. Alkalinization should be reserved for patients with metabolic acidosis.
c. Allopurinol should be given continuously to patients with myeloproliferative disorders and at least 12 hours before starting antitumor therapy to patients with the other hematologic malignancies. The usual dose is 300 to 600 mg/d PO; larger doses may be required. Intravenous allopurinol is also available but expensive. Allopurinol can be discontinued when the tumor burden has been sufficiently reduced.
2. Treatment. Rapid lowering of established hyperuricemia may be accomplished with IV rasburicase, a recombinant form of urate oxidase. Rasburicase is approved for both adult and pediatric use and is very expensive; doses of 0.15 to 0.2 mg/kg IV are given daily for several days. See also Chapter 31. Section VII.A.3.c.
3. Renal failure because of uric acid nephropathy
a. Ureteral lavage through nephrostomies and surgical removal of stones may be necessary to relieve acute renal pelvis and ureteral obstructions.
b. Hemodialysis should be used if the previously discussed measures fail to improve renal function because uric acid nephropathy is usually a complication of effective antitumor therapy. Hemodialysis is superior to peritoneal dialysis for clearing uric acid.
X. HYPOURICEMIA
A. Mechanisms. Hypouricemia is usually caused by defects in proximal renal tubular reabsorption of uric acid. Hypouricemia has also been reported to be associated with a variety of tumors, especially Hodgkin lymphoma and myeloma.
B. Diagnosis
1. Symptoms. Patients do not have symptoms.
2. Laboratory studies. Blood uric acid levels identify the abnormality.
3. Differential diagnosis
a. Proximal renal tubular disease
(1) Fanconi syndrome (myeloma is a common cause in adults)
(2) Wilson disease
(3) Isolated defect in otherwise healthy patients
b. Uricosuric agents
(1) Aspirin
(2) Radiographic contrast agents
(3) Glyceryl guaiacolate
(4) Losartan
(5) Probenecid
(6) Trimethoprim–sulfamethoxazole
c. Treatment with xanthine oxidase inhibitors (allopurinol) or urate oxidase (rasburicase)
d. Hereditary xanthinuria
e. Neoplastic diseases, especially Hodgkin lymphoma
f. Liver disease
g. SIADH
C. Management. Treatment of hypouricemia is not necessary.
XI. HYPERGLYCEMIA
A. Mechanisms
1. Diabetic glucose tolerance curves with relative insulin deficiency are present in many patients with cancer, particularly those with poor nutrition or cachexia. Nutritional replenishment appears to improve these abnormalities.
2. Hyperglycemia occurs in patients with glucagonoma, somatostatinoma, pheochromocytoma, and hypercortisolism. Use of dexamethasone or other glucocorticoids as an antiemetic or as part of a chemotherapy regimen may cause hyperglycemia. Pancreatic destruction by carcinoma may also cause diabetes.
3. Nonketotic hyperosmolar coma can be a complication of treatment with cyclophosphamide, vincristine, L-asparaginase, or prednisone in patients with even mild diabetes mellitus. Hyperosmolar coma also occurs as a result of hyperalimentation therapy.
B. Diagnosis. Random or 2-hour postprandial blood glucose determinations disclose the abnormality in most patients.
C. Management
1. Nutritional status should be improved in cancer patients with glucose intolerance, if feasible. Management of substantial hyperglycemia on account of tumor is effected by control of the neoplasm and by administration of insulin or oral hypoglycemics as needed.
2. Hyperosmolar coma must be vigorously treated with fluid replacement of volume losses with IV saline until the blood pressure is stable. Insulin infusion (1 to 4 U/h) usually controls the hyperglycemia.
3. Avoidance of glucocorticoids will prevent steroid-induced hyperglycemia.
XII. HYPOGLYCEMIA
A. Mechanisms. Insulin-like substances (most often proinsulin-like growth factor-2 [pro-IGF-2]) may be produced by some tumors, especially large, often retroperitoneal sarcomas, and occasionally other cancers. Hepatocellular carcinomas and extensive liver metastases from a variety of primary sites may deplete glycogen stores and impair gluconeogenesis. Insulinoma is discussed in Chapter 15, Section VI.C.
1. Etiologies of hypoglycemia
a. Malignant tumors
(1) Insulinoma
(2) Large retroperitoneal tumor producing pro-IGF-2
(3) Hepatocellular carcinoma
(4) Extensive hepatic metastasis
b. Drugs
(1) Surreptitious or therapeutic insulin administration
(2) Oral hypoglycemic agents
(3) Alcohol
(4) Salicylates
(5) Gatifloxacin
(6) Pentamidine
(7) Jamaican vomiting sickness (akee fruit)
(8) Quinine (in antimalarial doses)
c. Metabolic disorders
(1) Starvation
(2) Chronic hepatic or renal failure
(3) Hypoadrenalism
(4) Hypopituitarism
(5) Myxedema
(6) Glycogen storage diseases
(7) Reactive hypoglycemias (e.g., prediabetes, postgastrectomy)
(8) Sepsis
2. Pseudohypoglycemia. Falsely low glucose levels may occur in patients with marked granulocytosis, especially patients with myeloproliferative disorders, because of in vitro consumption of glucose.
B. Diagnosis
1. Symptoms and signs. Tumor-associated hypoglycemia produces mental status change, fatigue, convulsions, or coma. Some patients show features of fasting hypoglycemia, such as an altered morning personality that improves after breakfast. Tremors, sweating, tachycardia, and hunger pangs are suggestive of an acute decrease in blood sugar level.
2. Laboratory studies. A blood glucose concentration of <55 mg/dL establishes the presence of hypoglycemia. Further evaluation of fasting hypoglycemia is discussed in Chapter 15, Section VI.C.1.b. Patients who are thought to surreptitiously abuse insulin should have C-peptide and insulin serum levels measured during a hypoglycemic episode. Absent C-peptide with elevated insulin level suggests the diagnosis of exogenous insulin administration.
C. Management
1. Intravenous glucose. Any patient with unexplained hypoglycemia should have a blood sample drawn for glucose, insulin, and C-peptide determination, followed immediately by rapid IV infusion of 50 mL of 50% dextrose solution. Serum glucose may remain low even while concentrated glucose solutions are being administered. All patients with glucose levels of <40 mg/dL and symptomatic patients with glucose levels of <60 mg/dL should be treated by continuous infusion of 20% glucose at 50 to 150 mL/h; rates are adjusted to maintain glucose levels higher than 60 mg/dL. Blood glucose levels are measured every 3 to 4 hours until stabilization occurs.
2. Glucagon, 1 mg IM or IV, raises blood glucose by promoting glycogenolysis and gluconeogenesis. Long-term glucagon therapy has been given by infusion pump.
3. Octreotide, a somatostatin analog, can decrease insulin hypersecretion and has occasionally normalized serum glucose in patients with pro-IGF-2–secreting tumors but may sometimes worsen or provoke hypoglycemia by inhibiting glucagon and growth hormone secretion.
4. Other measures. If the blood glucose cannot be increased to safe levels with glucose infusions, prednisone or diazoxide should be administered (see Chapter 15, Section VI.C.2.d).
XIII. TUMOR LYSIS SYNDROME
A. Mechanisms. Effective chemotherapy of several malignancies may result in the massive release into the blood of potassium, phosphate, uric acid, and other breakdown products of dying tumor cells. Hypocalcemia may occur with severe hyperphosphatemia. Tumor lysis syndrome develops within hours to a few days of treatment for the underlying neoplasm.
1. Associated tumors most commonly are acute leukemia, Burkitt lymphoma, and occasionally other lymphoreticular malignancies. The syndrome rarely occurs after the treatment of solid tumors. A high tumor burden and elevated serum lactate dehydrogenase levels increase the risk of tumor lysis syndrome.
2. Life-threatening complications include renal failure from precipitation of uric acid or calcium phosphate crystals in the kidney, seizures from hypocalcemia, and cardiac arrhythmias from hyperkalemia or hypocalcemia.
B. Diagnosis
1. Physical examination. Oliguria may call attention to the metabolic disorders. Tetany may be a presenting feature. Cardiac arrhythmias or cardiopulmonary arrest develop if the process is not controlled.
2. Laboratory studies. Patients treated for acute leukemia or Burkitt lymphoma should have measurements of serum levels of potassium, calcium, phosphate, uric acid, and creatinine performed daily for 1 week and every few hours if the syndrome develops.
C. Management. Vigorous IV hydration with half-normal saline is initiated. Severe metabolic problems are treated as follows:
1. Hypocalcemia, see Section II.C.
2. Hyperphosphatemia, see Section III.C.
3. Hyperkalemia, see Section VII.C.
4. Hyperuricemia, see Section IX.C and Chapter 31. Section VII.A.3.c.
5. Hemodialysis may be necessary on an emergency basis for patients who do not respond to treatment or who develop renal insufficiency.
Suggested Reading
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Jan de Beur SM. Tumor-induced osteomalacia. JAMA 2005;294:1260.
Marinella MA. Refeeding syndrome in cancer patients. Int J Clin Pract 2008;62:460.
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