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  • Tests Useful in Differential Diagnosis of Hypercalcemia

    Serum calcium. Routine serum calcium assay measures the total serum calcium value. Total serum calcium contains about 50% bound calcium (literature range, 35%-55%) and about 50% nonbound calcium (literature range, 35%-65%). (Traditionally, nonbound calcium was called “ionized” calcium and is also known as “free” or “dialyzable” calcium.) Bound calcium is subdivided into calcium bound to protein and calcium complexed to nonprotein compounds. About 45% of total calcium (30%-50%) is protein-bound, of which 70%-80% is bound to albumin. The remaining 5% (5%-15%) of total calcium is complexed to ions such as citrate, phosphate, sulfate, and bicarbonate, which are not part of the serum proteins. Ionized calcium levels can be measured directly by ion-selective electrode techniques or less accurately can be estimated from total serum calcium and albumin or total protein values using certain formulas. The most commonly used calcium correction formula is that of R.B. Payne:

    Adjusted calcium = (measured calcium – serum albumin) + 4.0

    with calcium in mg/100 ml and albumin in g/100 ml. In international system (SI) units, the formula reads:

    Adjusted calcium = (calcium – 0.025 albumin) + 1.0

    with calcium in mmol/L and albumin in g/L. Ionized calcium values are affected by serum pH (a decreased of 0.1 pH unit increases ionization by 1.5%-2.5%). If serum is exposed to air and stands too long, the pH slowly increases. There is a small diurnal variation in ionized calcium, with the peak most often about 9 P.M. and the nadir about 9 A.M. There also is a small diurnal variation in urine calcium, with the peak most often about 11 P.M. and the nadir about 11 A.M.

    Ionized calcium is not affected by changes in serum albumin concentration, which is a significant advantage over total calcium assay. A decrease in the serum albumin level by 1 gm/100 ml produces an approximate decrease in the (total) serum calcium level of approximately 0.8 mg/100 ml from previous levels (this is an average value, and could be more or less in any individual patient). Since a decrease in the serum albumin level is frequent in patients with severe acute or chronic illness, an artifactual decrease of the serum calcium level is likewise frequent in hospitalized patients. The ionized calcium value is regarded by many investigators as more sensitive and reliable than the total calcium value in detection of PHPT. A certain number of their PHPT patients had elevated ionized calcium levels but normal total calcium levels. However, some investigators do not find that ionized calcium materially assists detection or diagnosis of PHPT. Also, certain conditions that produce hypercalcemia, such as myeloma, sarcoidosis, hypervitaminosis D, and metastatic carcinoma to bone, may in some cases be associated with increased ionized calcium levels. Most laboratories do not have the equipment necessary to perform ionized calcium assay, and although there are formulas that estimate ionized calcium from total calcium plus serum protein levels, there is disagreement in the literature concerning which formula is best. There is also disagreement whether such estimates are reliable enough to be used in the diagnosis of PHPT. The consensus in the literature seems to be that ionized calcium may be helpful in the diagnosis of PHPT in a minority of patients, such as those with borderline total calcium values or those with hypoalbuminemia, and is best determined using ion-selective electrode methodology.

    Serum phosphate. Decreased serum phosphate is one of the classic biochemical findings in PHPT. Phosphate usually is measured as the phosphorus ion. Only about 10%-15% is protein bound. There is a diurnal rhythm, with higher values in the afternoon and evening, which may be as much as double those in the morning. Serum phosphate (phosphorus) has not proved as useful as the earliest studies suggested, since phosphate levels in PHPT that are below the population reference range tend to be limited to patients with more severe disease. In fact, the serum phosphate level is decreased in only about 40%-50% of PHPT cases (literature range, 22%-80%). The reference range is fairly wide, which can mask small decreases; and some conditions such as a high-phosphate or a low-calcium diet increase serum phosphate levels. Renal dysfunction severe enough to produce an elevated blood urea nitrogen (BUN) level raises the serum phosphate level. Various conditions other than PHPT can decrease serum phosphate levels (discussed later in this chapter). Among those associated with hypercalcemia and hypophosphatemia, besides PHPT, are some patients with malignancy and occasional patients with sarcoidosis, myeloma, hyperthyroidism, and vitamin D intoxication.

    Serum alkaline phosphatase. Alkaline phosphatase in nonneoplastic calcium disorders is an index of bone involvement. X-ray bone abnormalities in PHPT are reported in 23%-36% of patients, with most of the relatively few reports being in the older literature. X-ray studies of the fingers demonstrate the most typical changes. It is estimated that alkaline phosphatase elevation occurs in about 95% of patients with PHPT who have bone x-ray changes but in only about 10%-15% of those who do not (therefore, there would be an ALP level increase in 20% to 30% of all PHPT cases; however, some find x-ray changes in present-day PHPT in only 15% of cases). Metastatic malignancy can produce elevated alkaline phosphatase levels due to either bone or liver involvement.

    Urine calcium excretion. Excretion of calcium in urine is increased in about 75% of patients with PHPT (literature range, 50%-91%). In addition to PHPT, a considerable number of other conditions may produce hypercalciuria (e.g., idiopathic hypercalciuria, said to be present in nearly 5% of the population; bone immobilization syndrome; Cushing’s syndrome; milk-alkali syndrome; hypervitaminosis D; renal tubular acidosis; and sarcoidosis).

    Assay is performed on 24-hour urine specimens. There is disagreement in the literature on whether to collect the specimens with the patient on a normal diet, a normal diet minus milk, cheese, and other milk products, or a standard 200-mg low calcium diet. Most investigators and urologists seem to prefer a normal diet, at least for screening purposes. Reference ranges differ according to type of diet. The Sulkowitch test is a semiquantitative chemical procedure for urine calcium measurement that was widely used before 1960 but is rarely performed today.

    Urine phosphate excretion. The older literature states that phosphate excretion is increased in most patients with PHPT. There are surprisingly little data on this subject in recent literature. However, hyperphosphaturia probably is not as frequent today, just as decreased serum phosphate levels are seen much less frequently. Increased urine phosphate excretion in PHPT is expected in 70%-75% of cases. Phosphate depletion (due to prolonged vomiting, nasogastric suction, or ingestion of aluminum-type antacids) and chronic renal disease can reduce or eliminate phosphate hyperexcretion. Conditions that can produce increased urine phosphate excretion besides PHPT include renal triple phosphate lithiasis, osteomalacia, and, in some patients, hyperthyroidism, sarcoidosis, Cushing’s syndrome, and malignancy. Reference values depend on diet.

  • Primary Hyperparathyroidism (PHPT)

    PHPT is caused by overproduction or inappropriate production of PTH by the parathyroid gland. The most common cause is a single adenoma. The incidence of parathyroid carcinoma is listed in reviews as 2%-3%, although the actual percentage is probably less. About 15% (possibly more) of cases are due to parathyroid hyperplasia, which involves more than one parathyroid gland. The most frequent clinical manifestation is renal stones (see the box). The reported incidence of clinical manifestations varies widely, most likely depending on whether the patient group analyzed was gathered because of the symptoms, whether the group was detected because of routine serum calcium screening, or whether the group was mixed in relation to the method of detection.

    Symptoms or Clinical Syndromes Associated with Primary Hyperparathyroidism, with Estimated Incidence*

    Urologic: nephrolithiasis, 30%-40% (21%-81%); renal failure
    Skeletal: 15%-30% (6%-55%); osteoporosis, fracture, osteitis fibrosa cystica
    Gastrointestinal: peptic ulcer, 15% (9%-16%); pancreatitis, 3% (2%-4%)
    Neurologic: weakness, 25% (7%-42%); mental changes 25% (20%-33%)
    Hypertension: 30%-40% (18%-53%)
    Multiple endocrine neoplasia syndrome: 2% (1%-7%)
    Asymptomatic hypercalcemia: 45% (2%-47%)
    *Numbers in parentheses refer to literature range.

    About 5% (literature range, 2%-10%) of patients with renal stones have PHPT.

    Laboratory tests. Among nonbiochemical tests, the hemoglobin level is decreased in less than 10% of cases (2%-21%) without renal failure or bleeding peptic ulcer. A large number of biochemical tests have been advocated for diagnosis of PHPT. The classic findings on biochemical testing are elevated serum calcium, PTH, and alkaline phosphatase levels and a decreased serum phosphate level.

    Serum calcium (total serum calcium). Most investigators consider an elevated serum calcium level the most common and reliable standard biochemical test abnormality in PHPT. Even when the serum calcium level falls within the population reference range, it can usually be shown to be inappropriately elevated compared with other biochemical indices. However, PHPT may exist with serum calcium values remaining within the reference range; reported incidence is about 10% of PHPT patients (literature range, 0%-50%). Normocalcemic PHPT has been defined by some as PHPT with at least one normal serum calcium determination and by others as PHPT in which no calcium value exceeds the upper reference limit. Some of the confusion and many of the problems originate from the various factors that can alter serum calcium values in normal persons, as listed here.

    1. Reference range limits used. Reference range values may be derived from the literature or from the reagent manufacturer or may be established by the laboratory on the local population. These values may differ significantly. For example, the values supplied by the manufacturer of our calcium method are 8.7-10.8 mg/100 ml (2.17-2.69 mmol/L), whereas our values derived from local blood donors (corrected for effects of posture) are 8.7-10.2 mg/100 ml (2.17-2.54 mmol/L).
    2. The patient’s normal serum calcium value before developing PHPT compared with population reference values. If the predisease value was in the lower part of the population reference range, the value could substantially increase and still be in the upper part of the range.
    3. Diet. A high-calcium diet can increase serum calcium levels up to 0.5 mg/100 ml. A high-phosphate diet lowers serum calcium levels, reportedly even to the extent of producing a normal calcium value in PHPT.
    4. Posture. Changing from an upright to a recumbent posture decreases the serum calcium concentration by an average of 4% (literature range, 2%-7%). A decrease of 4% at the 10.5 mg/100 ml level is a decrease of 0.4 mg/100 ml. Therefore, reference ranges derived from outpatients are higher than those established in blood donors or others who are recumbent. This means that high-normal results for outpatients would appear elevated by inpatient standards.
    5. Tourniquet stasis. Prolonged stasis is reported to produce a small increase in serum calcium and total protein values.
    6. Changes in serum albumin concentration (discussed under ionized calcium).
    7. Laboratory error or, in borderline cases, usual laboratory test degree of variation.

    Malignancy-associated hypercalcemia (MAH)

    Malignancy may produce hypercalcemia in three ways. The first is primary bone tumor; the only common primary bone tumor associated with hypercalcemia is myeloma, which begins in the bone marrow rather than in bone itself. Hypercalcemia is found in about 30% of myeloma patients (literature range, 20%-50%). The alkaline phosphatase level is usually normal (reported increase, 0%-48%) unless a pathologic fracture develops. About 5% of acute lymphocytic leukemia patients develop hypercalcemia. The second cause of hypercalcemia in malignancy is tumor production of a hormone resembling PTH called parathyroid hormone-related protein. This is known as the “ectopic PTH syndrome,” sometimes called “pseudohyperparathyroidism” (about 50% of solid-tumor MAH). The most frequent source of solid-tumor MAH is lung carcinoma (25% of MAH cases) followed by breast (20%), squamous nonpulmonary (19%) and renal cell carcinoma (8%).

    The third cause of MAH is metastatic carcinoma to bone (about 20% of solid tumor MAH). The breast is the most frequent primary site, followed by lung and kidney. Although prostate carcinoma is frequent in males, prostatic bone lesions are usually osteoblastic rather than osteolytic and serum calcium is usually not elevated.

    In addition, in some studies about 5% of patients with hypercalcemia and cancer also had PHPT.

    Selected nonneoplastic causes of hypercalcemia Among the conditions traditionally associated with hypercalcemia is sarcoidosis. There seems to be a much lower incidence of hypercalcemia in these patients today than in the past. Estimated frequency of hypercalcemia in sarcoidosis is about 5%-10% (literature range, 1%-62%). Serum phosphate levels are usually normal. Many of these patients have increased urine calcium excretion; the exact percentage is difficult to determine from the literature. Bone lesions are reported in 5%- 16% of cases. Tertiary hyperparathyroidism is another cause of hypercalcemia. In chronic renal failure, secondary hyperparathyroidism develops, consisting of decreased serum calcium, elevated PTH, elevated serum phosphate, and elevated alkaline phosphatase levels and development of rental osteodystrophy. If renal failure persists for a long time, secondary hyperparathyroidism may become tertiary hyperparathyroidism, which displays elevated serum calcium, elevated PTH, decreased serum phosphate, and elevated alkaline phosphatase levels and bone lesions (i.e., most of the biochemical changes usually associated with PHPT, but with diffuse hyperplasia of the parathyroid glands rather than a single adenoma). Hyperthyroidism produces hypercalcemia in about 15% of thyrotoxic patients and alkaline phosphatase (ALP) elevation in about 40%. Lithium therapy frequently increases serum total calcium levels. Although most calcium values remain within population reference range, about 12% of patients on long-term lithium therapy become hypercalcemic and about 16% are reported to develop elevated PTH assay results. Thus, discovery of hypercalcemia becomes a problem of differential diagnosis, with the major categories being artifact, neoplasia, PHPT, and “other conditions.” The incidence of asymptomatic hypercalcemia in unselected populations subjected to biochemical test screening ranges from 0.1%-6%. Many of the diagnostic procedures for PHPT have been developed to separate PHPT from other possible causes of hypercalcemia.

  • Tests in Calcium Disorders: Hypercalcemia

    Symptoms referable to hypercalcemia itself are very nonspecific; they include vomiting, constipation, polydipsia and polyuria, and mental confusion. Coma may develop in severe cases. There may be renal stones or soft tissue calcification. Hypercalcemia is most often detected on routine multitest biochemical screening panels, either in asymptomatic persons or incidental to symptoms from some disease associated with hypercalcemia (see the box on this page). In asymptomatic persons, primary hyperparathyroidism (PHPT) accounts for about 60% of cases. In hospital admissions, however, malignancy is the etiology for 40%-50% of cases and PHPT accounts for about 15%.

    Regulation of Serum Calcium Levels

    Regulation of serum calcium levels is somewhat complex. The major control mechanism is parathyroid hormone (PTH). Normally, parathyroid secretion of PTH is regulated by a feedback mechanism involving the blood calcium level. A decreased serum calcium level induces increased secretion of PTH, whereas an acute increase of the

    Selected Etiologies of Hypercalcemia

    Relatively common

    Neoplasia (noncutaneous)
    Bone primary
    Myeloma
    Acute leukemia
    Nonbone solid tumors
    Breast
    Lung
    Squamous nonpulmonary
    Kidney
    Neoplasm secretion of parathyroid hormone-related protein (PTHrP, “ectopic PTH”)
    Primary hyperparathyroidism (PHPT)
    Thiazide diuretics
    Tertiary (renal) hyperparathyroidism
    Idiopathic
    Spurious (artifactual) hypercalcemia
    Dehydration
    Serum protein elevation
    Lab technical problem

    Relatively uncommon

    Neoplasia (less common tumors)
    Sarcoidosis
    Hyperthyroidism
    Immobilization (mostly seen in children and adolescents)
    Diuretic phase of acute renal tubular necrosis
    Vitamin D intoxication
    Milk-alkali syndrome
    Addison’s disease
    Lithium therapy
    Idiopathic hypercalcemia of infancy
    Acromegaly
    Theophylline toxicity

    serum calcium level decreases secretion of PTH. PTH has a direct action on bone, increasing bone resorption and release of bone calcium and phosphorus. In addition, PTH increases the activity of the activating enzyme cyclic adenosine monophosphate (AMP) in the proximal tubules of the kidney, which increases conversion of calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxy-vitamin D). Calcitriol has metabolic effects that help to increase serum calcium levels, such as increased renal reabsorption of calcium, increased GI tract absorption of calcium, and the drawing out of some calcium from bone. On the other hand, an increased calcitriol level also initiates a compensatory series of events that prevents the calcium-elevating system from overreacting. An increased calcitriol level inhibits renal tubule phosphate reabsorption, which results in loss of phosphorus into the urine. This leads to a decreased serum phosphate level, which, in turn, inhibits production of calcitriol. The actions of PTH, phosphate, and calcitriol produce a roughly reciprocal relationship between serum calcium and phosphate levels, with elevation of one corresponding to a decrease of the other. Both PTH (through cyclic AMP) and phosphate act on the same enzyme (25-OH-D 1 a-hydroxylase), which converts calcidiol to calcitriol.

    Besides PTH, a hormone called “calcitonin” has important, although subsidiary, effects on calcium metabolism. Calcitonin is produced in the thyroid gland, and secretion is at least partially regulated by serum calcium levels. Acute elevation of serum calcium leads to increased calcitonin secretion. Calcitonin inhibits bone resorption, which decreases withdrawal of calcium and phosphorus and produces a hypocalcemic and hypophosphatemic effect that opposes calcium-elevating mechanisms.

  • Serum Electrolyte Panels

    Many physicians order serum “electrolyte panels” or “profiles” that include sodium potassium, chloride, and bicarbonate (“CO2”; when “CO2” is included in a multitest electrolyte panel using serum, bicarbonate comprises most of what is being measured). In my experience, chloride and “CO2” are not cost effective as routine assays on electrolyte panels. If there is some necessity for serum chloride assay, as for calculation of the anion gap, it can be ordered when the need arises. Assay of serum bicarbonate is likewise questionable as a routine test. In most patients with abnormal serum bicarbonate values, there is acidosis or alkalosis that is evident or suspected from other clinical or laboratory findings (e.g., as severe emphysema or renal failure). In patients with acid-base problems, blood gas measurement or PCO2 measurement is more sensitive and informative than serum bicarbonate assay.

  • Serum Chloride

    Chloride is the most abundant extracellular anion. In general, chloride is affected by the same conditions that affect sodium (the most abundant extracellular cation) and in roughly the same degree. Thus, in the great majority of cases, serum chloride values change in the same direction as serum sodium values (except in a few conditions such as the hyperchloremic alkalosis of prolonged vomiting). For example, if the serum sodium concentration is low, one can usually predict that the chloride concentration will also be low (or at the lower edge of the reference range). To confirm this I did a study comparing sodium and chloride values in 649 consecutive patients. There were 37 discrepancies (5.7%) in the expected relationship between the sodium and chloride values. On repeat testing of the discrepant specimens, 21 of the 37 discrepancies were resolved, leaving only 16 (2.5%). Of these, 6 (1%) could be classified as minor in degree and 10 (1.5%) as significant. Thus, in 649 patients only 1.5% had a significant divergence between serum sodium and chloride values.

  • Clinical Symptoms of Electrolyte Imbalance

    Before I conclude the discussion of sodium and potassium, it might be useful to describe some of the clinical symptoms of electrolyte imbalance. Interestingly enough, they are very similar for low-sodium, low-potassium, and high-potassium states. They include muscle weakness, nausea, anorexia, and mental changes, which usually tend toward drowsiness and lethargy. The electrocardiogram (ECG) in hypokalemia is very characteristic, and with serum values less than 3.0 mEq/L usually shows depression of the ST segment and flattening or actual inversion of the T wave. In hyperkalemia the opposite happens: the T wave becomes high and peaked; this usually begins with serum potassium values more than 7.0 mEq/L (reference values being 4.0-5.5 mEq/L). Hypokalemia may be associated with digitalis toxicity with digitalis doses that ordinarily are nontoxic because potassium antagonizes the action of digitalis. Conversely, very high concentrations of potassium are toxic to the heart, so IV infusions should never administer more than 20.0 mEq/hour even with good renal function.

    There is disagreement in the medical literature regarding preoperative detection and treatment of hypokalemia. On one hand, various reports and textbooks state that clinically significant hypokalemia (variously defined as less than 2.8, 3.0, or 3.2 mEq/L) produces a substantial number of dangerous arrhythmias. On the other hand, several investigators did not find any significant difference in intraoperative arrhythmias, morbidity, or mortality between those patients with untreated hypokalemia and those who were normokalemic.

  • Hyperkalemia

    High potassium values are not uncommon in hospitalized patients, especially in the elderly. One study reported serum potassium levels more than 5 mEq/L in 15% of patients over age 70. However, hyperkalemia is found in relatively few diseases.

    Decreased renal potassium excretion. Renal failure is the most common cause of hyperkalemia, both in this category and including all causes of hyperkalemia.

    Pseudohyperkalemia. Dehydration can produce apparently high-normal or mildly elevated electrolyte values. Artifactual hemolysis of blood specimens may occur, which results in release of potassium from damaged RBCs, and the laboratory may not always mention that visible hemolysis was present. In one series of patients with hyperkalemia, 20% were found to be due to a hemolyzed specimen, and an additional 9% were eventually thought to be due to some technical error. Rarely, mild hyperkalemia may appear with very marked elevation of platelets.

    Exogenous potassium intake. Examples include excessive oral potassium supplements or parenteral therapy that either is intended to supplement potassium (e.g., potassium chloride) or contains medications (e.g., some forms of penicillin) that are supplied as a potassium salt or in a potassium-rich vehicle. Some over-the-countersalt substitutes contain a considerable amount of potassium.

    Endogenous potassium sources. Potassium can be liberated from tissue cells in muscle crush injuries, burns, and therapy of various malignancies (including the tumor lysis syndrome), or released from RBCs in severe hemolytic anemias. In some cases where liberated potassium reaches hyperkalemic levels, there may be a superimposed element of decreased renal function.

    Endocrinologic syndromes. As noted previously, hyperkalemia may be produced by dehydration in diabetic ketoacidosis. Hyperkalemia is found in about 50% of patients with Addison’s disease. In one series, hyporeninemic hypoaldosteronism was found in 10% of patients with hyperkalemia. Decreased renal excretion of potassium is present in most endocrinologic syndromes associated with hyperkalemia, with the exception of diabetic acidosis.

    Drug-induced hyperkalemia. Some medications supply exogenous potassium, as noted previously. A few, including beta-adrenergic blockers such as propranolol and pindolol, digoxin overdose, certain anesthetic agents at risk for the malignant hyperthermia syndrome such as succinylcholine, therapy with or diagnostic infusion of the amino acid arginine, hyperosmotic glucose solution, or insulin, affect potassium shifts between intracellular and extracellular location. In the case of insulin, deficiency rather than excess would predispose toward hyperkalemia. Most other medications that are associated with increase in serum potassium produce decreased renal excretion of potassium. These include certain potassium-sparing diuretics such as spronolactone and triamterene; several nonsteroidal anti-inflammatory agents such as indomethacin and ibuprofen; angiotensin-converting enzyme inhibitors such as captopril; heparin therapy, including low-dose protocols; and cyclosporine immunosuppressant therapy.

  • Hypokalemia

    Hypokalemia has been reported in about 5% of hospitalized patients. Abnormalities in potassium have many similarities to those of sodium. Some conditions with potassium abnormalities are also associated with sodium abnormalities and were discussed earlier. Several different mechanisms may be involved.

    Inadequate intake. Ordinarily, 90% of ingested potassium is absorbed, so that most diets are more than adequate. Inadequate intake is most often due to anorexia nervosa or to severe illness with anorexia, especially when combined with administration of potassium-free therapeutic fluids. Alcoholism is often associated with inadequate intake, and various malabsorption syndromes may prevent adequate absorption.

    Gastrointestinal tract loss. Severe prolonged diarrhea, including diarrhea due to laxative abuse, can eliminate substantial amounts of potassium. One uncommon but famous cause is large villous adenomas of the colon.

    Clinical Conditions Commonly Associated With Serum Potassium Abnormalities

    Hypokalemia

    Inadequate intake (cachexia or severe illness of any type)
    Intravenous infusion of potassium-free fluids
    Renal loss (diuretics; primary aldosteronism)
    GI loss (protracted vomiting; severe prolonged diarrhea; GI drainage)
    Severe trauma
    Treatment of diabetic acidosis without potassium supplements
    Treatment with large doses of adrenocorticotropic hormone; Cushing’s syndrome
    Cirrhosis; some cases of secondary aldosteronism

    Hyperkalemia

    Renal failure
    Dehydration
    Excessive parenteral administration of potassium
    Artifactual hemolysis of blood specimen
    Tumor lysis syndrome
    Hyporeninemic hypoaldosteronism
    Spironolactone therapy
    Addison’s disease and salt-losing congenital adrenal hyperplasia
    Thrombocythemia

    Protracted vomiting is another uncommon cause. Patients with ileal loop ureteral implant operations after total cystectomy frequently develop hypokalemia if not closely watched.

    Renal loss. Twenty percent to 30% (range, 10%-40%) of hypertensive patients receiving diuretic therapy, particularly with the chlorothiazides, are reported to be hypokalemic. Combined with other conditions requiring diuretics, this makes diuretic therapy the most frequent overall cause of hypokalemia. Renal tubular acidosis syndromes might also be mentioned. Finally, there is a component of renal loss associated with several primarily nonrenal hypokalemic disorders. These include the various endocrinopathies (discussed next), diabetic ketoacidosis, and administration of potassium-poor fluids. The kidney is apparently best able to conserve sodium and to excrete potassium (since one way to conserve sodium is to excrete potassium ions in exchange), so that when normal intake of potassium stops, it takes time for the kidney to adjust and to stop losing normal amounts of potassium ions. In the meantime, a deficit may be created. In addition, renal conservation mechanisms cannot completely eliminate potassium excretion, so that 5-10 mEq/day is lost regardless of total body deficit.

    Endocrinopathies. These conditions are discussed in detail elsewhere. Patients with primary aldosteronism (Conn’s syndrome) are hypokalemic in about 80% of cases. Patients with secondary aldosteronism (cirrhosis, malignant hypertension, renal artery stenosis, increased estrogen states, hyponatremia) are predisposed toward hypokalemia. Cirrhosis may coexist with other predisposing causes, such as poor diet or attempts at diuretic therapy. About 20%-25% of patients with Cushing’s syndrome have a mild hypokalemic alkalosis. Congenital adrenal hyperplasia (of the most common 11-b-hydroxylase type) is associated with hypokalemia. Hypokalemia may occur in Bartter’s syndrome or the very similar condition resulting from licorice abuse. Most of the conditions listed in this section, except for cirrhosis, are also associated with hypertension.

    Severe trauma. In a review of three studies of trauma patients, hypokalemia was much more common (50%-68% of patients) than hyperkalemia. Hypokalemia usually began within 1 hour after the trauma and usually ended within 24 hours.

    Diabetic ketoacidosis. Extracellular fluid (ECF) may lose potassium both from osmotic diuresis due to hyperglycemia and from shift of extracellular to intracellular potassium due to insulin therapy. Nevertheless, these changes are masked by dehydration, so that 90% of patients have normal or elevated serum potassium values when first seen in spite of substantial total body potassium deficits. These deficits produce overt hypokalemia if fluid therapy of diabetic acidosis does not contain sufficient potassium.

    Hypokalemic alkalosis. Hypokalemia has a close relationship to alkalosis. Increased plasma pH (alkalosis) results from decreased ECF hydrogen ion concentrations; the ECF deficit draws hydrogen from body cells, leading to decreased intracellular concentration and therefore less H+ available in renal tubule cells for exchange with urinary sodium. This means increased potassium excretion in exchange for urinary sodium and eventual hypokalemia. Besides being produced by alkalosis, hypokalemia can itself lead to alkalosis, or at least a tendency toward alkalosis. Hypokalemia results from depletion of intracellular potassium (the largest body store of potassium). Hydrogen ions diffuse into body cells to partially replace the intracellular cation deficit caused by potassium deficiency; this tends to deplete ECF hydrogen levels. In addition, more hydrogen is excreted into the urine in exchange for sodium since the potassium that normally would participate in this exchange is no longer available. Both mechanisms tend eventually to deplete extracellular fluid hydrogen. As noted in Chapter 24, in alkalosis due to hypokalemia an acid urine is produced, contrary to the usual situation in alkalosis. This incongruity is due to the intracellular acidosis that results from hypokalemia.

    Medication-induced hypokalemia. Certain non-diuretic medications may sometimes produce hypokalemia. Ticarcillin, carbenicillin, and amphotericin B may increase renal potassium loss. Theophylline, especially in toxic concentration, may decrease serum potassium to hypokalemic levels.

    In one group of hospitalized patients with serum potassium levels less than 2.0 mEq/L, apparent etiology was potassium-insufficient IV fluids in 17%, diuretic therapy in 16%, GI loss in 14%, acute leukemia receiving chemotherapy in 13%, dietary potassium deficiency in 6%, renal disease with urinary potassium loss in 6%, diabetic acidosis in 5%, and all other single causes less than 5% each.

    Urine potassium assay in hypokalemia

    Measurement of urine potassium may sometimes be useful in differentiating etiologies of hypokalemia. Those conditions associated with decreased urine potassium include the following:

    1. Loss from the GI tract (diarrhea, villous adenoma, ileal conduit). Vomiting, however, is associated with alkalosis, which may increase renal potassium excretion.
    2. Shift of extracellular potassium to intracellular location (insulin therapy). However, hyperglycemic osmotic diuresis may confuse the picture.
    3. Inadequate potassium intake, in the absence of conditions that increase urine potassium excretion.
    4. Potassium deficiency associated with renal excretion of potassium (e.g., diuretic induced) after the stimulus for potassium loss is removed and renal loss ceases.

    Besides the first three categories, the other etiologies for hypokalemia usually demonstrate normal or increased urine potassium levels while active potassium loss is occurring.

  • Serum Potassium Abnormalities

    The potassium level in serum is about 0.4-0.5 mEq/L higher than the potassium level in whole blood or plasma (literature range, 0.1-1.2 mEq/L). This is attributed at least in part to potassium released from platelets during clotting. Serum specimens may have artifactual potassium level increase additional to that of normal clotting in patients with very high white blood cell (WBC) counts or platelet counts. The sodium concentration is about the same in serum, plasma, and whole blood. Potassium values increase 10%-20% if the patient follows the common practice of opening and closing his or her hand after a tourniquet is applied to the arm before venipuncture. Potassium can be increased in patient specimens by RBC hemolysis, sometimes considerably increased, which, unfortunately, is most often a laboratory artifact produced during venipuncture or when processing the specimen after venipuncture. Therefore, a pink or red color of plasma or serum usually means very inaccurate potassium values.

  • Hypernatremia

    Hypernatremia is much less common than hyponatremia. It is usually produced by a severe water deficit that is considerably greater than the sodium deficit and is most often accompanied by dehydration (see the box on this page). The water deficit can be due to severe water deprivation, severe hypotonic fluid loss (renal or nonrenal) without replacement, or a combination of the two. The serum sodium concentration and serum osmolality are increased. Urine volume is low and urine specific gravity or osmolality are high in water deprivation or in dehydration due to nonrenal water loss. Urine volume is high and urine specific gravity or osmolality is low in dehydration due to water loss through the kidneys. Other laboratory test values may suggest dehydration, and clinical signs of dehydration may be present. Although the serum sodium level is increased, the total body sodium level may be normal or even decreased, the sodium deficit being overshadowed by the water deficit. Occasionally, hypernatremia is caused by excess intake of sodium, which is usually not intentional.