CAT 3

 

CAT1

Chapters 240 and 241 in your Principles and Practice of Hospital Medicine text detail several electrolyte abnormalities. After completing your assigned readings, answer the following questions;

1.      How is serum calcium regulated?

1.      What body system dysfunctions would cause calcium abnormalities?

2.      The GI tract, kidneys, and skeletal system are integral in regulating calcium.

2.      What are potential causes of hypercalcemia? How can you differentiate the cause of hypercalcemia in your patient?

3.      How is hypercalcemia diagnosed and managed?

4.      What are potential causes of hypocalcemia?

5.      What are potential causes of potassium and magnesium disorders?

1.      What is pseudohypokalemia? What is the treatment for this?

6.      What are the potential consequences of potassium and magnesium disorders?

7.      How are potassium and magnesium disorders treated?

1.      What is the function of Calcium Gluconate in lowering potassium?

8.      How are potassium disorders treated in clinical situations with rapid potassium shifts, such as diabetic ketoacidosis, hyperglycemic hyperosmolar state, and periodic paralysis?

 

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hanges are present. It has become less common with the increased use of plasma for
potassium measurement, rather than serum. Plasma is the supernatant collected from
heparinized whole blood, whereas serum is the supernatant remaining after centrifugation
of a clotted whole blood sample. Serum K+ is normally 0.3 mmol/L above the plasma K+,
but may be higher if K+ is released from the clot formed in the tube. If pseudohyperkalemia
is suspected, the plasma potassium should be measured instead of the serum potassium.
Pseudohyperkalemia can also occur due to potassium release from muscle cells following
prolonged constriction with a tourniquet or limb exercise while a tourniquet is in place.

Redistribution of potassium

Redistribution of potassium from the intracellular to the extracellular space can occur in
severe acidosis due to nonorganic acid metabolic acidosis, hyperosmolar states, tissue
breakdown, and hyperkalemic periodic paralysis. Organic acids such as lactic acid and
ketoacids are less likely to cause hyperkalemia than non-organic acids. These organic
acids have greater transmembrane mobility, allowing movement into cells with H+, rather
than movement of K+ out of cells in exchange for H+. Hyperkalemia in diabetic
ketoacidosis usually results from insulin deficiency and hyperosmolality, rather than
acidosis. Hyperglycemia increases extracellular osmolality, drawing water from cells down
the osmotic gradient. Potassium follows the water movement (solvent drag), and
hyperkalemia results.

Tissue breakdown may liberate large amounts of intracellular potassium, resulting in
rapid, life-threatening increases in extracellular potassium. Rhabdomyolysis, tissue
necrosis, tumor lysis with chemotherapy, and large hematomas are common causes. In
rhabdomyolysis, hypokalemia may precede hyperkalemia, and contribute to muscle
breakdown by causing vasoconstriction and decreased blood flow to the involved muscle.

Hyperkalemic periodic paralysis is an autosomal dominant disorder involving the
muscle cell sodium channel. During these episodes, potassium moves from the
intracellular to extracellular space, accompanied by movement of sodium and water into
the cell. The hyperkalemia is accompanied by transient weakness or paralysis.

Decreased potassium excretion

Potassium excretion in the distal nephron depends upon adequate urine flow, aldosterone,
and activity of the basolateral Na+/K+-ATPase. The reabsorption of luminal Na+ through
aldosterone-sensitive epithelial sodium channels (ENaCs) creates an electrochemical
gradient for K+ excretion in the urine. Hyperkalemia can occur in aldosterone-resistant or
deficient states by attenuating the electrochemical gradient for K+ secretion. Acquired
mineralocorticoid resistance from diabetes mellitus, obstructive uropathy, chronic
tubulointerstitial disease, sickle cell anemia, lupus nephritis, and medications, as well as
decreased mineralocorticoid production (including medication induced), are commonly
associated with type IV renal tubular acidosis (RTA). Type IV RTA is characterized by
hyperkalemia, normal anion gap hyperchloremic acidosis, with serum HCO3 values
ranging between 16 and 22 mmol/L, and decreased urinary NH4

+ production, causing a
positive urine anion gap [Urine (Na+) + (K+) – (Cl−)]. In acute and chronic tubular injury, a

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decreased responsiveness to aldosterone can contribute to hyperkalemia. For acute kidney
injury associated with prerenal azotemia or hypovolemic states, decreased urinary flow to
the distal tubule and a reduction in sodium-potassium exchange can contribute to
hyperkalemia.

Excessive potassium intake

Excessive intake of K+ rarely causes hyperkalemia in the setting of normal renal function.
Renal secretion of potassium is typically adequate at glomerular filtration rates (GFR)
above 20 to 30 mL/min/1.73 m2. Patients with end-stage renal disease (ESRD) on
hemodialysis usually tolerate a daily K+ intake of 2000 mg (51 mEq). Upregulated gut
potassium excretion and shifts in transcellular K+ prevent hyperkalemia between dialysis
sessions. The loss of these mechanisms may result in the rapid development of
hyperkalemia, especially with large exogenous loads of potassium, such as massive blood
transfusions. Irradiation of blood and increased age of the blood increase the amount of
free potassium that is released during the blood transfusion. Seven-day-old blood has
approximately 23 mmol/L of K+, while 42-day-old blood has approximately 50 mmol/L of
K+.

PRACTICE POINT

In the setting of acute kidney injury, hyperkalemia associated with rapid transcellular
potassium shifts from the intracellular to extracellular compartment can be seen with
rhabdomyolysis, tissue necrosis, tumor lysis, and large hematomas.
Hyperkalemia in this setting may progress rapidly to cause life-threatening
arrhythmias. Emergent nephrology consultation for possible dialysis is required.

SIGNS AND SYMPTOMS

Clinical effects of hyperkalemia relate to altered membrane excitability due to changes in
the transcellular potassium gradient. Severe hyperkalemia leads to cardiac arrhythmias
and conduction abnormalities. It may also cause weakness of the lower extremities,
progressing superiorly to cause flaccid paralysis and respiratory failure. This presentation
may mimic Guillain-Barré syndrome, but is easily differentiated by the response to
potassium correction. Hyperkalemia may also contribute to metabolic acidosis by
interfering with renal ammonium excretion.

EVALUATION OF HYPERKALEMIA IN THE HOSPITALIZED PATIENT

In the hospital setting, the initial evaluation of hyperkalemia includes monitoring for life-
threatening arrhythmias, checking for pseudohyperkalemia, eliminating exogenous
sources of potassium, evaluating renal function, and evaluating for rapid transcellular
shifts of potassium (Figure 241-1).

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Figure 241-1 Diagnostic assessment of hyperkalemia. (ACE, angiotensin-converting
enzyme inhibitor; ARB, angiotensin receptor blocker; DKA, diabetic ketoacidosis; ECG,
electrocardiogram; GFR, glomerular filtration rate; HHS, hyperosmolar hyperglycemic state;
NSAIDs, nonsteroidal anti-inflammatory drugs.)

ECG changes

Even mildly elevated K+ levels may be associated with ECG changes, especially in the
setting of rapid rises in plasma K+ values. If ECG changes from hyperkalemia are found or
if the plasma K+ value is ≥ 7.0, continuous telemetry is indicated and should continue until
the plasma K+ value is ≤ 5.8 and there are no hyperkalemic ECG changes. Frequent
chemistry checks are indicated for plasma K+ greater than 5.8 or for hyperkalemia
associated with ECG changes, severe hyperglycemia, or any clinical condition which
predisposes the patient to rapid changes in plasma K+.

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Plasma potassium levels do not correlate with specific ECG changes. A symmetric
increase in T wave height may be seen initially. Hyperkalemia-induced peaked T waves
may be difficult to distinguish from the hyperacute T waves of myocardial injury. As
potassium levels rise further, flattening of the P waves, prolongation of the PR interval, and
prolonged QRS duration occur. Eventually, atrial standstill and a sine wave ECG pattern
may be seen (Figure 241-2).

Figure 241-2 ECG changes associated with hyperkalemia and hypokalemia. (Reproduced,
with permission, from Flomenbaum N, Goldfrank LR, Hoffman R, et al. eds. Goldfrank’s
Toxicologic Emergencies, 8th ed. New York, NY: McGraw-Hill; 2006. Fig. 5-11.)

Urine potassium, transtubular potassium gradient, and urine potassium/creatinine

A 24-hour urine K+ measurement can help differentiate between renal and nonrenal causes
of hyperkalemia. With hyperkalemia, urinary excretion of K+ should exceed 40 mmol/d.

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Alternatively, the transtubular potassium gradient (TTKG), a measurement of potassium
secretion by the distal nephron corrected for urine osmolality, has been used:

TTKG = (KU/KS) × (SOsm/UOsm)

KU and KS are the concentrations of K
+ in the urine and serum, and SOsm and UOsm are

the osmolalities of the serum and urine, respectively. Plasma potassium and osmolality
can be used instead of serum values to estimate TTKG with minimal effect on clinical
interpretation. The accuracy of the TTKG has been called into question by recent studies
of urea and potassium handling in the renal tubule. Previous studies using TTKG have
suggested that patients with normal renal function and normal potassium intake have a
TTKG of 8 to 9. In hyperkalemia, a low TTKG (< 5-7) suggests an inappropriately low secretion of potassium. A high TTKG with hyperkalemia suggests normal aldosterone action and an extrarenal cause of hyperkalemia, except in cases of volume depletion where aldosterone secretion is enhanced with a TTKG > 7, but total renal potassium
excretion is limited by low urine flow.

When the TTKG is inappropriately low in the setting of hyperkalemia, an increase in the
TTKG to >10 hours after the administration of 0.05 mg of fludrocortisone suggests
hypoaldosteronism. If fludrocortisone has no effect on the TTKG, drug-induced or intrinsic
renal resistance to aldosterone are likely.

If further studies cast doubt on the usefulness of TTKG, the urine potassium/creatinine
ratio will likely be used more frequently when a 24-hour urine potassium is not available. It
has been suggested that a patient with hyperkalemia and a normal renal response should
have a spot urine ratio of >200 mmol K+/g creatinine (=22.6 mmol K+/mmol creatinine).
For a typical patient with a daily creatinine excretion of over 1 g/d, this is significantly
more than the 24-hour urinary K+ excretion of >40 mmol used by some clinicians as a
cutoff for adequate renal potassium clearance in the setting of hyperkalemia. This further
underscores the point that it is difficult to define an exact cutoff for expected renal
potassium excretion or urine K+/Cr in the face of hyperkalemia without additional
investigation.

TREATMENT OF HYPERKALEMIA

Treatments exist for hyperkalemia which cause net excretion or removal of potassium,
such as gastrointestinal resins and laxatives or hemodialysis. As these therapies may not
act immediately or may involve logistical difficulties, they are often used in conjunction
with short-acting temporizing measures, such as cardiac membrane stabilization with
calcium, and agents such as insulin that cause transcellular potassium shifts (Table 241-
2).

TABLE 241-2 Treatment of Hyperkalemia

Mechanism Treatment Dose Onset Duration Comments
Cardiac
membrane
stabilization

Calcium Calcium
gluconate 10
mL of 10%
solution
infused over
2-3 min.

1-3 min 30-60
min

Do not mix with
bicarbonate; extreme
caution if on digoxin;
calcium chloride is an
alternative, but poses
a risk of tissue

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necrosis, and requires
a central line

Redistribution Insulin 10 units
regular
insulin IV. If
BG < 250 mg/dL, give 50 mL of 50% dextrose.

10-20 min 4-6 h
peak 30-
60 min

Most reliable
treatment to induce
redistribution

Redistribution Beta-2
agonist

Albuterol 10-
20 mg
nebulized.

30 min 2-4 h
peak 90
min

Dose is significantly
higher than dose for
respiratory treatments;
use with caution in
patients at risk for side
effects such as
tachycardia and
myocardial ischemia

Removal Kayexalate 30-60 g oral
in 20%
sorbitol or 60
grams in 250
mL water by
retention
enema.

1-2 h Variable Risk of colonic
necrosis if used in
postoperative patients;
do not use sorbitol
formulation when
administering via
enema

Removal Hemodialysis — Immediate Same
as
dialysis
duration

Intermittent or
continuous

Cardiac membrane stabilization

Intravenous calcium stabilizes the cardiac membrane by inhibiting membrane
depolarization. It is the most important initial treatment for severe hyperkalemia. Two
forms of calcium are commonly available: calcium gluconate and calcium chloride.
Calcium gluconate is preferred because it can be administered through a peripheral
intravenous line, whereas calcium chloride requires a central venous line to prevent tissue
necrosis. Tissue necrosis can occur if calcium chloride leaks from the venous access into
the surrounding tissue. A 10 mL ampule of calcium gluconate contains 90 mg (2.3 mmol)
of elemental calcium, and a 10 mL ampule of calcium chloride contains 272 mg (7.0
mmol) of elemental calcium.

The initial dose of calcium gluconate is 10 mL of 10% solution infused over 2 to 3
minutes. An equivalent amount of elemental calcium is contained in 3.3 mL of 10%
calcium chloride. The onset of action is 1 to 3 minutes, and duration of action is 30 to 60
minutes. Calcium cannot be mixed with bicarbonate solutions, because precipitation of
CaCO3 occurs.

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3
Administration of intravenous calcium to patients taking digoxin requires extreme

caution, as calcium has been shown to potentiate the effects of digoxin toxicity in animal
models, especially at very rapid infusion rates. The risk of calcium administration in this
setting can be reduced by infusing the calcium gluconate over 20 to 30 minutes. Another
option is to administer digoxin immune fab to neutralize the effect of the digoxin.

PRACTICE POINT

In the setting of digoxin toxicity, mild hyperkalemia (serum K+ > 5.0 mmol/L) has been
linked to significant mortality, and digoxin immune fab may be indicated.

Potassium redistribution

Insulin is the most reliable means of inducing transcellular potassium shifts. The usual
dose is 10 units of regular insulin intravenously, followed immediately by 50 mL of 50%
dextrose (25 g of dextrose). For a blood glucose > 250, insulin can be administered alone
with close glucose monitoring. The effect begins in 10 to 20 minutes, peaks at 30 to 60
minutes, and lasts 4 to 6 hours. Potassium levels typically drop by 0.5 to 1.2 mmol/L. An
infusion of 10 units of regular insulin can also be administered over 1 hour in 10%
dextrose.

Beta-2 agonists have an additive effect with insulin in transiently reducing plasma
potassium by redistribution. High doses of nebulized albuterol are used, typically 10 to 20
mg of nebulized albuterol in 4 mL of normal saline over 10 minutes. Plasma potassium
levels usually fall by 0.5 to 1 mmol/L. The effect begins in 30 minutes, peaks at 90
minutes, and lasts 2 to 4 hours. Intravenous albuterol has also been used, but it is not
available in the United States. As some patients, including those with renal failure, have a
reduced response to albuterol, it should not be the only agent used. Caution should be
exercised for individuals at risk for side effects such as cardiac ischemia from the
resulting increase in heart rate.

Sodium bicarbonate (NaHCO3) does not reliably lead to the redistribution of potassium,
and it should not be considered as first-line therapy for hyperkalemia. This is especially
true in high anion gap acidosis, where hyperkalemia is usually not a direct consequence of
the presence of organic acids. If intravenous or oral NaHCO3 is used to treat metabolic
acidosis caused by nonorganic anions, which is usually associated with a normal anion
gap, plasma potassium may fall, but it is not preferred treatment even in this setting. Oral
NaHCO3 is useful for chronic treatment of type IV renal tubular acidosis.

Potassium removal

Sodium polystyrene sulfonate (Kayexalate) exchanges Na+ for K+ in the gastrointestinal
tract. When taken orally, sorbitol has been typically added to the resin to speed passage
through the gastrointestinal tract. However, an FDA warning has been issued about the
risk of colonic necrosis when kayexalate is used with sorbitol, and thus the powdered form
of kayexalate not premixed with sorbitol is preferred. If Kayexalate with sorbitol is the only
form available, diluting with water is appropriate. Each gram of resin binds 0.5 to 1.2
mmol of K+. Oral doses of 15 to 60 g are typical. Sodium polystyrene sulfonate can also
be administered rectally as a retention enema, at a dose of 30 to 60 g in 250 mL of water

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every 6 hours. The solution should be introduced by gravity, flushed with an additional 50
to 100 mL of nonsodium containing fluid, retained 30 to 60 minutes or longer, and
cleansed with 250 to 1000 mL of nonsodium containing solution at body temperature.
Sorbitol should not be used rectally due to risk of colonic necrosis. Oral or rectal
Kayexalate should not be used in postoperative patients for the same reason.

Favorable data have been published for two novel potassium reduction agents.
Sodium zirconium cyclosilicate (ZS-9) is a highly selective potassium trap, whereas
patiromer is a nonabsorbed polymer which exchanges calcium for potassium, primarily in
the distal colon. Patiromer is FDA approved, ZS-9 is under FDA review, and further studies
are needed to evaluate their suitability for acute potassium reduction. Initial studies have
focused on their use for more chronic potassium reduction, which may allow broader use
of potassium-sparing medications.

Dialysis is required for treatment of refractory hyperkalemia. Intermittent hemodialysis
removes potassium most rapidly. Continuous renal replacement therapy is an option for
patients who have ongoing causes of severe hyperkalemia, such as tissue necrosis or
rhabdomyolysis. Peritoneal dialysis provides gradual removal of potassium. Although
peritoneal dialysis is rarely used in developed countries when the other modalities are
available, peritoneal dialysis is an established therapy for acute kidney injury. Since
electricity is not required for its use and access is placed in the peritoneal cavity rather
than in large veins, it is an option for hyperkalemia treatment in a variety of situations
such as difficulty with placing vascular access for hemodialysis, disasters associated with
overwhelming caseloads, or power failure

Diuretics are unreliable for the acute treatment of hyperkalemia in the setting of
compromised renal function. In patients with adequate renal function, the combination of
a loop and thiazide diuretic is more effective for potassium removal than either alone. Of
the loop diuretics, torsemide and bumetanide have higher bioavailability than furosemide.

Potassium intake reduction

The typical daily potassium intake for a patient with end-stage renal disease is 2000 mg
(51 mmol) of potassium per day, but patients with acute kidney injury may require even
more stringent potassium restriction.

HYPOKALEMIA
ETIOLOGY

Hypokalemia (K+ < 3.5 mmol/L) can result from redistribution, increased potassium excretion from renal and nonrenal sources, or decreased potassium intake. Medications, especially loop and thiazide diuretics, frequently cause hypokalemia. Hypokalemia is common with tubular toxins such as amphotericin B and cisplatin. High doses of penicillin or semisynthetic penicillins such as ticarcillin and carbenicillin occasionally cause renal potassium wasting in the distal nephron due to a transient anion effect. Inhalation of toluene (glue sniffing) may cause distal renal tubular acidosis with associated hypokalemia.

Pseudohypokalemia

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Falsely low serum or plasma potassium values may occur in conditions such as acute
leukemia due to time-dependent uptake of potassium by the increased abnormal white cell
mass. Rapid analysis of the sample, or storing the sample at 4°C prior to analysis, can
prevent the potassium uptake and confirm the diagnosis of pseudohypokalemia.

Redistribution

Insulin directly stimulates potassium entry into cells by increasing the activity of the
Na+/K+-ATPase pump. This mechanism is independent of stimulation of cellular glucose
entry. Beta-2-adrenergic activators stimulate Na+/K+-ATPase mediated cellular potassium
uptake by a slightly different cellular mechanism. Thus, insulin and beta-2-adrenergic
activation may act synergistically to cause hypokalemia. Aldosterone stimulates direct
cellular uptake and redistribution due to increased Na+/K+-ATPase activity. It also acts in
the distal renal tubule to enhance potassium excretion.

Thyrotoxic periodic paralysis causes severe hypokalemia by redistribution, in
conjunction with extremity and limb girdle weakness, hypophosphatemia, and
hypomagnesemia. It is more common in patients of Asian and Hispanic origin. Attacks
often occur during rest after vigorous physical activity, and can also be precipitated by
carbohydrate-rich meals. Other rare genetic forms of hypokalemic periodic paralysis also
exist.

Nonrenal potassium losses

Common nonrenal causes of hypokalemia include intestinal loss of potassium from
diarrhea, celiac disease, ileostomy, and chronic laxative abuse. Potassium loss from
vomiting and nasogastric suctioning can result in hypokalemia, although renal potassium
losses from aldosterone activation may be more important in this setting. Potassium
losses through the skin are usually low, except in the setting of extreme physical exertion.
Severe burns may lead to hypokalemia by multiple mechanisms.

Renal potassium loss

Aldosterone-producing adenomas (Conn syndrome) cause hypertension and hypokalemia
by stimulation of aldosterone receptors in the distal renal tubule. Cortisol also activates
the aldosterone receptor. Normally, cortisol is converted to cortisone by 11-beta-
hydroxysteroid dehydrogenase-2 (11βHSD-2) before it can reach the aldosterone receptor.
Very high cortisol levels, as seen in Cushing syndrome, overwhelm the ability of 11βHSD-2
to degrade cortisol to cortisone, and the nondegraded cortisol activates the aldosterone
receptor in the distal tubule and precipitates hypokalemia. Similarly, glycyrrhizinic acid, a
component of black licorice that is sometimes added to chewing tobacco, inhibits
11βHSD-2, preventing cortisol degradation and causing hypertension and hypokalemia.
With vomiting and nasogastric suctioning, potassium wasting in the urine occurs through
aldosterone secretion in the setting of volume depletion, as noted above.

Hypokalemia can be associated with an RTA, due to disease of either the proximal
(type II RTA) or distal (type I RTA) renal tubules. Either can result from autoimmune,
genetic, endocrine, medication-induced, toxin-induced, or idiopathic causes. Rare causes
of hypokalemia associated with metabolic alkalosis involve defects in the thick ascending
limb of Henle transport proteins (Bartter syndrome), mutations in the thiazide-sensitive

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Na+/Cl− cotransporter in the distal convoluted tubule (Gitelman syndrome), or increased
activation of the epithelial sodium channel (ENaC) in the distal tubule (Liddle syndrome).

Decreased potassium intake

Decreased potassium intake is rarely a cause of hypokalemia, except in severe
malnutrition. For patients with normal renal function who consume the recommended
4700 mg (120 mmol) of potassium per day, 90% (108 mmol) is excreted in the urine. When
intake is sharply reduced, urinary potassium loss decreases to < 15 to 20 mmol/d in order to conserve potassium.

SIGNS AND SYMPTOMS

Individuals with serum potassium levels between 3.0 and 3.5 mEq/L are often
asymptomatic. However, there is a risk of cardiac arrhythmias for individuals with
predisposing conditions such as coronary artery disease. At serum potassium levels
between 2.5 and 3.0 mEq/L, patients report generalized weakness and constipation. When
serum potassium levels drop below 2.5 mEq/L, there is an increased risk of muscle
necrosis and rhabdomyolysis. At serum potassium levels less than 2.0 mEq/L, ascending
paralysis and respiratory failure can occur.

EVALUATION OF HYPOKALEMIA

An algorithm for the diagnosis of hypokalemia is presented in Figure 241-3.
Pseudohypokalemia and transcellular shifts should be excluded. Magnesium levels
should be measured early in the workup of hypokalemia. Many disorders, such as diarrhea
and excess diuresis, deplete both potassium and magnesium. Moreover,
hypomagnesemia may lead to renal potassium wasting via potassium channels in the
distal tubule, and make hypokalemia more refractory to treatment.

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Figure 241-3 Diagnostic assessment of hypokalemia. (DKA, diabetic ketoacidosis; RTA,
renal tubular acidosis.)

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The next step is determining whether hypokalemia arose from a renal or nonrenal
source. An obvious cause may be apparent, such as profuse diarrhea or escalating doses
of a loop or thiazide diuretic. When the cause of hypokalemia is unclear, a 24-hour urine
potassium measurement may differentiate between renal and nonrenal losses. In the
setting of hypokalemia, urinary K+ losses should fall to less than 15 to 20 mmol/d.
Potassium excretion above this level suggests a renal contribution to hypokalemia.

When a 24-hour urine K+ is not available, a spot urine ratio of 22 mmol K+/g creatinine
(=2.5 mmol K+/mmol creatinine) marks the cutoff between hypokalemia secondary to
intracellular shifts (if < 22 mmol K+/g Cr) and renal loss (if >22 mmol K+/g creatinine).

The TTKG (see above) has been used to help establish the cause of hypokalemia, but
the use of TTKG has been cast into doubt by recent studies of urea and K+ handling in the
renal tubule. An inappropriately high TTKG (> 4) in hypokalemia has been interpreted as
suggesting an increased distal potassium secretion and renal potassium loss. A low TTKG
can occur with nonrenal potassium wasting, with urinary potassium losses from osmotic
diuresis, with hypokalemia secondary to diuretics which were discontinued at the time of
TTKG measurement, or with hypokalemia associated with K+ shifts.

Patients with renal potassium wasting should be further classified by acid-base status.
Patients with acidosis may have RTA, diabetic ketoacidosis, or tubular dysfunction from
drugs such as amphotericin B or acetazolamide. Patients with alkalosis and hypertension
may have mineralocorticoid excess or Liddle syndrome. Hypokalemia with alkalosis and
normal or low blood pressure may be caused by vomiting, diuretics, and Bartter or
Gitelman syndrome. The spot urine chloride is a useful diagnostic tool in evaluating the
etiology of hypokalemia in the setting of metabolic alkalosis, with a spot low urine
chloride (< 10 mmol/L) suggesting volume depletion and a chloride-responsive state.

ECG changes

ECG changes in hypokalemia are shown in Figure 241-2. U waves appear following the T
waves, and become progressively more prominent in comparison to the T waves as
potassium levels decrease. Ultimately, the U wave merges with the T wave, and the QT
interval appears prolonged.

TREATMENT OF HYPOKALEMIA

Potassium repletion is the cornerstone of therapy for hypokalemia. As extracellular
potassium comprises a fraction of the total body potassium store, relatively large
amounts of potassium are required to correct the total body potassium deficit. A plasma
K+ 1 mmol/L below normal corresponds to a total body potassium deficit of
approximately 200 to 400 mmol, and a drop in plasma K+ to 2 mmol/L below normal
requires 400 to 800 mmol for repletion. Typically, daily repletion is significantly less than
the total body deficit as the time required for redistribution is prolonged. Underlying
disorders such as metabolic alkalosis that are causing or perpetuating hypokalemia must
also be addressed. Continuous telemetry and frequent electrolyte checks should be
performed in severe hypokalemia, or in conditions in which the serum potassium may
decline rapidly, such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic
state (HHS).

Oral repletion

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If there is no immediate threat to life, oral potassium can be used to treat hypokalemia.
Generally, potassium chloride (KCl) is indicated for hypokalemia associated with diuretic
use or volume depletion. A typical initial dose in a patient with normal renal function is 40
to 100 mmol (40-100 mEq) per day, in two to three divided doses. Liquid, wax matrix, and
microencapsulated forms exist. Compliance is poor with the liquid form due to the strong
taste. Although the wax matrix form is easier to swallow, it has been associated with
erosions of the gastrointestinal tract. The microencapsulated formulation is associated
with the fewest complications.

Other potassium preparations are available for different indications. Oral potassium
phosphate is found in many foods, and is indicated for combined potassium and
phosphorus depletion. Terminology may be misleading. For example, Neutra-Phos actually
has more potassium than K-Phos. Potassium bicarbonate is useful for the treatment of
both metabolic acidosis and hypokalemia, while potassium citrate may prevent renal
stones.

Intravenous repletion

KCl is preferred for intravenous repletion. Potassium phosphate may be used for dual
phosphorus and potassium depletion. Potassium can be infused through a peripheral
intravenous line at a maximum rate of 10 mmol/h. Higher rates require a central venous
line and continuous ECG monitoring. Infusion rates of 20 to 40 mmol/h are reserved for
cases of life-threatening hypokalemia requiring emergent correction. One liter bags of IV
fluids typically have a maximum of 60 mEq of K+ added in order to avoid infusing an
excess amount of K+.

Intravenous potassium is a common cause of iatrogenic hyperkalemia. A typical
intravenous dose with normal renal function is 20 to 40 mmol (20-40 mEq). Although 20
mmol of intravenous KCl might increase plasma K+ by 0.25 mmol/L, transcellular shifts
make it difficult to predict the effect of therapy. Renal potassium clearance generally
decreases significantly at a GFR below 20 to 30 mL/min/1.73 m2, and requires reduction
in potassium dosing and additional monitoring.

Hypokalemia in DKA and HHS

The use of insulin in DKA and HHS drives potassium into the intracellular space, and also
decreases the hyperglycemia-induced osmolar driving force for movement of potassium
from the intracellular to the extracellular space. Rapid and sometimes life-threatening
potassium shifts may result. In 2009, the American Diabetes Association recommended
that insulin should not be started until the serum potassium is known. If the serum
potassium is < 3.3 mmol/L, insulin therapy is held until the potassium is repleted to 3.3 mmol/L or above. If the serum potassium is ≥ 3.3 mmol/L, insulin therapy can be initiated. For serum potassium ≥ 3.3 and < 5.2 mmol/L, potassium supplementation as 20 to 30 mEq K+ in each liter of IV fluid is given during insulin therapy. The goal is to achieve serum potassium values between 4 to 5 mmol/L. Potassium supplementation is initially held for serum potassium values > 5.2 mmol/L, but is often subsequently required, as total body
stores of potassium are usually depleted and insulin plus intravenous fluid therapy
eventually unmasks the total body potassium deficit.

PRACTICE POINT

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Extreme caution and frequent monitoring are required in the treatment of hyperkalemia
in diabetic ketoacidosis and hyperosmolar hyperglycemic state. Generally, these
patients have a total body potassium deficit. Administration of insulin drives
potassium intracellularly through direct stimulation of Na+/K+-ATPase, while both
insulin and intravenous fluids reduce the glucose-induced hyperosmolality that drives
solvent drag. These two interventions can lead to a rapid decrease in plasma
potassium.

PRACTICE POINT

Potassium should not be mixed with glucose-containing solutions, because the
glucose will stimulate insulin secretion and drive potassium from the extracellular to
the intracellular space.

Thyrotoxic hypokalemic periodic paralysis

Oral propranolol (3 mg/kg) is first-line treatment for thyrotoxic periodic paralysis because
it rapidly reverses hypokalemia, hypophosphatemia, and hypomagnesemia, and is not
associated with rebound hyperkalemia. Propranolol 1 mg IV pushed slowly every 10
minutes, up to a total of 3 mg IV, is an alternative regimen. Aggressive potassium repletion
for this disorder has been associated with a 25% or greater incidence of hyperkalemia, so
if oral or IV potassium is given, subsequent close serial monitoring of plasma potassium
is warranted. Treatment to establish a euthyroid state is the long term priority to prevent
future attacks.

MAGNESIUM BALANCE

A typical American diet contains 300 to 400 mg/d of elemental magnesium.
Approximately 30% to 40% of dietary magnesium is absorbed in the gut. Additionally, 40
mg/d of magnesium is secreted in the small intestine, of which 20 mg/d is reabsorbed in
the colon and rectum. Approximately 100 mg appears in the urine each day, which is 5% of
the filtered load. Specific cutoffs for hypomagnesemia and hypermagnesemia are difficult
to establish because of the poor correlation between extracellular concentration and total
body stores. Plasma magnesium levels of 1.7 to 2.3 mg/dL (0.70-0.95 mmol/L) are
considered normal, but a normal serum level may be present despite total body
magnesium depletion.

PRACTICE POINT

Magnesium unit conversion
41.2 mmol of elemental magnesium is equivalent to 1 g of magnesium (24.3 mg = 1
mmol). Since the charge of the magnesium cation is 2+, 1 mmol = 2 mEq. For a
common preparation used for IV magnesium repletion, 1 g of magnesium sulfate
(MgSO47H2O) contains 8.1 mEq (98.6 mg) of elemental magnesium.

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HYPOMAGNESEMIA
ETIOLOGY OF HYPOMAGNESEMIA

Hypomagnesemia results from low dietary intake, gastrointestinal losses, and renal
losses. Poor intake of magnesium is common in alcoholics and hospitalized patients
receiving inadequate magnesium supplementation in parenteral nutrition or intravenous
fluids. The causes of impaired gastrointestinal absorption include diarrhea, inflammatory
bowel disease, laxative abuse, proton pump inhibitors, and small bowel resection.

Osmotic and loop diuretics provoke urinary losses of magnesium. Acutely, thiazide
diuretics increase magnesium absorption in the distal convoluted tubule, but long-term
use can reduce magnesium reabsorption and cause hypomagnesemia. Urinary
magnesium wasting is also seen in alcoholics. Many nephrotoxic drugs, such as
amphotericin B, aminoglycosides, cisplatin, foscarnet, and cyclosporine, interfere with
magnesium reabsorption in the thick ascending limb or distal convoluted tubule and
cause magnesium wasting. Rare familial disorders, such as Gitelman syndrome, are also
associated with urinary magnesium losses.

Miscellaneous causes of hypomagnesemia include acute pancreatitis, in which
magnesium and calcium are saponified in necrotic fat, hungry bone syndrome, where
magnesium, calcium, and phosphate are absorbed by bone after parathyroidectomy for
hyperparathyroidism, and diabetic ketoacidosis, where magnesium levels fall due to
osmotic diuresis and insulin-related transmembrane shifts.

HYPOMAGNESEMIA AND ASSOCIATED ELECTROLYTE ABNORMALITIES

Hypokalemia

Hypomagnesemia and hypokalemia often coexist due to similar common underlying
etiologies, such as excess gastrointestinal losses and diuretics. Hypokalemia is often
difficult to treat without magnesium repletion.

Hypercalcemia

Elevated ionized serum calcium levels induce renal Mg2+ wasting. Hypomagnesemia is
common in hypercalcemia of malignancy. However, in hypercalcemia secondary to
hyperparathyroidism, magnesium deficiency is rare due to the parathyroid hormone (PTH)-
induced stimulation of renal Mg2+ reabsorption.

Hypocalcemia

Hypomagnesemia may cause hypocalcemia due to inhibition of PTH secretion and by
induction of skeletal resistance to PTH. Hypocalcemia may be present in up to half of
patients with hypomagnesemia.

CLINICAL MANIFESTATIONS

Mild hypomagnesemia may be asymptomatic. Severe hypomagnesemia leads to
neuromuscular, neurologic, and cardiovascular symptoms. Neuromuscular abnormalities
include hyperreflexia, carpopedal spasm, delirium, seizures, tetany, and paralysis.
Chvostek and Trousseau signs may be present. ECG manifestations include torsades de
pointes, premature ventricular contractions, ventricular tachycardias, and ventricular

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fibrillation. There is also an increased risk of digitalis cardiac toxicity. As serum
magnesium levels do not always correlate with total body magnesium stores,
normomagnesemic magnesium depletion may be considered in patients with unexplained
hypocalcemia and hypokalemia and clinical risk factors for magnesium deficiency.

EVALUATION OF HYPOMAGNESEMIA

Urine studies

Urine studies are useful to evaluate renal vs nonrenal causes of hypomagnesemia. The
fractional excretion of magnesium (FeMg) is given by:

The 0.7 in the denominator is a correction factor for the 30% of plasma magnesium
bound to plasma proteins. A FeMg of > 3% in a patient with normal GFR indicates renal
magnesium loss. A 24-hour magnesium collection can also be obtained and is normally 3
to 5 mmol (75-125 mg)/24 hours. In the presence of hypomagnesemia, normal kidneys
should be able to reduce the 24-hour urinary excretion of magnesium even further, to 1
mmol or less.

TREATMENT OF HYPOMAGNESEMIA

Oral repletion

The most popular formulation for oral replacement is magnesium oxide (242 mg = 20
mEq Mg2+ per 400 mg tablet), with a typical dose of 400 mg two to three times per day.
Magnesium chloride, magnesium gluconate, magnesium lactate, and magnesium L-
aspartate are other options. Diarrhea is a common side effect. It may be reduced with the
use of a sustained release formulation, such as magnesium chloride (64 mg per 535 mg
tablet). The potassium-sparing diuretics triamterene and amiloride, which block ENaC in
the distal renal tubule, can assist in treatment of hypomagnesemia refractory to oral
supplementation.

PRACTICE POINT

Refractory hypokalemia and hypocalcemia occur with severe Mg2+ deficiency, and
Mg2+ repletion is necessary for correction.

Intravenous repletion

Symptomatic or severe hypomagnesemia should be treated with intravenous magnesium.
For active seizures or cardiac arrhythmias, an initial dose of 8 to 16 mEq of Mg2+ (1-2 g of
MgSO47H2O) is administered over 2 minutes. For nonemergency repletion, 64 mEq of Mg

2+

(8 g of MgSO47H2O) can be given over the first 24 hours, followed by 32 mEq of Mg
2+ daily

for six additional days. Since magnesium is renally cleared, the dose should be reduced by
25% to 50% and the plasma magnesium level monitored after each dose for GFR < 20 to 30 mL/min/1.73 m2.

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HYPERMAGNESEMIA
ETIOLOGY

Hypermagnesemia usually results from iatrogenic causes, such as magnesium treatment
for preeclampsia or eclampsia, or inadvertent administration of excessive doses of
magnesium-containing supplements, laxatives, Epsom salts, enemas, or antacids. The risk
of hypermagnesemia is particularly high for patients with severely impaired renal function.

CLINICAL MANIFESTATIONS

Clinical manifestations are unusual with plasma magnesium levels < 4.5 to 5 mg/dL. Above this range, nausea, vomiting, cutaneous flushing, hyporeflexia, and mild hypotension can be seen. For plasma magnesium levels > 7 to 10 mg/dL, there may be
loss of tendon reflexes, muscle weakness, and hypotension. Respiratory muscle paralysis
occurs when magnesium levels exceed 12 to 15 mg/dL. ECG changes with plasma
magnesium values > 5 mg/dL include prolonged PR interval, an increased QRS interval,
prolonged QT interval, and bradycardia. Complete heart block is seen for plasma Mg2+ >
10 to 15 mg/dL, and cardiac arrest for levels > 15 mg/dL.

TREATMENT

In mild cases, stopping magnesium administration may be sufficient. Dialysis can be
performed for extreme cases. Intravenous calcium (100-200 mg of elemental calcium
given over 5-10 minutes) can be used to temporarily antagonize the effects of magnesium
until dialysis can be performed. Details regarding intravenous calcium administration can
be found in the section on treatment of hyperkalemia. Intravenous volume infusion may
be helpful in promoting magnesium excretion in patients who are not volume overloaded
and who have adequate renal function.

DISCHARGE CHECKLIST

For patients with potassium disorders at risk for cardiac arrhythmias, is the potassium
level within the normal range prior to discharge?
For patients with potassium disorders at low risk of cardiac arrhythmias, is the
potassium level between 3 and 5.6? Are clinical symptoms or ECG changes associated
with potassium disorders absent? If the patient is discharged with mild hypokalemia or
mild hyperkalemia, is there a clinical plan to achieve a normal plasma potassium (3.5-
5) which can be re-evaluated at follow-up?
Have patients with hypokalemia been counselled regarding potential dietary sources of
potassium? (These include dark leafy greens, avocadoes, peaches, prunes, raisins,
potatoes, squash, beans, and fish, as well as the commonly cited bananas and orange
juice.)
Has follow-up testing been arranged for potassium, magnesium, and creatinine, if
appropriate?

SUGGESTED READINGS

1578185 – McGraw-Hill Professional ©

Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med.
2009;361:62-72.

Gennari FJ. Disorders of potassium homeostasis: hypokalemia and hyperkalemia. Crit
Care Clin. 2002;18:273-288.

Kamel KS, Halperin ML. Intrarenal urea recycling leads to a higher rate of renal excretion of
potassium: a hypothesis with clinical implications. Curr Opin Nephrol Hypertens.
2011;20:547-554.

Kim HJ, Han SW. Therapeutic approach to hyperkalaemia. Nephron. 2002;92(Suppl 1):33-
40.

Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. American Diabetes Association
Consensus Statement: hyperglycemic crisis in adult patients with diabetes. Diabetes
Care. 2009;32:1335-1343.

Palmer BF. A physiol

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CHAPTER 240
Calcium Disorders

Elizabeth H. Holt, MD, PhD

John P. Bilezikian, MD

Key Clinical Questions

How is serum calcium regulated?
What are the causes of hypercalcemia in hospitalized patients?
How is hypercalcemia diagnosed and managed?
What causes hypocalcemia in hospitalized patients? How is it diagnosed and
managed?

INTRODUCTION
Abnormalities of calcium metabolism are common in hospital practice. Hypercalcemia
has a prevalence of 0.1% in the general population and 1% among hospitalized patients.
In the inpatient setting, hypercalcemia often portends serious illness, especially
malignancy. Hypocalcemia is also common in the hospital, especially in patients with
chronic renal failure or sepsis. Hypocalcemia may also be a manifestation of vitamin D
deficiency, which has a prevalence of up to 80% on specialized geriatric inpatient units.

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CALCIUM METABOLISM
Precise regulation of calcium homeostasis is essential because of the critical role of
calcium in many physiological activities. It is the major mineral of bone. It also plays
major roles in neuronal transmission, muscle contraction, and blood coagulation. Calcium
is also required for the proper functioning of many enzymes, endocrine secretory
processes, and biochemical signaling pathways.

NORMAL SERUM CALCIUM LEVELS

A typical laboratory range for serum total calcium concentration is between 8.4 and 10.2
mg/dL. Approximately half of this total amount is bound to albumin, with the remainder in
free (ionized) form. The normal free calcium concentration range is 4.5 to 5.3 mg/dL. A
small fraction (10%) of circulating calcium is complexed with anions, such as citrate and
phosphate.

REGULATION OF CALCIUM HOMEOSTASIS

The three organ systems that together regulate serum calcium are the gastrointestinal
tract, kidneys, and skeleton. The two principal regulatory hormones are parathyroid
hormone (PTH) and 1,25-dihydroxyvitamin D3. PTH is a peptide secreted from the
parathyroid glands in its active full-length configuration, known as PTH(1-84). Its plasma
half-life is very short, on the order of 3 to 5 minutes. The major regulator of PTH secretion
is the free calcium concentration in extracellular fluid. Elevated levels of free or ionized
calcium promptly block secretion of PTH, while reduced serum calcium levels promptly
increase secretion of PTH.

1,25-dihydroxyvitamin D3 is produced by a sequence of activation steps (Figure 240-
1), starting with the generation of cholecalciferol (vitamin D3) through exposure of skin to
ultraviolet light of a specified wavelength (90-315 nm). Cholecalciferol or its plant
analogue, ergocalciferol (vitamin D2), can also be obtained by dietary sources or in
nutritional supplements. Cholecalciferol or ergocalciferol is converted in the liver to a
hydroxylated form, 25-hydroxyvitamin D3 or 25-hydroxyvitamin D2. The 25-hydroxylated
forms of vitamin D are converted to their active forms by a second hydroxylation step in
the kidney leading to 1,25-dihydroxyvitamin D2 or D3. Both dihydroxylated forms of
vitamin D are active in human subjects, although there is controversy over whether vitamin
D3 is more potent than vitamin D2. PTH maintains serum calcium concentrations by
conserving calcium that has been filtered at the kidney glomerulus and by mobilizing
calcium from bone. 1,25-dihydroxyvitamin D maintains serum calcium by facilitating
absorption of calcium from the gastrointestinal tract and, like PTH, mobilizing calcium
from bone. Under normal conditions, the calcium absorbed by the gut (approximately 150-
200 mg/d) is matched by the calcium eliminated by the kidney. At the dynamic skeletal
interface, as much as 500 mg of calcium is turned over daily. This process is in a steady
state, with net calcium neither gained nor lost. Thus, under normal circumstances, there
are no significant fluctuations in body calcium stores, nor is there any major change in
circulating serum calcium concentrations.

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Figure 240-1 Vitamin D synthesis and activation. Vitamin D is synthesized in the skin in
response to ultraviolet radiation and is also absorbed from the diet. It is then transported
to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating
form of vitamin D. The final step in hormone activation, 1-hydroxylation, occurs in the
kidney. (Reproduced, with permission, from Fauci AS, Braunwald E, Kasper DL, et al.
Harrison’s Principles of Internal Medicine, 17th ed. New York, NY: McGraw-Hill; 2008, Fig.
346-4.)

Changes in free or ionized calcium concentration are registered virtually instantly by
parathyroid cells via the calcium-sensing receptor (CaSR). This receptor is located on the
parathyroid cell surface, where its extracellular domain senses binding of calcium ions. If
the circulating calcium concentration rises, the Ca2+-CaSR complex leads to a rise in
intracellular calcium, inhibiting both PTH secretion and synthesis. If the serum calcium
concentration falls, the Ca2+-CaSR complex sends a reduced signal to the cell, leading to
an increase in PTH secretion and synthesis.

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1,25-dihydroxyvitamin D decreases PTH production, although not as powerfully as
does the ionized calcium signal. There is a stronger interaction between levels of 25-
hydroxyvitamin D and PTH. They have an inverse relationship, with PTH levels rising when
25-hydroxyvitamin D levels fall below approximately 25 to 30 ng/mL. In turn, increased
PTH stimulates the 1-alpha hydroxylase enzyme in the kidney that converts 25-
hydroxyvitamin D to 1,25-dihydroxyvitamin D (Figure 240-2). When PTH levels are
elevated (ie, primary hyperparathyroidism), 1,25-dihydroxyvitamin D levels increase. When
PTH levels are low (ie, hypoparathyroidism), 1,25-dihydroxyvitamin D levels are typically
low. The three organ systems (bone, gastrointestinal tract, and kidneys) and the two
calcium-regulating hormones (PTH and 1,25-dihydroxyvitamin D) work together to
maintain normal calcium homeostasis. When they are not perturbed by disease or by the
aging process, they are an exquisitely sensitive and effective servomechanism.

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Figure 240-2 Schematic representation of the hormonal control loop for vitamin D
metabolism and function. A reduction in the serum calcium below 2.2 mmol/L (8.8 mg/dL)
increases secretion of parathyroid hormone (PTH), mobilizing additional calcium from
bone. PTH promotes the synthesis of 1,25(OH)2D in the kidney, which, in turn, stimulates
the mobilization of calcium from bone and intestine, and regulates the synthesis of PTH by
negative feedback. (Reproduced, with permission, from Fauci AS, Braunwald E, Kasper DL,
et al. Harrison’s Principles of Internal Medicine, 17th ed. New York, NY: McGraw-Hill; 2008,
Fig. 346-5.)

LABORATORY MEASUREMENT OF BLOOD CALCIUM

The measurement of serum calcium may be helpful when a disturbance of calcium
metabolism is suspected. However, in many disorders of calcium metabolism, such as

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osteoporosis or Paget disease of bone, the serum calcium concentration is typically
normal. Serum measurements may be performed by spectrophotometry or by atomic
absorption spectrophotometry, with the latter yielding more accurate measurements.
Spuriously high readings may occur if the tourniquet is in place too long before blood is
drawn and hemoconcentration occurs. Under these circumstances, the measured serum
calcium value can rise by as much as 0.4 mg/dL. On the other hand, the sample can read
falsely low if the blood sample is obtained from a central, high-flow site via a central
venous catheter. For most clinical situations, the total serum calcium is measured. This
may need to be corrected for the circulating albumin concentration. For every 1 g/dL
reduction in the serum albumin, the total calcium is adjusted upward by 0.8 mg/dL. This
may be calculated as follows:Corrected total calcium = measured total calcium + 0.8 (4.0
– serum albumin)

In theory, free or ionized serum calcium is a more accurate physiological measurement
than the adjusted total serum calcium concentration, but the sampling technique (the
blood has to be free-flowing and not impeded by a tourniquet) and strict anaerobic
collection conditions are problematic. Moreover, the measuring instrument has to be in
regular use and properly calibrated. Samples have to be measured immediately. These
technical issues somewhat limit the clinical utility of the ionized calcium measurement.

HYPERCALCEMIA
Signs and symptoms of hypercalcemia may be absent or subtle, except when calcium is
significantly elevated or has increased rapidly. The diagnostic workup of hypercalcemia is
usually straightforward (Figure 240-3) because two causes, primary hyperparathyroidism
and malignancy-associated hypercalcemia, account for approximately 90% of cases. In
addition, most individuals with primary hyperparathyroidism are asymptomatic and
discovered on routine biochemical screening tests, while most individuals with
malignancy-associated hypercalcemia have a known advanced malignancy at the time
that hypercalcemia occurs. If the malignancy is not known, it is generally quickly apparent.
When neither of these two etiologies is readily apparent, identification of the other
potential etiologies requires a comprehensive history, physical examination, laboratory
tests, and, occasionally, diagnostic imaging studies.

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Figure 240-3 Diagnostic approach to hypercalcemia. FHH, familial hypocalciuric
hypercalcemia; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein.
*A low 24-hour urinary calcium does not necessarily rule out primary hyperparathyroidism.

PRESENTING SYMPTO

MS AND HISTORY

Many individuals with mild hypercalcemia (serum calcium level < 11 mg/dL) are asymptomatic, although some may report mild fatigue, vague changes in cognitive function, depression, or constipation. Symptomatic manifestations of hypercalcemia are more apparent when the serum calcium concentration is between 12 and 14 mg/dL. These symptoms include anorexia, nausea, weakness, and depressed mental status. As hypercalcemia may induce polyuria and nephrogenic diabetes insipidus, dehydration may occur should the compensatory polydipsia not keep up with urinary water losses. When serum calcium levels rise above 14 mg/dL, profound dehydration, renal dysfunction, and central nervous system changes, such as progressive lethargy, disorientation, and coma, may develop.

In addition to the absolute magnitude of the serum calcium elevation, the rate of
increase in serum calcium also influences symptoms. Individuals who are chronically

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hypercalcemic may have relatively few symptoms, even with serum calcium values up to
15 to 16 mg/dL. In contrast, those whose calcium level has risen abruptly may have
symptoms at much more modest calcium levels. Elderly or debilitated patients are more
likely to be affected by hypercalcemia than younger individuals.

The medical record may contain clues to etiology. Prescription medications (Table
240-1), foods, and vitamin and nutritional supplements should be reviewed. A careful
family history might uncover a familial endocrine condition. A history of family members
with endocrine tumors of the pituitary or pancreas suggests multiple endocrine neoplasia
type 1 syndrome (MEN-1). A family history of pheochromocytoma or medullary thyroid
cancer is consistent with MEN-2 syndrome. Patients with sarcoidosis may have a history
of unexplained fever, lymphadenopathy, skin rashes, or pulmonary symptoms. Bone pain
suggests myeloma or other malignancies, although it may also be a nonspecific finding of
hypercalcemia.

TABLE 240-1 Causes of Hypercalcemia

PTH mediated

Primary hyperparathyroidism

Parathyroid adenoma
Parathyroid hyperplasia
Parathyroid carcinoma

Tertiary hyperparathyroidism

Familial hypocalciuric hypocalcemia
Lithium
Thiazide diuretics

PTH independent HHM: PTHrP mediated
Squamous carcinoma of the lung, oropharynx,
nasopharynx, larynx, and esophagus
Gynecologic (cervical, ovarian)
Urologic (renal, transitional cell of bladder)
Pheochromocytoma
Pancreatic islet cell tumors
T-cell lymphoma
Others

HHM: 1,25-(OH)2-D3 mediated
B-cell lymphoma

Local osteolytic hypercalcemia
Multiple myeloma
Breast carcinoma metastatic to bone
Lymphoma
Others

Medications/supplements
Vitamin D

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Vitamin A
Thiazide diuretics
Calcium-containing antacids (in milk-alkali syndrome)

Granulomatous diseases
Sarcoidosis
Tuberculosis
Histoplasmosis
Leprosy

Other conditions
Factitious hypercalcemia (due to increased plasma protein
levels)
Acute renal failure
Severe thyrotoxicosis
Adrenal insufficiency
Immobilization

HHM, humoral hypercalcemia of malignancy; PTH, parathyroid hormone; PTHrP, parathyroid
hormone-related protein.

THE PHYSICAL EXAMINATION

The physical examination is directed at identifying signs of hypercalcemia. Evidence of
dehydration such as orthostasis or dry mucous membranes may be present, although
hypercalcemia must be marked and prolonged for these physical findings to be
appreciated. The physical examination is often normal in patients with hypercalcemia,
especially if calcium levels are only modestly elevated. Rarely, severe and prolonged
hypercalcemia may produce a visible horizontal deposit of calcium salts on the cornea, a
finding called band keratopathy.

Effort should be made to identify signs of common causes of hypercalcemia, such as
malignancy and primary hyperparathyroidism. The physical examination in primary
hyperparathyroidism, like most hypercalcemic states, is usually not noteworthy. A mass is
virtually never found in the neck, because enlarged parathyroid glands are still too small to
be felt. However, when the serum calcium is markedly elevated, a neck mass may signify a
parathyroid carcinoma. Symptomatic kidney stones might be accompanied by
costovertebral tenderness. Enlarged lymph nodes suggest sarcoid, lymphoma, or
metastatic carcinoma.

DIAGNOSIS

Laboratory studies

The first step in evaluating hypercalcemia is adjustment for serum albumin. If the
corrected serum calcium is elevated, it should be repeated. Renal function should also be
assessed, because hypercalcemia may develop or worsen in the setting of acute renal
failure. If hypercalcemia is confirmed, the next step is measurement of serum PTH. The
PTH level is the most important test for distinguishing between the two most common
causes of hypercalcemia, primary hyperparathyroidism and malignancy-associated

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hypercalcemia (Table 240-1). The so-called intact immunochemiluminometric assay for
PTH assay primarily measures the intact molecule, PTH(1-84), as well as a large
circulating fragment that is foreshortened at the amino terminus, PTH(7-84). A more
specific assay that measures only PTH(1-84), the bio-intact assay, is also available, but it
has not shown any clear advantages over the older assay, which has been in clinical use
for over 20 years. When the creatinine clearance falls below 60 mL/min, these assays may
begin to show elevations in PTH due to the accumulation of inactive fragments, and also
perhaps due to increased secretory activity of the parathyroids (secondary
hyperparathyroidism).

When the parathyroid glands are functioning normally, hypercalcemia should suppress
PTH levels. Hypercalcemia is said to be PTH-mediated if serum calcium is elevated, and
the PTH level is high or inappropriately normal. In this latter situation, one is usually
dealing with primary hyperparathyroidism, although familial hypocalciuric hypercalcemia
(FHH) and medication-induced hypercalcemia, as from thiazide diuretics or lithium, can
also be associated with elevated PTH levels. When PTH levels are appropriately
suppressed in hypercalcemia, the differential diagnosis includes malignancy,
granulomatous disease, medications, milk-alkali syndrome, thyrotoxicosis, and adrenal
insufficiency.

Other recommended tests in the evaluation of hypercalcemia include serum
electrolytes and 25-hydroxyvitamin D. Levels of 25-hydroxyvitamin D typically exceed 150
ng/mL in vitamin D toxicity due to excess intake. Levels this high cannot be achieved by
sun exposure alone. High 1,25-(OH)2D levels may be seen in any granulomatous disease,
particularly sarcoidosis or certain lymphomas. Inorganic phosphorus measurement may
be helpful, as a low-normal serum phosphate is often seen in primary
hyperparathyroidism, while high phosphate may be seen in vitamin D intoxication. An
elevated serum creatinine may indicate dehydration or true renal dysfunction due to renal
deposition of calcium salts or other causes. An elevated alkaline phosphatase level
suggests elevated bone turnover. This may be confirmed by measuring bone-specific
alkaline phosphatase or other indices of bone turnover, such as serum osteocalcin, serum
C-terminal collagen peptide measurement, or urinary N-terminal collagen peptide. Most
forms of hypercalcemia are accompanied by hypercalciuria (24-hour urine calcium
excretion > 4 mg/kg/24 hours). However, in primary hyperparathyroidism, renal calcium
excretion is lower than expected for the degree of hypercalcemia, because PTH conserves
filtered calcium in the distal renal tubule.

Additional tests

The electrocardiogram may show a shorted QTc interval, particularly if hypercalcemia has
occurred over a short period of time. Bone mineral density (BMD) by dual energy x-ray
absorptiometry (DXA) may be helpful. In primary hyperparathyroidism, there is a typical
pattern of BMD with relative preservation of cancellous bone, as in the lumbar spine, and
significant loss of cortical bone, as in the femoral neck and distal third of the radius.
Abdominal imaging studies (CT or ultrasound) may identify renal stones or
nephrocalcinosis. Serum and urine protein electrophoresis should be obtained if myeloma
is suspected. Skeletal radiographs may reveal lytic lesions of multiple myeloma or other
malignancies. In primary hyperparathyroidism, skeletal radiographs may show
subperiosteal bone resorption or brown tumors of bone, but are rarely needed for
diagnosis.

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CAUSES OF PTH-MEDIATED HYPERCALCEMIA

Primary hyperparathyroidism

Elevation of both serum calcium and PTH concentrations, in the absence of lithium use or
low urinary calcium excretion as seen in familial hypocalciuric hypercalcemia, supports a
diagnosis of primary hyperparathyroidism. In this condition, PTH levels are usually within
1.5 to 2.0 times above the upper limit of normal. Extremely high levels of PTH raise the
specter of parathyroid carcinoma. Typical primary hyperparathyroidism is associated with
mild hypercalcemia, within 1 mg/dL above the upper limit of normal. The PTH level may
be elevated, but may also fall in the upper portion of the normal range, which is
inappropriate in hypercalcemia. Normocalcemic primary hyperparathyroidism is a new
diagnostic entity applied to patients whose total and free serum calcium levels are normal,
but in whom the PTH level is consistently elevated. In the absence of a secondary cause
for elevated PTH levels, it is felt that these individuals have an early form of primary
hyperparathyroidism.

Primary hyperparathyroidism is the most common cause of hypercalcemia in
outpatients. The incidence is estimated to be approximately 21.6 per 100,000 person-
years. The mean age at diagnosis is in the sixth decade of life, and there is a female-to-
male ratio of 2:1. The clinical manifestations depend largely on the severity of the
hypercalcemia. When primary hyperparathyroidism was first described more than 80 years
ago, most patients presented with advanced disease with overt radiographic abnormalities
of bone (osteitis fibrosa cystica) and kidneys (nephrolithasis or nephrocalcinosis). Since
the introduction more than 40 years ago of automated multichannel autoanalyzers for
measuring serum chemistry, primary hyperparathyroidism is most often diagnosed by
routine blood testing, well before the development of other signs or any symptoms. It also
may be uncovered during the evaluation of osteoporosis or during the workup of renal
stone disease. The most common clinical presentation today is mild asymptomatic
hypercalcemia. In 75% to 80% of cases, a solitary, benign parathyroid adenoma is present.
Hyperplasia involving multiple parathyroid glands is found in 15% to 20% of cases, and
parathyroid carcinoma is present in less than 0.5%. On occasion, double adenomas are
found. Patients with MEN-1 or MEN-2 usually have parathyroid hyperplasia involving all
parathyroid glands.

Parathyroid surgery is always indicated in symptomatic primary hyperparathyroidism,
unless there are medical contraindications. The role of parathyroid surgery in
asymptomatic primary hyperparathyroidism is more controversial. According to the
guidelines of the Fourth International Workshop on the Management of Asymptomatic
Primary Hyperparathyroidism, indications for surgery in asymptomatic patients include a
serum calcium > 1 mg/dL above the upper limit of normal; creatinine clearance < 60 mL/min; 24-hour urine calcium > 400 mg/d and increased stone risk by biochemical stone
risk analysis; presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound or CT; T-
score < –2.5 at lumbar spine, hip, or distal third of the radius; vertebral fracture by x-ray, CT, MRI or VFA; and age < 50. Patients who do not meet these guidelines can be followed expectantly. Thiazide diuretics and lithium should be avoided. Dietary calcium should not be restricted, because such restriction may promote further elevation of PTH, and possibly have adverse effects on bone mass. In patients who are vitamin D deficient, cautious replacement of vitamin D is advised. Patients should maintain hydration. Bisphosphonates increase lumbar spine BMD in primary hyperparathyroidism, without a

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major effect on the serum calcium concentration. The calcimimetic agent, cinacalcet,
reduces serum calcium in primary hyperparathyroidism without having a major effect on
BMD. Cinacalcet is indicated for use in patients with parathyroid cancer, as well as
patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy.
Alendronate has not been approved by the Food and Drug Administration (FDA) for use in
primary hyperparathyroidism.

Lithium can change the set point for the calcium-sensing receptor on the parathyroid
gland, such that a higher serum calcium concentration is needed to inhibit PTH secretion.
This can lead to mild biochemical abnormalities, such as high levels of calcium and high-
normal to elevated PTH levels, that mimic primary hyperparathyroidism, but do not require
medical intervention.

Thiazide-associated hypercalcemia also occurs. Many patients with hypercalcemia on
thiazides probably have primary hyperparathyroidism. When thiazide therapy is
discontinued, the hypercalcemia often persists, and the diagnosis of primary
hyperparathyroidism is made.

Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia, also known as benign familial hypercalcemia, is a
rare genetic condition caused by inactivating mutations in the CaSR. This results in lack of
sensitivity of the parathyroid cell to ambient serum calcium, a higher set point for the
extracellular ionized calcium concentration, and inappropriately normal to mildly elevated
PTH levels. Patients with FHH have chronic asymptomatic hypercalcemia, with very low
urinary calcium excretion. The relatively low urinary calcium excretion in FHH helps
distinguish it from primary hyperparathyroidism, although low urinary calcium excretion
may also occur in individuals with primary hyperparathyroidism. A family history of
asymptomatic mild hypercalcemia, especially in individuals younger than 40 years, is
suggestive of FHH. Other supportive evidence for FHH includes a very low urinary calcium
to creatinine clearance ratio (< 0.01), and a history of family members who have undergone noncurative parathyroidectomy for presumed primary hyperparathyroidism. When FHH is suspected, further evaluation is necessary, such as screening of other family members for hypercalcemia. Genetic testing for FHH may be appropriate, as it may otherwise be exceedingly difficult to distinguish FHH from primary hyperparathyroidism.

Tertiary hyperparathyroidism

Conditions associated with low serum calcium are usually also associated with
chronically elevated PTH levels, which is an appropriate physiological response. This is
called secondary hyperparathyroidism. The rise in PTH may restore the serum calcium to
normal, or calcium may remain low or in the low-normal range. Secondary
hyperparathyroidism is not a hypercalcemic state. Common causes of secondary
hyperparathyroidism include vitamin D deficiency, intestinal malabsorption of calcium or
vitamin D, renal-based hypercalciuria, severe nutritional calcium deficiency, and especially
chronic renal insufficiency. Correction of the underlying cause usually returns serum PTH
concentrations to normal. Normalization of PTH may be relatively rapid, if the cause is of
recent onset, or it may be protracted, if the associated condition has been longstanding. In
patients with prolonged secondary hyperparathyroidism, the reactive state can become
semiautonomous, leading to hypercalcemia. This condition, known as tertiary

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hyperparathyroidism, is most often seen in patients with poorly controlled chronic kidney
disease. Tertiary hyperparathyroidism is usually associated with hyperplasia of multiple
glands, but may also be caused by a parathyroid adenoma from a single clone of
parathyroid cells.

Further investigations

Most patients with primary hyperparathyroidism have a serum calcium concentration
below 11 mg/dL. Serum phosphate tends to be in the low-normal range (2.5-3.2 mg/dL).
Rarely, a nonanion gap hyperchloremic acidosis from a PTH-induced defect in bicarbonate
resorption may be seen. Urinary calcium excretion tends to be in the upper range of
normal. However, hypercalciuria in primary hyperparathyroidism does not always
predispose to renal stones, despite the fact that hypercalciuria is a risk factor for kidney
stones in euparathyroid subjects. Bone turnover markers tend to be at the upper limit or
normal, but occasionally can be frankly elevated.

Once the diagnosis of primary hyperparathyroidism is made, it should be determined
whether or not the patient meets clinical criteria for parathyroidectomy (Table 240-2). If
the clinical situation is appropriate, consideration should be given to the possibility of one
of the MEN syndromes, particularly if the patient is young, or has a personal or family
history of a related endocrinopathy. A diagnosis of MEN-1 or MEN-2 should prompt a
search for multiple parathyroid gland disease.

TABLE 240-2 Indications for Parathyroidectomy in Primary Hyperparathyroidism

Fragility fracture at any site
Serum calcium > 1.0 mg/dL above upper limit of normal
On bone mineral density by DXA: T-score < −2.5 at lumbar spine, total hip, femoral neck or distal 1/3 radius (use of Z-scores instead of T-scores is recommended for measurement of BMD in premenopausal women and men younger than 50 years of age). Vertebral fracture by x-ray, CT, MRI, or Vertebral Fracture Assessment (VFA) Creatinine clearance < 60 cc/min 24-h urine for calcium > 400 mg/d and increased stone risk by biochemical stone risk
analysis
Presence of nephrolithiasis or nephrocalcinosis clinically or by x-ray, ultrasound or CT
Age < 50 Surgery is also indicated in individuals where medical monitoring is not desired or possible, or for those selecting surgery, without meeting any guidelines, if there are no medical contraindications.

Source: Adapted from Bilezikian JP, et al. Guidelines for management of asymptomatic primary
hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol
Metab. 2014;99:3561-3569.

CAUSES OF PTH-INDEPENDENT HYPERCALCEMIA

If the serum calcium concentration is elevated but the PTH level is appropriately
suppressed, the patient has hypercalcemia due to causes other than hyperparathyroidism

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(PTH-independent hypercalcemia). Cancer is the most common cause. Other causes
include thyrotoxicosis, vitamin D intoxication, sarcoidosis, immobilization, Addison
disease, and various drugs and supplements.

In hypercalcemia of malignancy, calcium is usually moderately or severely elevated,
and PTH is low or undetectable. Significant dehydration and generalized debility are
usually evident, along with other cancer-related symptoms. Usually, the diagnosis of
malignancy has already been established when patients become hypercalcemic.
Hypercalcemia of malignancy has two forms: humoral hypercalcemia of malignancy
(HHM) and local osteolytic hypercalcemia. HHM results from tumor production of a
circulating factor with systemic effects on calcium metabolism, acting on skeletal calcium
release, renal calcium handling, or intestinal calcium absorption. The usual cause of HHM
is parathyroid hormone-related protein (PTHrP). Normally, PTHrP serves as a paracrine
factor in tissues such as bone, skin, breast, uterus, placenta, and blood vessels, where it is
involved in cellular calcium handling, smooth muscle contraction, and growth and
development. The amino terminus of the PTHrP peptide is closely homologous with native
PTH, and they share a common receptor. When PTHrP circulates at supraphysiologic
concentrations, it produces effects similar to PTH, activating osteoclasts to resorb bone,
decreasing renal calcium output, and increasing renal phosphate clearance.

Tumors that produce HHM by secreting PTHrP are typically squamous cell carcinomas
of the lung, esophagus, head and neck, or cervix. Other tumors that may elaborate PTHrP
include adenocarcinoma of the breast or ovary, renal carcinoma, transitional cell
carcinoma of the bladder, islet cell tumors of the pancreas, T-cell lymphoma, and
pheochromocytoma. As tumors that produce PTHrP do so in relatively small amounts, the
syndrome typically develops in patients with a large tumor burden. It is therefore unusual
for HHM to be the presenting feature of a cancer. The diagnosis may be confirmed by a
commercially available radioimmunoassay for PTHrP. Care should be taken to ensure that
blood for PTHrP levels is drawn and handled correctly to avoid spurious low results.
Rarely, HHM is caused by the unregulated production of 1,25-dihyroxyvitamin D, usually by
B-cell lymphomas, or other mediators that interfere with calcium homeostasis.

The other major mechanism of malignancy-associated hypercalcemia is the direct
invasion of bone by tumor, with lytic destruction and calcium release. While this was
formerly thought to be a mechanical process, it now appears to be driven by the local
elaboration of cytokines leading to osteoclast-mediated bone resorption. In local osteolytic
hypercalcemia, PTHrP and calcitriol are within normal limits. Bony metastases are usually
obvious on imaging studies. The classic tumor associated with this syndrome is multiple
myeloma, although breast cancer and certain lymphomas may also be responsible. Local
osteolytic hypercalcemia may be perpetuated by a positive feedback loop. Factors
produced by bone promote the growth and survival of metastases, and the tumor induces
osteoclasts to produce factors promoting tumor growth, bone resorption, and
hypercalcemia. Interruption of this positive feedback loop is the rationale for the use of
bisphosphonates in the treatment of multiple myeloma.

PTH-independent hypercalcemia also occurs in sarcoidosis, tuberculosis, and other
granulomatous diseases. Macrophages in the granuloma convert 25-hydroxyvitamin D to
1,25-dihydroxyvitamin D, via an unregulated 1-α hydroxylase enzyme. 25-hydroxyvitamin D
levels are typically not elevated. When serum 25-hydroxyvitamin D levels are elevated,
excessive vitamin D intake becomes the more likely etiology. Endocrine conditions that
may occasionally lead to hypercalcemia include severe hyperthyroidism, which stimulates

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bone resorption, and Addison disease, where volume depletion reduces calcium clearance
and control of calcium absorption is mitigated by glucocorticoid deficiency.

Immobilization stimulates bone resorption and may increase serum calcium levels,
particularly in bedbound hospitalized patients. This is usually seen in persons with high
bone turnover, such as adolescents and patients with unrecognized hyperparathyroidism
or Paget disease of bone. Drugs and dietary supplements may lead to hypercalcemia.
Vitamin D intoxication and excessive intake of vitamin A, which activates bone resorption,
are occasional culprits. Thiazide diuretics may cause hypercalcemia due to enhanced
renal retention of calcium. In many cases, this develops in individuals with underlying mild
primary hyperparathyroidism.

In patients with an extensive negative workup, the rare possibility of occult malignancy
should be considered, especially when PTHrP is elevated. Further imaging studies would
then be needed for tumor localization, including a plain chest radiograph or a computed
tomographic scan of the chest to rule out lung malignancy. If these are unrevealing,
consideration should be given to otolaryngoscopic examination, esophagoscopy, or CT of
the abdomen, followed by radiographic or endoscopic evaluation of the genitourinary tract
if necessary.

PRACTICE POINT

In the early 20th century, the Chicago physician Bertram Sippy gained celebrity
because of his “Sippy diet” for peptic ulcers—a regimen of milk, cream, eggs, and
cereal 3 times a day, punctuated by aggressive antacid therapy with hourly sodium
bicarbonate and magnesium hydroxide. This may or may not have been curative for
ulcers, but some patients certainly did develop severe hypercalcemia, in what became
known as milk-alkali syndrome. Patients developed a metabolic alkalosis, which
favors renal reabsorption of calcium, and the resulting hypercalcemia led to renal
vasoconstriction, a fall in GFR, and further increases in serum calcium. Up to one-third
of these patients had chronic renal failure. Milk-alkali syndrome became rare with the
introduction of H2-blockers and proton pump inhibitors for peptic ulcer disease.
A similar disorder is seen increasingly in postmenopausal women who consume large
amounts of supplemental calcium carbonate and vitamin D for the prevention of
osteoporosis. Pregnant or bulimic women with metabolic alkalosis from emesis who
are taking calcium and vitamin D are also at risk. It has been suggested that the
disorder be renamed the calcium-alkali syndrome. Treatment is volume expansion with
saline, cessation of alkali intake, and limitation of calcium supplementation.

TREATMENT OF HYPERCALCEMIA

Hypercalcemia that requires urgent management is usually due to malignancy, rather than
primary hyperparathyroidism. Urgent management includes aggressive rehydration,
bisphosphonate therapy to decrease bone resorption, and elimination of contributing
factors, such as calcium or vitamin D supplements, thiazide diuretic therapy, and
immobilization. Second-line therapies include calcitonin to increase renal calcium
excretion, and glucocorticoids to diminish intestinal calcium absorption.

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Saline hydration

Most patients with emergent hypercalcemia are dehydrated due to anorexia and polyuria.
Intravascular volume should be aggressively restored with intravenous normal saline, with
an initial bolus of 500 to 1000 mL, followed by maintenance fluids at a rate of 200 mL/h
or more, depending on the patient’s renal function and cardiac reserve (Table 240-3).
Typically, patients require 3 to 4 L for rehydration in the first 24 hours. Patients need
careful monitoring of fluid intake and output to prevent fluid overload. Normal saline
dilutes serum calcium, and facilitates calciuresis by increasing glomerular filtration rate
and the amount of filtered calcium, and decreasing tubular calcium reabsorption.
Administration of furosemide or other loop diuretics to further promote calcium excretion
may be considered after intravascular volume is restored. However, the use of loop
diuretics to treat hypercalcemia has not been studied in randomized controlled trials, and
may not be superior to vigorous use of saline alone. Thiazide diuretics should be avoided,
as they enhance calcium reabsorption.

TABLE 240-3 Treatment of Hypercalcemia

Intravenous fluids
Normal saline
Loop diuretic
Furosemide intravenous (titrated to response, if necessary)
Medications

Bisphosphonates

• Pamidronate (30-90 mg IV)
• Zoledronic acid (4 mg IV)

Calcitonin (4 IU/kg SC every 12 h)
Prednisone (20-100 mg orally daily or equivalent)—in selected situations
Plicamycin (15-25 μg/kg IV)—no longer used
Gallium nitrate (200 mg/m2/d infusion over 5 d)—no longer used
Other interventions
Decrease calcium and vitamin D intake (if causative)
Maintain adequate oral hydration
Primary therapy directed at tumor
Chemotherapy
Radiation
Surgery

Bisphosphonates

The major target of medical management in severe hypercalcemia is osteoclast-mediated
bone resorption. First-line therapy is an intravenous bisphosphonate, such as pamidronate
or zoledronic acid. Pamidronate is administered in a dosage of 30 to 90 mg intravenously

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over several hours. Serum calcium levels should decline in 24 to 48 hours, although the
maximal effect may not be evident for several days. Zoledronic acid is given at a dosage
of 4 mg intravenously, over no less than 15 minutes. It appears to have a greater potency
and a longer duration of action than pamidronate. The need for repeat treatment with
either pamidronate or zoledronic acid depends on the aggressiveness of the underlying
malignancy. The first dose of intravenous bisphophonates may be associated with fever,
headache, arthralgias, and myalgias. Intravenous bisphosphonates should be used with
caution in renal dysfunction. Dose reduction of zoledronic acid is recommended for
creatinine clearance below 60 mL/min, and use in patients with creatinine clearance below
30 mL/min is not recommended. Pamidronate may be used with caution in patients with
renal insufficiency, but the dose should be infused slowly, over 4 to 6 hours. The newer
bisphophonate ibandronate may be associated with a lower risk of nephrotoxicity than
other intravenous agents.

Denosumab

Denosumab is a RANK ligand inhibitor that interferes with osteoclast development and
maturation. For hypercalcemia of malignancy, 120 mg subcutaneously is administered
every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month of
therapy. Common side effects include nausea and dyspnea. Denosumab is associated
with osteonecrosis of the jaw, so a dental exam should be performed prior to therapy, and
invasive dental procedures should be avoided during therapy. Atypical femur fractures
occur rarely with denosumab.

Other approaches to emergent hypercalcemia

Intravenous bisphosphonates do not act immediately. If serum calcium needs to be
reduced quickly, combined subcutaneous calcitonin (4 IU/kg every 12 hours) and
intravenous bisphosphonate has become popular. Although rather weak, calcitonin acts
rapidly, probably by facilitating urinary calcium excretion. The combination of a short-
acting and long-acting anticalcemic can be very effective. In severe or refractory cases,
hemodialysis against a low-calcium bath may be employed. Plicamycin and gallium
nitrate are treatments of largely historical interest, either because of toxicity (plicamycin)
or ineffectiveness (gallium nitrate).

Glucocorticoids

In myeloma, vitamin D intoxication, or disorders associated with ectopic production of
1,25-dihydroxyvitamin D, such as sarcoidosis and lymphoma, glucocorticoids can be very
effective. Glucocorticoids impair vitamin D action, inhibit intestinal calcium absorption,
and may have a direct antitumor effect.

Addressing the underlying disorder

Successful management of acute hypercalcemia also requires treating the underlying
etiology. When primary hyperparathyroidism is the cause, parathyroid surgery is indicated
when the patient is stable enough to undergo the procedure. In malignancy-associated
hypercalcemia, surgery, radiotherapy or chemotherapy may be appropriate. However,

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because hypercalcemia is often an end-stage complication of malignancy, such
interventions may not be warranted.

DISCHARGE CHECKLIST: HYPERCALCEMIA

Has outpatient follow-up been arranged, with short-term repeat measurements of
calcium, creatinine, and other electrolytes?
Is there a long-range plan to prevent recurrent hypercalcemia, such as repeat
bisphosphonate dosing?
Have patients been instructed to seek prompt care if recurrent symptoms of
hypercalcemia develop, such as nausea, vomiting, malaise, and polyuria?
For patients with a new diagnosis of hypercalcemia of malignancy, have they been
educated as to their underlying condition? Has outpatient oncology follow-up been
arranged?
If hypercalcemia has arisen in the setting of advanced malignancy with poor prognosis,
has hospice therapy been considered?

HYPOCALCEMIA

Hypocalcemia is a serum calcium level which is below normal after correction for the
albumin concentration. As with hypercalcemia, a free (ionized) calcium determination on a
correctly collected sample can be useful to confirm hypocalcemia.

PRESENTING SYMPTO