3. 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
7. 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
10. 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
12. 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
14. 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
15. 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
17. 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,
19. 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
20. 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
22. 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
24. 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-
25. 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
27. 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
28. 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.
31. 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.
32. 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,
35. 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
37. 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
38. 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).
41. 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
42. 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
44. 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
45. 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,
47. 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
49. 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
50. 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.
52. 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.
54. 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.
56. 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
58. 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
59. 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
61. 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, hypophos phatemia, 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
63. 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.
65. 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.
66. 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
68. 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
